count source_label source_id relationship target_label target_id entity_type solr_id publication_id sentences 8 ANTXR1 UNIPROT:Q9H6X2 inhibits MESH:D010712 Phenotype 42ff411e-3aa3-11e8-a51f-001a4a160176 25841381 PA was able to bind to cellular ATR/TEM8 and was completely inhibited by rATR/TEM8 VWA, which confirmed the biological activity of rATR/TEM8. 8 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D003094 Phenotype b26b93b4-c8df-11e5-a1fd-001a4ae51246 16762926 To examine further whether TEM8 expression can increase cell attachment to collagen, we used next a different cell type, primary rabbit synovial fibroblasts, because they are efficiently infected with adenovirus and this cell type uses α1 and α2β1 integrins to bind collagen I when integrins are activated with divalent cations, (26).|||In contrast, in primary fibroblasts, TEM8 expression increased cell attachment and spreading on collagen I, even in the presence of β1 integrin blocking antibodies, indicating that in this context TEM8 function appears to be independent of β1 integrins.|||Although there are many possible interpretations, the observations in both cell types could be explained by TEM8 partnering with other molecules at the plasma membrane, modulating collagen I induced cell attachment and spreading.|||TEM8 expression increased cell attachment to collagen in the absence of added Mn2+(Fig. 2B). 6 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:Q16769 Protein e7fd25d8-bc05-11e5-8abe-001a4ae51246 10.1016/j.yexcr.2004.12.025 Increased TEM8 expression enhances the motility of EC and antagonism of TEM8 indicates it is an essential component of the migratory response.|||TEM8 expression promotes EC motility The regulation of TEM8 by differentiation in vitro prompted the creation of cell lines to allow us to dissect the role of TEM8 in angiogenesis.|||We also observed that the ED of TEM8 preferentially binds collagen 1 and TEM8 expression promotes adhesion of EC to and motility on collagen-based matrices. 5 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009369 Phenotype f99a7150-bc06-11e5-9b9d-001a4ae51247 10.1080/14653240601048369 Here, we report that TEM8 DNA, while inactive as a single agent, greatly increased tumor immunity when administered in concert with DNA encoding the tumor Ag HER2/neuand hTYRP1/hgp75.|||TEM8 DNA enhances tumor immunity when combined with DNA vaccines encoding HER2/neuor TYRP1/gp75 DNA vaccines encoding the extracellular domain of rat HER2/neuinhibit tumor incidence and growth in a transgenic mouse model of spontaneous breast tumorigenesis[36,48–51]and this effect is enhanced by cytokines[52–57].|||Although administration of TEM8 DNA alone had no effect on tumor growth, TEM8 DNA in combination with either HER2/neuor hTYRP1/hgp75 DNA enhanced the immunity to breast and melanoma tumors, respectively.|||Co-ordinate administration of both HER2/neuand TEM8 vaccines induced long-term (100 days) tumor protection in 60% of the mice (Figure 2B). 5 ANTXR1 UNIPROT:Q9H6X2 activates GO:0006955 Phenotype f99a7150-bc06-11e5-9b9d-001a4ae51247 10.1080/14653240601048369 CD8+T cells contribute to enhanced anti-tumor immunity elicited by TEM8 DNA when combined with either HER2/neuor hTYRP1/hgp75 vaccines In order to assess the contribution of CD8+T cells to TEM8-dependent immunity, these cells were depleted in mice just prior to tumor challenge and for 3 weeks afterwards.In vivodepletion of CD8+T cells was performed by intraperitoneal injections of rat MAb clone 53–6.7.2.|||TEM8 DNA enhances tumor immunity when combined with DNA vaccines encoding HER2/neuor TYRP1/gp75 DNA vaccines encoding the extracellular domain of rat HER2/neuinhibit tumor incidence and growth in a transgenic mouse model of spontaneous breast tumorigenesis[36,48–51]and this effect is enhanced by cytokines[52–57].|||Here, we report that TEM8 DNA, while inactive as a single agent, greatly increased tumor immunity when administered in concert with DNA encoding the tumor Ag HER2/neuand hTYRP1/hgp75.|||In order to investigate whether TEM8 DNA injection also increased anti-tumor immunity to other tumor types and in combination with other tumor Ag, we combined TEM8 with a DNA vaccine encoding the melanocyte differentiation Ag, xenogeneic (human) hTYRP1/hgp75.|||Although administration of TEM8 DNA alone had no effect on tumor growth, TEM8 DNA in combination with either HER2/neuor hTYRP1/hgp75 DNA enhanced the immunity to breast and melanoma tumors, respectively. 4 ANTXR1 UNIPROT:Q9H6X2 decreases UNIPROT:P17948 Protein 360f5c54-c477-11e5-91a7-001a4ae51247 25819040 TEM8 forms a complex with VEGFR2 in endothelial cells and inhibits transcription of VEGFR1, thus protecting the cells from excessive signaling. 4 ANTXR1 UNIPROT:Q9H6X2 decreases UNIPROT:P17948 Protein 0db106a4-c477-11e5-85e4-001a4ae51246 25766658 A subset of these patients harbor mutations in VEGFR2 or integrin-like receptor TEM8, which forms a complex with β1 integrin, inhibits integrin/NFAT signaling and reduces VEGFR1 expression. 4 ANTXR1 UNIPROT:Q9H6X2 inhibits UNIPROT:P29279 Protein 3b353c9c-374f-11e8-b868-001a4a160176 PMC5478475 Given that loss of ANTXR1 function potentiates CTGF and VEGF up-regulation in human and mouse models[5,16], it is appealing to speculate that dynamic regulation of CTGF and VEGF may be a part of an anti-fibrotic repair program; when ANTXR1 is absent, fibrosis occurs. 4 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:P37275 Protein e54b797a-340d-11e8-87fd-001a4a160176 24913694 Silencing ANTXR1 resulted in increased expression of luminal-enriched genes but decreased Wnt signaling [Low-density lipoprotein receptor-related protein 6 (LRP6) and zinc finger E-box binding homeobox 1 (ZEB1)] and lead to decreased self-renewal, invasion, metastasis and tumorigenicity. 4 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:O75581 Protein e54b797a-340d-11e8-87fd-001a4a160176 24913694 Silencing ANTXR1 resulted in increased expression of luminal-enriched genes but decreased Wnt signaling [Low-density lipoprotein receptor-related protein 6 (LRP6) and zinc finger E-box binding homeobox 1 (ZEB1)] and lead to decreased self-renewal, invasion, metastasis and tumorigenicity. 4 ANTXR1 UNIPROT:Q9H6X2 decreases UNIPROT:P13423 Protein 73421e8e-bc54-11e5-8abe-001a4ae51246 10.1016/j.biocel.2004.06.005 Accordingly, we conclude that MT1-MMP-dependent shedding of the cell-bound protective antigen rather than the cell surface-associated TEM8 receptor caused the reduced levels of PA83 and PA63, which have been observed in the cells expressing the MT1-MMP activity. 4 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D063646 Phenotype b01af2ae-351a-11e8-a51f-001a4a160176 28651234 Thereby, novel targets ANTXR1 and RSPO2 were confirmed to be suppressed by miR-493 directly, and overexpression of ANTXR1 and RSPO2 could restore tumorigenesis in miR-493 treated HCC cell. 4 ANTXR1 UNIPROT:Q9H6X2 inhibits FPLX:VEGF ProteinFamily 3b353c9c-374f-11e8-b868-001a4a160176 PMC5478475 Given that loss of ANTXR1 function potentiates CTGF and VEGF up-regulation in human and mouse models[5,16], it is appealing to speculate that dynamic regulation of CTGF and VEGF may be a part of an anti-fibrotic repair program; when ANTXR1 is absent, fibrosis occurs. 4 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009369 Phenotype fd64bb62-bbdc-11e5-9b9d-001a4ae51247 PMC3289547 Host-Derived TEM8 Promotes the Growth of Human Tumor Xenografts To determine whether TEM8 could promote the growth of human tumor xenografts, we generatedTem8KO mice on an immunocompromised athymic nude background.|||Furthermore, previous studies have shown that a soluble TEM8-Fc trap, TEM8 vaccines, or sublethal doses of anthrax toxin can inhibit angiogenesis, slow tumor growth, and prolong survival (Duan et al., 2007; Felicetti et al., 2007; Liu et al., 2008; Rouleau et al., 2008; Ruan et al., 2009; Yang et al., 2010).|||We reasoned that TEM8 may promote proliferation of tumor ECs, based on previous studies that showed a role for CMG2 in promoting endothelial proliferation (Reeves et al., 2010). 4 ANTXR1 UNIPROT:Q9H6X2 activates GO:0030154 Phenotype e7fd25d8-bc05-11e5-8abe-001a4ae51246 10.1016/j.yexcr.2004.12.025 We report that TEM8 protein is expressed on the EC of human umbilical vein in situ and in vitro, and is up-regulated 5-fold in HUVEC undergoing differentiation/tube formation on collagen.|||In conclusion, we have demonstrated that TEM8 is expressed in human umbilical vein in situ and low passage HUVEC in vitro, and that TEM8 is up-regulated in angiogenic EC undergoing differentiation/tube formation on collagen. 4 ANTXR1 UNIPROT:Q9H6X2 activates GO:0035148 Phenotype e7fd25d8-bc05-11e5-8abe-001a4ae51246 10.1016/j.yexcr.2004.12.025 We report that TEM8 protein is expressed on the EC of human umbilical vein in situ and in vitro, and is up-regulated 5-fold in HUVEC undergoing differentiation/tube formation on collagen.|||In conclusion, we have demonstrated that TEM8 is expressed in human umbilical vein in situ and low passage HUVEC in vitro, and that TEM8 is up-regulated in angiogenic EC undergoing differentiation/tube formation on collagen. 4 ANTXR1 UNIPROT:Q9H6X2 activates FPLX:Wnt ProteinFamily c2ec8c4e-bc36-11e5-9b9d-001a4ae51247 PMC3148219 We predicted that if TEM8 up-regulates Wnt signaling, then PA should stabilize beta catenin levels in TEM8 expressing endothelial cells.|||The phenotypic similarities between PA-TEM8 effects in CAM and forced beta catenin signaling in endothelial cells in vivo, lead us to test the hypothesis that PA and/or TEM8 expression promotes Wnt beta-catenin signaling in the chicken CAM.|||We propose that TEM8 modulates canonical Wnt signaling during normal vascular development in the CAM and PA functions as an agonist by engaging TEM8, further increasing beta catenin activation. 4 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D003094 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 ANTXR1 on tumor cells can bind collagen I and mediate collagen uptake, which is associated with tumor growth[49].|||ANTXR1 was shown to be a key regulator of connective tissue development and homeostasis (ECM synthesis) because ANTXR1 increases collagen I production in the infantile hemangioma matrix via VEGF signaling [60,61] (Fig. 2C).|||Therefore, the relationship between ANTXR1 and MMP-2 activity could not explain why mutation of ANTXR1 causes specific types of collagen increases because MMP-2 degrades a variety of collagen components in the ECM.|||A recent study provides some solid evidence for the relationship between ANTXR1 and the accumulation of collagen I, where tumor growth was found to depend on ANTXR1-mediated collagen I uptake[49]. 4 UNIPROT:P22681 ubiquitinatesProtein ANTXR1 UNIPROT:Q9H6X2 Protein 004c0886-3551-11e8-9192-001a4a160175 17157551 Upon association to PA-heptamers, TEM8 and CMG2 are subsequently ubiquitylated within lipid rafts by the E3 ubiquitin ligase Cbl (Casitas B-lineage lymphoma) [45••]. 4 UNIPROT:O43934 activates ANTXR1 UNIPROT:Q9H6X2 Protein ec503544-c46b-11e5-8491-001a4ae51247 PMC4041834 Both TEM8 and CMG2 can be strongly upregulated by ET through PKA-dependent pathways. 4 CHEBI:85045 decreases ANTXR1 UNIPROT:Q9H6X2 Chemical 88b908b2-455d-11f0-b8fe-0050569a1f61 10.1016/j.fct.2022.113044 Therefore, the expression of TEM8 is down-regulated by H3K27me3, which in turn is mediated by DON exposure; this significantly inhibits cell migration. 4 FPLX:E3:Ub:ligase ubiquitinatesProtein ANTXR1 UNIPROT:Q9H6X2 ProteinFamily 004c0886-3551-11e8-9192-001a4a160175 17157551 Upon association to PA-heptamers, TEM8 and CMG2 are subsequently ubiquitylated within lipid rafts by the E3 ubiquitin ligase Cbl (Casitas B-lineage lymphoma) [45••]. 3 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009369 Phenotype aee1c0b4-bbf7-11e5-8abe-001a4ae51246 PMC4224515 "The reduced tumorigenicity in the TEM8 knockout suggests that TEM8 functions to promote tumor angiogenesis.|||TEM8 targeted PET imaging could aid in identifying angiogenic tumors that might be amenable to anti-TEM8 therapy." 3 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D002470 Phenotype 92462df6-375a-11e8-a34b-001a4a160175 PMC5780170 The results of the cell cycle experiment demonstrated that TEM8 knockdown blocked cell cycle progression at the G1 phase, and results of the Transwell assay demonstrated that TEM8 silencing decreased the invasion ability of XWLC-05, indicating that silenced TEM8 can reduce the cell viability of XWLC-05, induce apoptosis, block the cell cycle at G1 phase and inhibit the invasive ability.|||The influence that TEM8 knockdown had on XWLC-05 activity and apoptosis demonstrated that silenced TEM8 could reduce XWLC-05 lung cancer cell viability and increase its rate of apoptosis. 3 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:P08134 Protein 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 We speculated that the RhoC/ROCK1 pathway activated by TEM8 could activate SMAD5, which was involved in the stemness of tumor cells and tumor angiogenesis32–34.|||GNAS knockdown reversed TEM8-induced increase of active RhoC (Fig.3iand Supplementary Fig.6b), whereas GNAS overexpression further enhanced RhoC activation (Fig.3jand Supplementary Fig.6d).|||Our results have revealed that TEM8 increased RhoC signaling through recruiting GNAS. 3 ANTXR1 UNIPROT:Q9H6X2 decreases UNIPROT:P24385 Protein 91048890-f19b-11e5-95fd-001a4ae51246 PMC4800672 TEM8 knock-down attenuated ERK1/2 phosphorylation, down-regulated cyclinD1 expression and upregulated p21 and p27 in osteosarcoma As our previous research demonstrated12, ERK1/2 signaling pathway was closely correlated in the development of osteosarcoma, and anthrax lethal factor induced tyrosine/threonine phosphorylation of MAPKs in cultured macrophage13.|||TEM8 ablation decreased cyclinD1 protein level (Fig. 5).|||At the same time, we found that TEM8 ablation decreased cyclinD1 protein level in osteosarcoma cells. 3 ANTXR1 UNIPROT:Q9H6X2 activates GO:0001525 Phenotype 4ba310c8-ae96-11ec-ae7b-0050569a1f61 PMC8440287 Next, we found from tube formation experiments that overexpression of N-Myc and TEM8 significantly promoted angiogenesis in prostate cancer (Fig. 3C).|||Our tubule formation assays confirmed that N-Myc and TEM8 may promote angiogenesis in prostate cancer cells.|||Moreover, the overexpression of N-Myc and TEM8 promoted proliferation of prostate cancer cells and angiogenesis. 3 ANTXR1 UNIPROT:Q9H6X2 activates GO:0008283 Phenotype 91048890-f19b-11e5-95fd-001a4ae51246 PMC4800672 Meanwhile, we showed that the mechanism of TEM8-mediated proliferation was linked to alternations in the expression of the cell cycle inhibitors p21 and p27 as well as the CDK regulator cyclinD1.|||TEM8 knock-down increased p21, p27 and suppressed cyclin D1 expression mediated by ERK1/2 activity To further investigate the mechanism of TEM8 mediated proliferation, we used U0126 (a highly selective and potent inhibitor of pERK1/2) on TEM8-143B-sh1 and TEM8-143B-shNC cells.|||In the present study, we found that pERK1/2 was decreased in TEM8-ablated cells, suggesting that TEM8-induced proliferation and tumorigenesis may be due to modulation of ERK1/2 activity. 3 ANTXR1 UNIPROT:Q9H6X2 inhibits GO:0008283 Phenotype 91048890-f19b-11e5-95fd-001a4ae51246 PMC4800672 Additional Information How to cite this article: Cao, C.et al. Down-regulation of tumor endothelial marker 8 suppresses cell proliferation mediated by ERK1/2 activity.Sci.|||We successfully screened shRNA1 to stably down regulate the expression of TEM8 (Fig. 4A), and also found that ablation of TEM8 greatly attenuated the proliferation(Fig. 4Band Figure S3B) and induced G1 to S cell cycle inhibition(Fig. 4C,D) in osteosarcoma cells.|||Strikingly, TEM8 knock-down significantly attenuated cell proliferation rate through through trypan blue exclusion assay (Fig. 3B) and MTT analysis (Figure S3A). 3 ANTXR1 UNIPROT:Q9H6X2 activates GO:0008283 Phenotype 4ba310c8-ae96-11ec-ae7b-0050569a1f61 PMC8440287 Furthermore, we found that overexpression of N-Myc and TEM8 significantly increased the proliferation of PCa cells after ADT treatment.|||CCK8 experiment demonstrated that LNCaP/N-Myc and LNCaP/TEM8 cells could promote the proliferation of prostate cancer cells after ADT treatment.|||Moreover, the overexpression of N-Myc and TEM8 promoted proliferation of prostate cancer cells and angiogenesis. 3 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009369 Phenotype 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 Xenograft experiments supported the effect of TEM8 overexpression on increasing EphA2 expression, dextran leakage, pericyte density, and tumor vessel density (Fig.1j, k), whereas TEM8 knockdown decreased tumor vessel density (Fig.1l).|||The results showed that Y-27632 significantly suppressed in vivo tumor growth accelerated by TEM8 (Fig.5a and b), as well as BTIC enrichment (Fig.5c) and tumor VM density (Fig.5d).|||The in vivo xenograft experiments also showed that SMAD5 knockdown suppressed TEM8-enhanced tumor growth (Fig.4j), and the enrichment of BTICs (Fig.4k), as well as the increase in tumor VM density (Fig.4l). 3 ANTXR1 UNIPROT:Q9H6X2 activates GO:0007155 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 With respect to ANTXR1, although there is still a lack of direct evidence on whether cells migrate along ECM stiffness to traverse it, we already know that ANTXR1 independently promotes cell adhesion and migration[15]and that its expression is associated with ECM stiffness (Fig. 2B).|||In terms of function, similar to integrins, ANTXR1 promotes cell adhesion and migration, regulating ECM homeostasis in associated with collagen I and VI.|||Therefore, the function of ANTXR1 in promoting cell adhesion and migration is associated with angiogenesis. 3 UNIPROT:Q9ULV0 inhibits ANTXR1 UNIPROT:Q9H6X2 Protein f2dc4150-bc05-11e5-9b9d-001a4ae51247 PMC2886593 As a consequence, Myosin Vb tail expression inhibited cell spreading on PA-coated substrata by both Hek293 cells exogenously expressing TEM8 or B16F10 melanoma cells endogenously carrying this receptor.|||To confirm our previous findings, we tested whether Myosin Vb tail would disrupt the cell adhesion function of endogenously expressed TEM8.|||Thus, we tested the effects of disrupting receptor recycling by the expression of myosin Vb tail on TEM8-mediated cell spreading on PA-coated surfaces. 2 ANTXR1 UNIPROT:Q9H6X2 decreases UNIPROT:P35968 Protein 5b7223c6-bc3b-11e5-8d2d-001a4ae51247 PMC2593632 Overexpression of wild-type TEM8 in hemEC2 and 21A as well as hemEC4(TEM8)increased VEGFR1 expression and reduced phospho-VEGFR2 and phospho-ERK levels (Fig. 4c). 2 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:O43602 Protein 4869f94e-bc3a-11e5-8d2d-001a4ae51247 PMC4223722 It is tempting to speculate that treatment with IFN-α, whilst inhibiting the expression of IL-1β, may also suppress the maturation-induced TEM-8 upregulation of DC observed in non-immunoresponsive patients, thus revertingthe TEM-8 associated immunosuppressive phenotype. 2 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:P02751 Protein 3b353c9c-374f-11e8-b868-001a4a160176 PMC5478475 These findings, combined with increased activity of Hif1-α and VEGFR2 in ANTXR1-deficient fibroblasts, suggest that other ANTXR1-associated mediators may contribute to VEGF-dependent regulation of collagen type I and fibronectin. 2 ANTXR1 UNIPROT:Q9H6X2 inhibits UNIPROT:Q9H4A6 Protein b5393300-3776-11e8-87fd-001a4a160176 15694864 Involvement of the MIDAS motif has been further demonstrated by the fact that binding of ATR/TEM8 to PA was abolished by mutating MIDAS residue Asp50, a change predicted to result in loss of cation binding [37•]. 2 ANTXR1 UNIPROT:Q9H6X2 activates GO:0001525 Phenotype e09bd594-004f-11f0-9e78-0050569a1f61 10.1016/j.ncrna.2024.09.006 In prostate cancer, N-Myc elevates TEM8 expression to induce angiogenesis, furthering cancer progression and contributing to therapy resistance. 2 ANTXR1 UNIPROT:Q9H6X2 activates GO:0001525 Phenotype aee1c0b4-bbf7-11e5-8abe-001a4ae51246 PMC4224515 "The reduced tumorigenicity in the TEM8 knockout suggests that TEM8 functions to promote tumor angiogenesis." 2 ANTXR1 UNIPROT:Q9H6X2 activates GO:0001525 Phenotype e7fd25d8-bc05-11e5-8abe-001a4ae51246 10.1016/j.yexcr.2004.12.025 The regulation of TEM8 by differentiation in vitro prompted the creation of cell lines to allow us to dissect the role of TEM8 in angiogenesis. 2 ANTXR1 UNIPROT:Q9H6X2 inhibits GO:0016477 Phenotype 88b908b2-455d-11f0-b8fe-0050569a1f61 10.1016/j.fct.2022.113044 DON also down-regulates the expression of TEM8, which significantly inhibits cell migration. 2 ANTXR1 UNIPROT:Q9H6X2 inhibits MESH:D009369 Phenotype 8ba31092-c46e-11e5-9cc6-001a4ae51246 PMC4024326 In preclinical cancer models, targeting of TEM8 inhibited tumor angiogenesis and tumor growth (53). 2 ANTXR1 UNIPROT:Q9H6X2 activates GO:0007155 Phenotype e7fd25d8-bc05-11e5-8abe-001a4ae51246 10.1016/j.yexcr.2004.12.025 We also observed that the ED of TEM8 preferentially binds collagen 1 and TEM8 expression promotes adhesion of EC to and motility on collagen-based matrices. 2 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D051379 Phenotype 4342661a-f1a4-11ee-9133-0050569a1f61 10.1016/S0006-2952(02)01455-7 Subsequently, it was shown in mice that ATR/TEM8 is up-regulated in endothelium associated with both normal and tumor-associated blood vessel formation[50]. 2 ANTXR1 UNIPROT:Q9H6X2 activates GO:0006915 Phenotype 9ddb7fb0-1ba3-11f0-b759-0050569a791b 10.1016/j.ejmg.2024.104929 Growth deficiency is thus explained by the downregulation of the ANTXR1/Runx2 axis, which leads to chondrocytic apoptosis (Jiang et al., 2020). 2 ANTXR1 UNIPROT:Q9H6X2 increases MESH:D003094 Phenotype b26b93b4-c8df-11e5-a1fd-001a4ae51246 16762926 In HEK293 cells, TEM8 expression did not increase the already high levels of collagen binding activity; however, promoted cell spreading on collagen I. Because cell attachment to collagen I was completely abrogated with β1-integrin function blocking antibodies, we conclude that in this cell type, TEM8 does not participate in collagen binding, but cooperates with β1 integrins promoting cell spreading on this ECM ligand, downstream of ligand recognition. 2 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D003094 Phenotype affbadb8-bc36-11e5-ac4e-001a4ae51246 PMC3210173 ANTXR1/TEM8 also functions as an adhesion receptor and mediates actin-dependent spreading of cells on collagen[34]. 2 ANTXR1 UNIPROT:Q9H6X2 inhibits MESH:D013577 Phenotype 3b353c9c-374f-11e8-b868-001a4a160176 PMC5478475 More recently, it was found that loss-of-function mutations in ANTXR1 cause the GAPO syndrome, a recessive disorder with several connective tissue manifestations and vascular anomalies[2]. 2 ANTXR1 UNIPROT:Q9H6X2 inhibits GO:0001763 Phenotype c2ec8c4e-bc36-11e5-9b9d-001a4ae51247 PMC3148219 TEM8 receptor engagement with the ligand Protective Antigen (PA) reduces branching morphogenesis and blood vessel density, similar to canonical Wnt pathway activation TEM8 expression analysis (Fig. 1) indicates that TEM8 is the major anthrax toxin receptor expressed in the CAM. 2 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D000505 Phenotype 3b353c9c-374f-11e8-b868-001a4a160176 PMC5478475 Homozygous ANTXR1 loss-of-function mutations cause growth retardation, alopecia, pseudo-anodontia and optic atrophy in GAPO patients[2,14]. 2 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009896 Phenotype 3b353c9c-374f-11e8-b868-001a4a160176 PMC5478475 Homozygous ANTXR1 loss-of-function mutations cause growth retardation, alopecia, pseudo-anodontia and optic atrophy in GAPO patients[2,14]. 2 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D057770 Phenotype 1e2caeec-c473-11e5-9cc6-001a4ae51246 PMC2721800 "Interestingly, mutations in the TEM8 homologue CMG2 have been found to cause the disorders juvenile hyaline fibromatosis and infantile systemic hyalinosis (17,18)." 2 ANTXR1 UNIPROT:Q9H6X2 decreases FPLX:ERK ProteinFamily 5b7223c6-bc3b-11e5-8d2d-001a4ae51247 PMC2593632 Overexpression of wild-type TEM8 in hemEC2 and 21A as well as hemEC4(TEM8)increased VEGFR1 expression and reduced phospho-VEGFR2 and phospho-ERK levels (Fig. 4c). 2 ANTXR1 UNIPROT:Q9H6X2 activates FPLX:Actin ProteinFamily affbadb8-bc36-11e5-ac4e-001a4ae51246 PMC3210173 ANTXR1/TEM8 also functions as an adhesion receptor and mediates actin-dependent spreading of cells on collagen[34]. 2 ANTXR1 UNIPROT:Q9H6X2 activates FPLX:Wnt ProteinFamily e54b797a-340d-11e8-87fd-001a4a160176 24913694 Silencing ANTXR1 resulted in increased expression of luminal-enriched genes but decreased Wnt signaling [Low-density lipoprotein receptor-related protein 6 (LRP6) and zinc finger E-box binding homeobox 1 (ZEB1)] and lead to decreased self-renewal, invasion, metastasis and tumorigenicity. 2 ANTXR1 UNIPROT:Q9H6X2 activates FPLX:Wnt ProteinFamily b01af2ae-351a-11e8-a51f-001a4a160176 28651234 It was reported that ANTXR1 interacted with LRP6 and modulated canonical Wnt signaling[34,42–46]. 2 ANTXR1 UNIPROT:Q9H6X2 activates PF:PF01391 ProteinFamily f2dc4150-bc05-11e5-9b9d-001a4ae51247 PMC2886593 TEM8 recycling could mediate Collagen I and Collagen VI clearance, as these molecules accumulate in the extracellular matrix of TEM8-deficient animals[9]. 2 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:Q13464 Protein 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 To identify the predominant downstream effectors of ROCK1 induced by TEM8, a phospho-kinase array was used in TEM8-overexpressing cells to identify alterations of multiple downstream signals, and the results were confirmed by western blotting.|||We speculated that the RhoC/ROCK1 pathway activated by TEM8 could activate SMAD5, which was involved in the stemness of tumor cells and tumor angiogenesis32–34. 2 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:P62158 Protein c2ec8c4e-bc36-11e5-9b9d-001a4ae51247 PMC3148219 The phenotypic similarities between PA-TEM8 effects in CAM and forced beta catenin signaling in endothelial cells in vivo, lead us to test the hypothesis that PA and/or TEM8 expression promotes Wnt beta-catenin signaling in the chicken CAM.|||We found that TEM8 is selectively and transiently induced in the CAM during a discrete developmental stage of vascular morphogenesis, correlating with intussusceptive angiogenesis. 2 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:P35222 Protein c2ec8c4e-bc36-11e5-9b9d-001a4ae51247 PMC3148219 Furthermore, additional reports link TEM8 to Wnt signaling: TEM8 interacts with LRP6, a co-receptor for Wnt ligands, and causes beta catenin stabilization in a cell line model system[34],[35].|||The phenotypic similarities between PA-TEM8 effects in CAM and forced beta catenin signaling in endothelial cells in vivo, lead us to test the hypothesis that PA and/or TEM8 expression promotes Wnt beta-catenin signaling in the chicken CAM. 2 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:Q99717 Protein 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 These data indicated that the activation of SMAD5 induced by TEM8 was mediated directly by the RhoC/ROCK1 pathway.|||These results demonstrated that TEM8-activated SMAD5 played an important role in promoting BTIC enrichment and tumor VM formation. 2 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:Q9H6X2 Protein f2dc4150-bc05-11e5-9b9d-001a4ae51247 PMC2886593 Thus, regulation of TEM8 cell surface levels by receptor delivery to or retrieval from the plasma membrane could modulate TEM8 toxin-independent functions, such as cell adhesion and/or metabolism of extracellular matrices.|||Since recycling of receptors to the plasma membrane is essential for cell spreading and cell migration processes[30], we hypothesized that reduction of TEM8 transport to the cell surface should decrease TEM8-mediated cell spreading. 2 ANTXR1 UNIPROT:Q9H6X2 activates CHEBI:28744 Chemical fd64bb62-bbdc-11e5-9b9d-001a4ae51247 PMC3289547 We reasoned that TEM8 may promote proliferation of tumor ECs, based on previous studies that showed a role for CMG2 in promoting endothelial proliferation (Reeves et al., 2010).|||Although our understanding of its physiological function is limited, TEM8 has been found to bind to collagens and promote migration of ECs in vitro (Nanda et al., 2004; Werner et al., 2006). 2 ANTXR1 UNIPROT:Q9H6X2 activates GO:0042592 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 Similarly, ANTXR1 also mediates significant effects on ECM homeostasis in both physiological and pathological settings.|||In terms of function, similar to integrins, ANTXR1 promotes cell adhesion and migration, regulating ECM homeostasis in associated with collagen I and VI. 2 ANTXR1 UNIPROT:Q9H6X2 inhibits MESH:D009369 Phenotype f624ca2a-bc06-11e5-8abe-001a4ae51246 10.1080/14653240601118444 In the Felicetti study[7], a syngeneic TEM8 DNA vaccine by itself was unable to prevent the growth of transplanted tumors in a prophylactic setting.|||However, when combined with a xenogenic Her2/neu DNA vaccine in an effort to target the murine breast tumor 233-VSGA1, the TEM8 vaccine was able to inhibit tumor growth significantly and extend tumor-free survival beyond that achieved with the Her2/neu vaccine alone. 2 ANTXR1 UNIPROT:Q9H6X2 activates GO:0007049 Phenotype 92462df6-375a-11e8-a34b-001a4a160175 PMC5780170 The results of the cell cycle experiment demonstrated that TEM8 knockdown blocked cell cycle progression at the G1 phase, and results of the Transwell assay demonstrated that TEM8 silencing decreased the invasion ability of XWLC-05, indicating that silenced TEM8 can reduce the cell viability of XWLC-05, induce apoptosis, block the cell cycle at G1 phase and inhibit the invasive ability.|||Effect of silencing TEM8 on the cell cycle of lung cancer cell XWLC-05 Fig. 10andTable Idemonstrate that more cells were detected in G1 phase and fewer in S phase in the TME-8-shRNA group compared to the control group or empty group (P<0.05) while no significant differences were observed in G2 phase among the three groups, suggesting that silencing TEM8 blocked the cell cycle of XWLC-05 cells at G1 phase. 2 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009361 Phenotype 92462df6-375a-11e8-a34b-001a4a160175 PMC5780170 The results of the cell cycle experiment demonstrated that TEM8 knockdown blocked cell cycle progression at the G1 phase, and results of the Transwell assay demonstrated that TEM8 silencing decreased the invasion ability of XWLC-05, indicating that silenced TEM8 can reduce the cell viability of XWLC-05, induce apoptosis, block the cell cycle at G1 phase and inhibit the invasive ability.|||The activity of XWLC-05 cells was decreased and the cell cycle was blocked at G1 phase following silencing of TEM8, inhibiting the cell invasion ability. 2 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D001943 Phenotype 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 Taken together, the results suggested that TEM8 promoted VM in breast tumor cells.|||TEM8 overexpression promoted breast tumor growth and metastasis (Supplementary Fig.3f–h), whereas TEM8 knockdown had the opposite effects (Supplementary Fig.3i–k), as previously reported20. 2 ANTXR1 UNIPROT:Q9H6X2 activates GO:0048844 Phenotype 7d9b73fa-c463-11e5-a92e-001a4ae51246 PMC4718698 Exactly how antxr1 contributes to arteriogenesis is unclear.|||Conclusions conclusions Using a mouse model of hindlimb ischemia, we demonstrate that increased expression of anthrax toxin receptor 1 (Antxr1) is necessary for arteriogenesis, the radial expansion of existing arteries. 2 FPLX:IFNA activates ANTXR1 UNIPROT:Q9H6X2 ProteinFamily 4869f94e-bc3a-11e5-8d2d-001a4ae51247 PMC4223722 It is tempting to speculate that treatment with IFN-α, whilst inhibiting the expression of IL-1β, may also suppress the maturation-induced TEM-8 upregulation of DC observed in non-immunoresponsive patients, thus revertingthe TEM-8 associated immunosuppressive phenotype. 2 MESH:D000242 increases ANTXR1 UNIPROT:Q9H6X2 Phenotype a029e4a8-bc2d-11e5-8abe-001a4ae51246 PMC1973154 Since it is known that EF is an adenylate cyclase which elevates intracellular levels of cAMP, our data could be interpreted to suggest that increased cAMP level in cells stimulate increased transcription of both ANTXR1 and ANTXR2 genes. 2 UNIPROT:Q16769 increases ANTXR1 UNIPROT:Q9H6X2 Protein e7fd25d8-bc05-11e5-8abe-001a4ae51246 10.1016/j.yexcr.2004.12.025 In this study, we found that TEM8 is expressed by human embryonic EC and is up-regulated during the process of EC differentiation/tube formation. 2 UNIPROT:Q9BYI3 inhibits ANTXR1 UNIPROT:Q9H6X2 Protein b01af2ae-351a-11e8-a51f-001a4a160176 28651234 ANTXR1 and RSPO2 were confirmed to be suppressed directly by miR-493 in HCC cells, while some known targets of miR-493, as RhoC and FZD4, were not decreased in miR-493 transfected HCC cells, suggesting that the discrepancies in the functions of miR-493 in different types of cancer may reflect differences in target genes. 2 UNIPROT:P04198 increases ANTXR1 UNIPROT:Q9H6X2 Protein e09bd594-004f-11f0-9e78-0050569a1f61 10.1016/j.ncrna.2024.09.006 In prostate cancer, N-Myc elevates TEM8 expression to induce angiogenesis, furthering cancer progression and contributing to therapy resistance. 2 UNIPROT:Q9H6X2 activates ANTXR1 UNIPROT:Q9H6X2 Protein f2dc4150-bc05-11e5-9b9d-001a4ae51247 PMC2886593 Since recycling of receptors to the plasma membrane is essential for cell spreading and cell migration processes[30], we hypothesized that reduction of TEM8 transport to the cell surface should decrease TEM8-mediated cell spreading.|||Thus, regulation of TEM8 cell surface levels by receptor delivery to or retrieval from the plasma membrane could modulate TEM8 toxin-independent functions, such as cell adhesion and/or metabolism of extracellular matrices. 2 UNIPROT:P04198 increases ANTXR1 UNIPROT:Q9H6X2 Protein 4ba310c8-ae96-11ec-ae7b-0050569a1f61 PMC8440287 N-Myc overexpression upregulated TEM8 expression in PCa cells.|||Further experiments revealed that overexpression of N-Myc upregulated the expression of TEM8 in prostate cancer cells. 1 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:Q02763 Protein 909a1210-f58d-11eb-9572-001a4a160176 30439561 The result of late treatment showed that NOS inhibitor treatment decreased TEM8 expression, whereas NO donor and NaNO2 treatment increased TEM8, and decreased Tie2 expression control wound (Fig. 10). 1 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:P03372 Protein e4bac346-bc35-11e5-ac4e-001a4ae51246 PMC4363784 TEM8 glycosylation promotes ER exit The surface biotinylation analysis indicates that fully glycosylation-deficient TEM8 and CMG2 do not or only partially reach the plasma membrane. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits UNIPROT:Q13469 Protein 5b7223c6-bc3b-11e5-8d2d-001a4ae51247 PMC2593632 Expression of mutant TEM8 significantly reduced association of NFATc2 with the VEGFR1 promoter; expression of wild-type TEM8 or wild-type VEGFR2 in hemEC4(TEM8)increased the association (Fig. 5d). 1 ANTXR1 UNIPROT:Q9H6X2 decreases UNIPROT:P17948 Protein d5740a04-bc18-11e5-9b9d-001a4ae51247 PMC3317109 Intriguingly, TEM-8 mutation disrupted the expression of VEGFR1 and VEGFR2 signaling. 1 ANTXR1 UNIPROT:Q9H6X2 increases UNIPROT:P17948 Protein 5b7223c6-bc3b-11e5-8d2d-001a4ae51247 PMC2593632 Overexpression of wild-type TEM8 in hemEC2 and 21A as well as hemEC4(TEM8)increased VEGFR1 expression and reduced phospho-VEGFR2 and phospho-ERK levels (Fig. 4c). 1 ANTXR1 UNIPROT:Q9H6X2 increases UNIPROT:P17948 Protein 4ae7ada0-c483-11e5-9cc6-001a4ae51246 PMC3252584 Analysis of patient endothelial cells revealed a mutation in TMD of TEM8 (A326T) as well as mutations in VEGFR2, which were found to enhance the formation of a ternary complex β1 integrin–VEGFR2–TEM8, which in turn triggered a decrease in VEGFR1 expression (Jinninet al, 2008). 1 ANTXR1 UNIPROT:Q9H6X2 decreases UNIPROT:P17948 Protein 5b7223c6-bc3b-11e5-8d2d-001a4ae51247 PMC2593632 Overexpression of mutant TEM8 in HDMEC reduces active β1 integrin on the cell surface, decreases the association between NFAT and the VEGFR1 promoter, and decreases VEGFR1 expression. 1 ANTXR1 UNIPROT:Q9H6X2 increases UNIPROT:P17948 Protein f3cde89e-bbdc-11e5-8abe-001a4ae51246 10.1016/j.ccr.2008.11.009 The authors showed that wild-type TEM8 increased VEGFR1 expression and reduced VEGFR2 signaling in hemECs. 1 ANTXR1 UNIPROT:Q9H6X2 decreases UNIPROT:P35968 Protein d5740a04-bc18-11e5-9b9d-001a4ae51247 PMC3317109 Intriguingly, TEM-8 mutation disrupted the expression of VEGFR1 and VEGFR2 signaling. 1 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:Q13285 Protein 76845c20-c47d-11e5-91a7-001a4ae51247 20497237 Seven of the 52 genes,TEM8, TNFSFF4,CD34, KIT,TNS3,KDRandCXCR4,were found to be significantly up-regulated during culture in SF1, while only a single gene, VCAM-1, became significantly down-regulated in SF1. 1 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:P50281 Protein bdea3778-bc18-11e5-8abe-001a4ae51246 PMC3640537 Investigation of this hypothesis led to the discovery that both ANTXR1 and ANTXR2 positively regulate MT1-MMP activity in cultured cells [23]. 1 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:P50281 Protein 922fb800-bc37-11e5-9b9d-001a4ae51247 PMC3328497 This data demonstrates that ANTXR1 and ANTXR2 positively regulate MT1-MMP activity. 1 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:Q86X29 Protein a4e85cf1-f57c-11eb-904b-001a4a160176 32123390 This difference means that the receptors are different: the Ib receptor is Lipolysis-stimulated lipoprotein receptor (LSR), and the PA receptors are capillary morphogenesis protein 2 (CMG2) and tumor endothelial marker 8 (TEM8)38,39. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits UNIPROT:P09488 Protein 96c2b8f2-c83d-11ee-9aaa-0050569a1f61 10.1016/j.etap.2023.104154 In addition, DON was found to inhibit the expression of TEM8 by increasing the level of H3K27me3 in the TEM8 promoter, thereby suppressing cell migration (Mu et al., 2020). 1 ANTXR1 UNIPROT:Q9H6X2 increases UNIPROT:P35222 Protein c2ec8c4e-bc36-11e5-9b9d-001a4ae51247 PMC3148219 Albeit not statistically significant, recombinant TEM8 expression alone was sufficient to increase beta catenin levels. 1 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:Q9Y5Y0 Protein 4ba310c8-ae96-11ec-ae7b-0050569a1f61 PMC8440287 Furthermore, we found that overexpression of N-Myc and TEM8 significantly increased the proliferation of PCa cells after ADT treatment. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits UNIPROT:P36575 Protein e3ae3ba1-f32f-11e9-b126-001a4a160176 PMC6797195 Whatever the reasons for the lack of toxicity in this other study, our results demonstrating toxicity with an L2 CAR even at doses of 4 million CAR-expressing T-cells per mouse, combined with evidence for TEM8-mediated selective loss of high avidity CAR T-cells from the circulation of healthy mice, highlights the risk of on-target, off-tumour effects should a TEM8-specific CAR, especially one based on the L2 antibody, be tested in patients. 1 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:O95467 Protein 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 Our results have revealed that TEM8 increased RhoC signaling through recruiting GNAS. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits UNIPROT:P58335 Protein 8d12de80-c47d-11e5-8491-001a4ae51247 PMC2932583 "Similarly, TEM8 may also potentiate CMG2 knockout in addition to serving as a low-affinity receptor (13)." 1 ANTXR1 UNIPROT:Q9H6X2 inhibits UNIPROT:P58335 Protein 7e556b6c-ae94-11ec-ae7b-0050569a1f61 PMC8716333 This analysis showed that the combined elimination of CMG-2 and TEM-8 completely prevented intoxication of all tissues examined.To determine the role of TEM-8 and CMG-2 in intoxication of leukocytes, single-cell suspensions of CD45-positive leukocytes from spleens were analyzed by flow cytometry. 1 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:P02788 Protein 54315906-c8de-11e5-9624-001a4ae51246 PMC1797656 "Furthermore, using a new assay for TEM8-mediated LF-independent PA cytotoxicity, we found that the action of AmPrβCD does not even require the binding of LF to the PA/TEM8 complex." 1 ANTXR1 UNIPROT:Q9H6X2 increases UNIPROT:P08134 Protein 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 TEM8 increased active RhoC level by recruiting GNAS To determine whether the effect of TEM8 on promoting VM was mediated by ligand binding, the truncates with intracellular domain or extracellular domain-deleted (both retained transmembrane region) were stably transfected into MDA-MB-231 cells. 1 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:Q9H6X2 Protein 909a1210-f58d-11eb-9572-001a4a160176 30439561 The result of late treatment showed that NOS inhibitor treatment decreased TEM8 expression, whereas NO donor and NaNO2 treatment increased TEM8, and decreased Tie2 expression control wound (Fig. 10). 1 ANTXR1 UNIPROT:Q9H6X2 decreases UNIPROT:Q9H6X2 Protein 31ac9eb6-c476-11e5-85e4-001a4ae51246 PMC4716791 Suppression of TEM-8 expression reduces the growth rate of HaCaT keratinocytes To determine the effect of reduced TEM-8 expression on keratinocyte cell growth, HaCaT keratinocytes were transfected with ribozyme transgenes specifically targeted to the TEM-8 transcript to reduce TEM-8 transcript levels within HaCaT cells, as assessed by RT-PCR (Fig. 2A). 1 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:P04626 Protein f99a7150-bc06-11e5-9b9d-001a4ae51247 10.1080/14653240601048369 Here, we report that TEM8 DNA, while inactive as a single agent, greatly increased tumor immunity when administered in concert with DNA encoding the tumor Ag HER2/neuand hTYRP1/hgp75. 1 ANTXR1 UNIPROT:Q9H6X2 activates UNIPROT:Q06828 Protein f590e800-bc06-11e5-9b9d-001a4ae51247 10.1080/14653240701307293 In the article ‘Tumor endothelial marker 8 enhances tumor immunity in conjunction with immunization against differentiation Ag’ by P Felicetti*, M Mennecozzi*, A Barucca, S Montgomery, F Orlandi, K Manova, AN Houghton, PD Gregor*, A Concetti* and FM Venanzi*, published inCytotherapyVol 9, No 1, pp 23–34, the authors marked * have contributed equally to the work. 1 ANTXR1 UNIPROT:Q9H6X2 increases UNIPROT:P24385 Protein 91048890-f19b-11e5-95fd-001a4ae51246 PMC4800672 TEM8 knock-down attenuated ERK1/2 phosphorylation, down-regulated cyclinD1 expression and upregulated p21 and p27 in osteosarcoma As our previous research demonstrated12, ERK1/2 signaling pathway was closely correlated in the development of osteosarcoma, and anthrax lethal factor induced tyrosine/threonine phosphorylation of MAPKs in cultured macrophage13. 1 ANTXR1 UNIPROT:Q9H6X2 activates CHEBI:52211 Chemical 5c700311-f586-11eb-8a6e-001a4a160175 30686531 The inhibitory effect of ANTXR1 knockdown in BMMs on RANKL-induced osteoclast differentiation and function To confirm physiological role of ANTXR1 in osteoclastogenesis, we prepared siRNA of ANTXR1 and subsequently delivered it into BMMs by transient transfection. 1 ANTXR1 UNIPROT:Q9H6X2 activates CHEBI:49468 Chemical f99a7150-bc06-11e5-9b9d-001a4ae51247 10.1080/14653240601048369 In order to investigate whether TEM8 DNA injection also increased anti-tumor immunity to other tumor types and in combination with other tumor Ag, we combined TEM8 with a DNA vaccine encoding the melanocyte differentiation Ag, xenogeneic (human) hTYRP1/hgp75. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0031012 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 In terms of function, similar to integrins, ANTXR1 promotes cell adhesion and migration, regulating ECM homeostasis in associated with collagen I and VI. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits GO:0031012 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 Therefore, the relationship between ANTXR1 and MMP-2 activity could not explain why mutation of ANTXR1 causes specific types of collagen increases because MMP-2 degrades a variety of collagen components in the ECM. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0043542 Phenotype f99a7150-bc06-11e5-9b9d-001a4ae51247 10.1080/14653240601048369 TEM8 protein is also expressed in HUVEC cells, is up-regulated upon tube formation, and increases endothelial cell migration on collagen[26]. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0043542 Phenotype e3ae3ba1-f32f-11e9-b126-001a4a160176 PMC6797195 TEM8 binds collagen and promotes endothelial cell migration in vitro and is thereby thought to play an important role in angiogenesis[11, 12]. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0001525 Phenotype 31ac9eb6-c476-11e5-85e4-001a4ae51246 PMC4716791 Previous studies have shown that the genetic disruption and antibody-mediated disruption of TEM-8 in mice inhibited tumour angiogenesis and growth, but did not perturb acute wound healing observed for ≤7 days (16,17). 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0001525 Phenotype 01dec922-7218-11ee-add2-0050569a791b PMC10409967 N-Myc increases TEM8 expression to induce growth and angiogenesis in prostate cancer cells, and is associated with therapy resistance (Li et al.2021a,b,c,d,e,f). 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0001525 Phenotype 7e560b98-bc34-11e5-9b9d-001a4ae51247 PMC4266608 In TEM8 Knockout mice physiological angiogenesis and wound healing occur normally, but in tumor bearing mice, tumor growth is impaired, showing that TEM8 may be required to promote tumor angiogenesis but not normal development[43]. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0001525 Phenotype fd64bb62-bbdc-11e5-9b9d-001a4ae51247 PMC3289547 Furthermore, previous studies have shown that a soluble TEM8-Fc trap, TEM8 vaccines, or sublethal doses of anthrax toxin can inhibit angiogenesis, slow tumor growth, and prolong survival (Duan et al., 2007; Felicetti et al., 2007; Liu et al., 2008; Rouleau et al., 2008; Ruan et al., 2009; Yang et al., 2010). 1 ANTXR1 UNIPROT:Q9H6X2 inhibits GO:0001525 Phenotype 5faae518-c464-11e6-a57a-001a4ae51247 PMC5124654 Since TEM8 expression is specific for tumor vasculature, antagonists of TEM8 might disrupt tumor angiogenesis and inhibit tumor progression [39,98]. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits GO:0001525 Phenotype 8ba31092-c46e-11e5-9cc6-001a4ae51246 PMC4024326 In preclinical cancer models, targeting of TEM8 inhibited tumor angiogenesis and tumor growth (53). 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0001525 Phenotype 6a94c0b4-c5d0-11ee-b346-0050569a791b 10.1016/j.yexcr.2024.113937 Interestingly, inhibition of tumor endothelial marker 8 impedes the angiogenesis and growth of non-SCLC (NSCLC)in vivo[18]. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0016477 Phenotype 31ac9eb6-c476-11e5-85e4-001a4ae51246 PMC4716791 A similar role for TEM-8 in promoting cell migration was observed in previous studies demonstrating that TEM-8 mediates spreading of endothelial cellsin vitro(8). 1 ANTXR1 UNIPROT:Q9H6X2 inhibits GO:0016477 Phenotype 96c2b8f2-c83d-11ee-9aaa-0050569a1f61 10.1016/j.etap.2023.104154 In addition, DON was found to inhibit the expression of TEM8 by increasing the level of H3K27me3 in the TEM8 promoter, thereby suppressing cell migration (Mu et al., 2020). 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D008545 Phenotype 86c5ac54-f58c-11eb-8c79-001a4a160175 30029203 This has been demonstrated in an mouse model in which the melanoma growth was disrupted by ANTXR1 knockout while other tissues remained unaffected[75]. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D008545 Phenotype 4e48ea46-bc3a-11e5-8d2d-001a4ae51247 PMC4625691 Although the vaccine had no activity as a single agent, TEM8 DNA significantly enhanced anti-tumor immunity when administered with a rat HER2 DNA vaccine for breast cancer, and also in combination with a tyrosine-related protein-1 DNA vaccine in melanoma. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0006955 Phenotype f590e800-bc06-11e5-9b9d-001a4ae51247 10.1080/14653240701307293 In the article ‘Tumor endothelial marker 8 enhances tumor immunity in conjunction with immunization against differentiation Ag’ by P Felicetti*, M Mennecozzi*, A Barucca, S Montgomery, F Orlandi, K Manova, AN Houghton, PD Gregor*, A Concetti* and FM Venanzi*, published inCytotherapyVol 9, No 1, pp 23–34, the authors marked * have contributed equally to the work. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0006955 Phenotype 4e48ea46-bc3a-11e5-8d2d-001a4ae51247 PMC4625691 Although the vaccine had no activity as a single agent, TEM8 DNA significantly enhanced anti-tumor immunity when administered with a rat HER2 DNA vaccine for breast cancer, and also in combination with a tyrosine-related protein-1 DNA vaccine in melanoma. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0006351 Phenotype c2ec8c4e-bc36-11e5-9b9d-001a4ae51247 PMC3148219 TEM8 and its ligand PA positively regulate Wnt induced gene transcription An increased nucleo-cytoplasmic ratio of beta catenin levels by TEM8-PA receptor-ligand complexes predicts a transcriptional induction of canonical Wnt-responsive genes. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0051318 Phenotype 92462df6-375a-11e8-a34b-001a4a160175 PMC5780170 The results of the cell cycle experiment demonstrated that TEM8 knockdown blocked cell cycle progression at the G1 phase, and results of the Transwell assay demonstrated that TEM8 silencing decreased the invasion ability of XWLC-05, indicating that silenced TEM8 can reduce the cell viability of XWLC-05, induce apoptosis, block the cell cycle at G1 phase and inhibit the invasive ability. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits GO:0038084 Phenotype 1bdabbca-bc03-11e5-9b9d-001a4ae51247 PMC3759327 Notably, a recent study of genetic risk factors for hemangioma identified germline mutations in the genes encoding vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and anthrax toxin receptor 1 (also known as tumor endothelial marker 8) that perturb VEGF signaling and contribute to disorganized angiogenesis (Jinnin et al., 2008). 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0008283 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 Through these signaling pathways, ANTXR1 has been found to promote tumor cell proliferation, cell cycle progression, cell invasion, migration and self-renewal, and tumorigenesis and metastasis[26–29]. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0008283 Phenotype fd64bb62-bbdc-11e5-9b9d-001a4ae51247 PMC3289547 We reasoned that TEM8 may promote proliferation of tumor ECs, based on previous studies that showed a role for CMG2 in promoting endothelial proliferation (Reeves et al., 2010). 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0008283 Phenotype 86c5ac54-f58c-11eb-8c79-001a4a160175 30029203 Their work indicated that overexpression of ANTXR1 activated key genes in cell proliferation, DNA replication, and Wnt signaling pathway, conferring enhanced tumorigenic and metastatic potentials upon those BC cells[26]. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits MESH:D009369 Phenotype 91048890-f19b-11e5-95fd-001a4ae51246 PMC4800672 TEM8 knock-down attenuated xenograft tumor growth To determine whether TEM8 affects the tumorigenicity of osteosarcoma cellsin vivo, shTEM8 143B or empty vector-143B cells were subcutaneously injected into nude mice. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009369 Phenotype f624ca2a-bc06-11e5-8abe-001a4ae51246 10.1080/14653240601118444 Perhaps the most perplexing question is how the TEM8 vaccine augments the anti-tumor effects of two independent tumor-targeted vaccines while having no discernable effect on its own. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits MESH:D009369 Phenotype fd64bb62-bbdc-11e5-9b9d-001a4ae51247 PMC3289547 These results support the conclusion that physiological and pathological angiogenesis are distinct and that antibody-mediated targeting of TEM8 can selectively inhibit pathological tumor growth while sparing normal healing processes that also require vascularization. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009369 Phenotype 6a03f4ba-bc4e-11e5-8d2d-001a4ae51247 PMC3014418 Several recent preclinical studies support the idea that TEM8 functions to promote tumor growth and that inhibition of TEM8 may represent a useful anti-tumor strategy. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009369 Phenotype f590e800-bc06-11e5-9b9d-001a4ae51247 10.1080/14653240701307293 In the article ‘Tumor endothelial marker 8 enhances tumor immunity in conjunction with immunization against differentiation Ag’ by P Felicetti*, M Mennecozzi*, A Barucca, S Montgomery, F Orlandi, K Manova, AN Houghton, PD Gregor*, A Concetti* and FM Venanzi*, published inCytotherapyVol 9, No 1, pp 23–34, the authors marked * have contributed equally to the work. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits MESH:D009369 Phenotype 5faae518-c464-11e6-a57a-001a4ae51247 PMC5124654 Since TEM8 expression is specific for tumor vasculature, antagonists of TEM8 might disrupt tumor angiogenesis and inhibit tumor progression [39,98]. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009369 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 Consequently, most studies have suggested that ANTXR1 represents a potential antiangiogenic therapeutic target in tumors [46,47] because ANTXR1 promotes the migration of tumor endothelial cells. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009369 Phenotype affbadb8-bc36-11e5-ac4e-001a4ae51246 PMC3210173 Here, we used a high throughput approach to identify additional CISs in MMTV-induced mammary tumors and found several novel MMTV target genes includingArhgap18,Tcf7l2,PrkacaandAntxr1/Tem8(calledAntxr1from here-on). 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009369 Phenotype 4b4b95d8-8d7f-11e7-82ff-001a4ae51246 PMC5544473 TEM8 interacts with the α3 subunit of collagen VI and is suspected to elicit angiogenic effects and tumor progression[82]. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009369 Phenotype 5faae518-c464-11e6-a57a-001a4ae51247 PMC5124654 Since TEM8 expression is specific for tumor vasculature, antagonists of TEM8 might disrupt tumor angiogenesis and inhibit tumor progression [39,98]. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009369 Phenotype 1e2caeec-c473-11e5-9cc6-001a4ae51246 PMC2721800 "Thus, TEM8 expression in the host seems to preferentially promote the growth of certain tumor types." 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009369 Phenotype b0664432-bc33-11e5-8abe-001a4ae51246 PMC4141756 In particular, ANTXR1 (also known astumor endothelial marker 8, TEM8) is expressed in the mouse dentate gyrus granule cell layer (Allen atlas;http://mouse.brain-map.org/gene/show/45380) and has been reported to promote cell spreading in human tumor tissues[20],[21]: therefore, it was hypothesized that reduced expression of miR487a will increase ANTXR1 levels, leading to granule cell spreading (i.e. dispersion or bilamination, i.e. GCP 2). 1 ANTXR1 UNIPROT:Q9H6X2 inhibits MESH:D009369 Phenotype 3e632064-de7d-11e5-8b0c-001a4ae51247 10.1158/0008-5476.CAN-09-0725 "The mere binding of TEM8 or preventing TEM8 from binding its physiologic partner may be enough to decrease tumor vessel density." 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009369 Phenotype 7e560b98-bc34-11e5-9b9d-001a4ae51247 PMC4266608 In TEM8 Knockout mice physiological angiogenesis and wound healing occur normally, but in tumor bearing mice, tumor growth is impaired, showing that TEM8 may be required to promote tumor angiogenesis but not normal development[43]. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0009405 Phenotype 7d9b73fa-c463-11e5-a92e-001a4ae51246 PMC4718698 To determine whether Antxr1 may contribute to the pathogenesis of human disease, we evaluated Antxr1 expression levels in muscle tissues from patients diagnosed with peripheral artery disease. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D066253 Phenotype 7d9b73fa-c463-11e5-a92e-001a4ae51246 PMC4718698 Antxr1-mediated vascular remodeling may play an important role in the pathogenesis of anthrax. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0007049 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 Through these signaling pathways, ANTXR1 has been found to promote tumor cell proliferation, cell cycle progression, cell invasion, migration and self-renewal, and tumorigenesis and metastasis[26–29]. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0006897 Phenotype d4c5d1fe-ae93-11ec-b4ed-0050569a1f61 PMCPMC8776658 SVA virion can interact specifically with the ANTXR1 for initiating endocytosis to invade a permissive cell, and then the viral genome would be released from an early endosome to bind to the ribosome for encoding protein.We demonstrated that enhanced green fluorescent protein (eGFP)-tagged SVA could initiate eGFP expression identifiable as early as 6 hpi in cells. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0006897 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 In addition, binding to collagen I promotes the endothelial cell migration rate, without affecting the activation of integrin β1[41]; ANTXR1 bound PA self-associates to form a ring-shaped heptameric complex[42]and then triggers endocytosis; While endocytosis of ANTXR1 differentially affects cell adhesion and cell intoxication functions[43]; and ANTXR1 has been identified as the high-affinity cellular receptor for SVV[44]that is a target tumor therapy. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0016055 Phenotype 86c5ac54-f58c-11eb-8c79-001a4a160175 30029203 Their work indicated that overexpression of ANTXR1 activated key genes in cell proliferation, DNA replication, and Wnt signaling pathway, conferring enhanced tumorigenic and metastatic potentials upon those BC cells[26]. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D063646 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 Through these signaling pathways, ANTXR1 has been found to promote tumor cell proliferation, cell cycle progression, cell invasion, migration and self-renewal, and tumorigenesis and metastasis[26–29]. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009362 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 Through these signaling pathways, ANTXR1 has been found to promote tumor cell proliferation, cell cycle progression, cell invasion, migration and self-renewal, and tumorigenesis and metastasis[26–29]. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009362 Phenotype b5f9fa5c-c692-11ee-ae05-0050569a1f61 10.1016/j.bbcan.2023.189033 Nonetheless, whether there exists regulatory relationship between angiogensis and bone metastasis, which were both mediated by N-Myc/TEM8, is not clear enough, and more animal experiments are urgent to clarify the underlying mechanism in vivo. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009362 Phenotype 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 TEM8 overexpression promoted breast tumor growth and metastasis (Supplementary Fig.3f–h), whereas TEM8 knockdown had the opposite effects (Supplementary Fig.3i–k), as previously reported20. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009362 Phenotype 8f3c6612-3555-11e9-8aa6-001a4a160176 PMC5771806 Increased expression ofANTXR1, the TEM8 gene, has been correlated with a poorer survival outcome in TNBC and induction of TEM8 expression in murine 4T1 breast cancer cells increased growth and metastasis (11, 13, 14). 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0030316 Phenotype 5c700311-f586-11eb-8a6e-001a4a160175 30686531 The inhibitory effect of ANTXR1 knockdown in BMMs on RANKL-induced osteoclast differentiation and function To confirm physiological role of ANTXR1 in osteoclastogenesis, we prepared siRNA of ANTXR1 and subsequently delivered it into BMMs by transient transfection. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D000881 Phenotype 183fe120-c473-11e5-8491-001a4ae51247 PMC2718377 "The fact that the death of theCMG2−/−mice caused by multiple LT challenge occurred quite late (8–10 days after the first toxin injection vs. 3–4 days forTEM8−/−and the control mice,Fig. 2C-E) suggests that the in vivo toxicity of anthrax lethal toxin mediated by TEM8 results from cumulative damage that is qualitatively different from that mediated by CMG2." 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D000881 Phenotype 68ab5a30-c479-11e5-91a7-001a4ae51247 PMC3264307 CMG2 and TEM8 are upregulated in response to ET in nonmyeloid cells in mice.It was previously reported that ET induces the upregulation of both anthrax toxin receptorsin vitrobut that this effect is limited to monocytic cells (6,25). 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D000881 Phenotype 9c8824d0-c9fd-11e5-9b70-001a4ae51247 14871805 "The validity of TEM8 as a target is supported by several recent studies using anthrax toxin as an antitumor agent." 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D009361 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 Through these signaling pathways, ANTXR1 has been found to promote tumor cell proliferation, cell cycle progression, cell invasion, migration and self-renewal, and tumorigenesis and metastasis[26–29]. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0007155 Phenotype 7fbc3d6e-bbd9-11e5-8abe-001a4ae51246 10.1016/j.vaccine.2010.07.014 Further research proved that TEM8 protein interacted with the C5 domain of collagen α3, which was also preferentially expressed in tumor endothelium and TEM8 expression stimulated endothelial cell adhesion and migration[20,21]. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0007155 Phenotype 4ae7ada0-c483-11e5-9cc6-001a4ae51246 PMC3252584 Upon binding of cells to collagen I‐coated plates, TEM8 was found to promote adhesion and spreading, in a manner dependent on its interaction with actin (Werneret al, 2006). 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0007155 Phenotype 91048890-f19b-11e5-95fd-001a4ae51246 PMC4800672 Then TEM8 expression stimulated endothelial cell adhesion and migration1617. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0007155 Phenotype a1bd9f4e-bc37-11e5-8d2d-001a4ae51247 PMC3422265 Evidence also suggests that TEM8 promotes endothelial cell adhesion and migration, which it seems to achieve by interacting with cell matrix proteins[42]. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits MESH:D001943 Phenotype 86c5ac54-f58c-11eb-8c79-001a4a160175 30029203 As ANTXR1 is selectively expressed on the surface of cancer cells that are dependent on ANTXR1 to accelerate angiogenesis or maintain stemness, ANTXR1-targeted therapeutics may suppress breast tumor growth and weaken BCSCs without excessive damage to normal tissues. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0006260 Phenotype 86c5ac54-f58c-11eb-8c79-001a4a160175 30029203 Their work indicated that overexpression of ANTXR1 activated key genes in cell proliferation, DNA replication, and Wnt signaling pathway, conferring enhanced tumorigenic and metastatic potentials upon those BC cells[26]. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits GO:0030154 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 Further, down-regulation of ANTXR1 partly inhibits mechanically promoted chondrogenic differentiation of BMSCs. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D051379 Phenotype fd64bb62-bbdc-11e5-9b9d-001a4ae51247 PMC3289547 Host-Derived TEM8 Promotes the Growth of Human Tumor Xenografts To determine whether TEM8 could promote the growth of human tumor xenografts, we generatedTem8KO mice on an immunocompromised athymic nude background. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D051379 Phenotype d4175db4-bc18-11e5-8abe-001a4ae51246 PMC3564063 However, all theCMG2−/−/TEM8−/−mice survived the challenge without displaying any sign of disease (Figure 2C), indicating the delayed lethal effects shown above inCMG2−/−mice were mediated by TEM8 but not integrin β1 or other potential low affinity toxin receptors. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits GO:0006915 Phenotype 92462df6-375a-11e8-a34b-001a4a160175 PMC5780170 The influence that TEM8 knockdown had on XWLC-05 activity and apoptosis demonstrated that silenced TEM8 could reduce XWLC-05 lung cancer cell viability and increase its rate of apoptosis. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits MESH:D003094 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 Therefore, the relationship between ANTXR1 and MMP-2 activity could not explain why mutation of ANTXR1 causes specific types of collagen increases because MMP-2 degrades a variety of collagen components in the ECM. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D003094 Phenotype f99a7150-bc06-11e5-9b9d-001a4ae51247 10.1080/14653240601048369 TEM8 protein is also expressed in HUVEC cells, is up-regulated upon tube formation, and increases endothelial cell migration on collagen[26]. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D015496 Phenotype f99a7150-bc06-11e5-9b9d-001a4ae51247 10.1080/14653240601048369 Another possibility is that TEM8 induces a CD4+T-cell response that augments the overall response to the tumor Ag by providing T-cell help. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D013577 Phenotype 1a0a6d0e-dc97-11ea-8c98-001a4a160176 29706485 " GAPO syndrome, another form of premature aging and premature follicle depletion, is caused by mutations of the anthrax toxin receptor 1 gene ANTXR1 [74]." 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D013577 Phenotype 97b0c70a-f56b-11eb-8afe-001a4a160176 31230109 Strancky et al. showed that GAPO syndrome is caused by a mutation in ANTXR1 gene which is involved in extracellular matrix homeostasis [7]. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits MESH:D012516 Phenotype 91048890-f19b-11e5-95fd-001a4ae51246 PMC4800672 We found that down regulation of TEM8 attenuated osteosarcoma cell growthin vitrowhich was accompanied by cell cycle G1 phase to S phase arrest. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0035148 Phenotype 5c700311-f586-11eb-8a6e-001a4a160175 30686531 While HUVECs transfected with negative control siRNA or ANTXR1 siRNA did not affect osteoclast formation, BMCs with silenced ANTXR1 suppressed tube formation of HUVECs as compared with that in the control group (Fig. 4A–D). 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0007165 Phenotype 8cd7fc30-c8e6-11e5-9ad8-001a4ae51247 17420227 The strong co-expression of this receptor protein andCOL6A3, its natural ligand [41], suggests that the ANTXR1-mediated signaling pathway may play a significant role in BMSC's intrinsic function and also, possibly, anthrax pathogenesis. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits GO:0033622 Phenotype f3cde89e-bbdc-11e5-8abe-001a4ae51246 10.1016/j.ccr.2008.11.009 These findings suggested that TEM8 and VEGFR2 negatively regulate β1 integrin activation and in turn suppress NFAT transcriptional activity. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits MESH:D010712 Phenotype 3ba09f66-c468-11e5-8491-001a4ae51247 PMC3859190 Hence, we conclude that compounds isolated from the current screens exert inhibition by binding TEM8, rather than PA. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D010712 Phenotype fe5e823e-bc52-11e5-8d2d-001a4ae51247 PMC2832758 We next performed RNAi against CHC in these cells and found that formation of pPA7mer was abolished during the first 45 min (Fig. 1E), indicating that CHC was implicated not only in TEM8 mediated PA uptake but also CMG2-mediated uptake. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D010712 Phenotype beb173f2-bc3a-11e5-8abe-001a4ae51246 PMC2783407 Such ANTXR1-specific amino acid substitutions, when combined with matrix metalloproteinase-activated forms of PA, may find utility as candidate cancer therapies that employ lethal toxin. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0016049 Phenotype 31ac9eb6-c476-11e5-85e4-001a4ae51246 PMC4716791 Suppression of TEM-8 expression reduces the migrational rates of HaCaT cells As TEM-8 expression was reduced in non-healing wounds compared to acute wounds and suppression of TEM-8 expression also reduced cell growth, the effects of TEM-8 knockdown on keratinocyte migration directly were investigated. 1 ANTXR1 UNIPROT:Q9H6X2 activates GO:0046931 Phenotype e017770e-bc34-11e5-8abe-001a4ae51246 PMC1824706 Our results also illuminate the genetic basis for the previous observation that there was a one unit difference in the pH threshold at which ANTXR2 and ANTXR1 allowed toxin pore formation, and support a model where toxin pore formation may be occurring in different endosomal compartments depending on the receptor bound[14]. 1 ANTXR1 UNIPROT:Q9H6X2 activates MESH:D006391 Phenotype b289c96c-c8f7-11ee-ae05-0050569a1f61 10.1016/j.actbio.2023.01.006 ANTXR1 was shown to be a key regulator of connective tissue development and homeostasis (ECM synthesis) because ANTXR1 increases collagen I production in the infantile hemangioma matrix via VEGF signaling [60,61] (Fig. 2C). 1 ANTXR1 UNIPROT:Q9H6X2 activates FPLX:Clathrin ProteinFamily 4ae7ada0-c483-11e5-9cc6-001a4ae51246 PMC3252584 Once ubiquitinated, the CMG2/TEM8 cytosolic tails trigger the formation of a clathrin coat in a manner dependent on the adaptor complex AP1 (Abramiet al, 2010a;Figure 3). 1 ANTXR1 UNIPROT:Q9H6X2 decreases FPLX:NFAT ProteinFamily cc1db51c-c47a-11e5-85e4-001a4ae51246 PMC3204018 Interestingly, VEGFR-1 expression in HemECs is low.15The mechanism for this low expression was shown to be caused by sequestration of β1-integrin in a multiprotein complex composed by TEM8 and VEGFR-2 that inhibits NFAT-mediated VEGFR-1 transcription. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits FPLX:VEGF ProteinFamily a9e73060-bc3f-11e5-9b9d-001a4ae51247 10.1016/j.gene.2013.02.053 ANTXR1 and KDR play an important role in KDR signaling, the mutations identified in ANTXR1 or KDR can prevent VEGF from activating KDR and its downstream targets. 1 ANTXR1 UNIPROT:Q9H6X2 dephosphorylatesProtein FPLX:ERK ProteinFamily 91048890-f19b-11e5-95fd-001a4ae51246 PMC4800672 TEM8 knock-down attenuated ERK1/2 phosphorylation, down-regulated cyclinD1 expression and upregulated p21 and p27 in osteosarcoma As our previous research demonstrated12, ERK1/2 signaling pathway was closely correlated in the development of osteosarcoma, and anthrax lethal factor induced tyrosine/threonine phosphorylation of MAPKs in cultured macrophage13. 1 ANTXR1 UNIPROT:Q9H6X2 activates FPLX:ERK ProteinFamily 91048890-f19b-11e5-95fd-001a4ae51246 PMC4800672 Therefore we attempt to determine whether TEM8 (also named anthrax toxin receptor 17) mediated ERK1/2 signaling. 1 ANTXR1 UNIPROT:Q9H6X2 inhibits FPLX:Actin ProteinFamily 0d50a7c6-c46a-11e5-85e4-001a4ae51246 PMC4036183 Decreased association of actin with ANTXR-1 increases the affinity of PA for ANTXR-1 (65,66). 1 ANTXR1 UNIPROT:Q9H6X2 activates FPLX:Actin ProteinFamily beb173f2-bc3a-11e5-8abe-001a4ae51246 PMC2783407 Also ANTXR1 has been shown to promote cell spreading, an actin dependent process (Werner et al., 2006). 1 ANTXR1 UNIPROT:Q9H6X2 activates FPLX:Actin ProteinFamily b26b93b4-c8df-11e5-a1fd-001a4ae51246 16762926 Our results indicate that the cytosolic domain of TEM8 mediates actin-dependent cell spreading when binding to the immobilized ligand. 1 UNIPROT:P03372 ubiquitinatesProtein ANTXR1 UNIPROT:Q9H6X2 Protein 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 TEM8 was ubiquitylated by ERα trans-activated ASB10 Though TEM8 protein expression was significantly higher in TNBC, the mRNA expression of TEM8 was not higher in TNBC than in other BC subtypes (Fig.6a). 1 UNIPROT:P03372 activates ANTXR1 UNIPROT:Q9H6X2 Protein e4bac346-bc35-11e5-ac4e-001a4ae51246 PMC4363784 Therefore the absence of PA binding to the 3NA mutant is likely due to a defect in folding in the cellular context in the absence of glycosylation, which would be consistent with the full ER retention of TEM8 3NA. 1 UNIPROT:P03372 inhibits ANTXR1 UNIPROT:Q9H6X2 Protein 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 Furthermore, ASB10 knockdown in ERα+MCF-7 cells significantly upregulated the TEM8 protein (Supplementary Fig.8n). 1 UNIPROT:P22681 ubiquitinatesProtein ANTXR1 UNIPROT:Q9H6X2 Protein f2dc4150-bc05-11e5-9b9d-001a4ae51247 PMC2886593 Cell surface receptors bind the toxin and re-localize to lipid rafts where they undergo endocytosis via a mechanism dependent on clathrin-coated vesicles and on TEM8 ubiquitination by the E3 ligase Cbl[1]. 1 MESH:D005910 inhibits ANTXR1 UNIPROT:Q9H6X2 Phenotype 46bdd882-ae95-11ec-8b2e-0050569a1f61 PMCPMC8702332 miR-381-3p Involves in Glioma Progression by Suppressing Tumor-Promoter Factor ANTXR1. 1 UNIPROT:Q9ULV0 activates ANTXR1 UNIPROT:Q9H6X2 Protein f2dc4150-bc05-11e5-9b9d-001a4ae51247 PMC2886593 Furthermore, myosin Vb tail expression caused a prominent accumulation of TEM8 and TFR in an EGFP myosin Vb-positive perinuclear compartment, phenotype consistent with entrapment of receptors in the recycling endosome (Fig. 4). 1 CHEBI:46024 increases ANTXR1 UNIPROT:Q9H6X2 Chemical 6a03f4ba-bc4e-11e5-8d2d-001a4ae51247 PMC3014418 Indeed, TSA rescued TEM8 expression on the cell surface in a in a dose-dependent manner (Fig. 3E and F), suggesting that TEM8 expression is regulated by histone acetylation. 1 MESH:D008985 activates ANTXR1 UNIPROT:Q9H6X2 Phenotype f2dc4150-bc05-11e5-9b9d-001a4ae51247 PMC2886593 Monensin treatment increased TEM8 co-precipitation with TFR after 1 h of drug treatment (Fig. 2D, compare lanes 2 and 4). 1 MESH:D009369 activates ANTXR1 UNIPROT:Q9H6X2 Phenotype beb173f2-bc3a-11e5-8abe-001a4ae51246 PMC2783407 These altered forms of PA should allow for very specific toxin targeting to tumor vasculature cells that selectively overexpress ANTXR1 (Chen et al., 2007; Alfano et al., 2008). 1 MESH:D009369 increases ANTXR1 UNIPROT:Q9H6X2 Phenotype fd64bb62-bbdc-11e5-9b9d-001a4ae51247 PMC3289547 To determine potential tumor microenvironmental factors that induce TEM8 expression on tumor vasculature, we examined cultured human microvascular endothelial cells (HMECs) in response to several conditions. 1 MESH:D009369 activates ANTXR1 UNIPROT:Q9H6X2 Phenotype 8f3c6612-3555-11e9-8aa6-001a4a160176 PMC5771806 Overexpressing TEM8 in a preclinical breast cancer model increased tumor growth and metastasis (13). 1 MESH:D009569 activates ANTXR1 UNIPROT:Q9H6X2 Phenotype 909a1210-f58d-11eb-9572-001a4a160176 30439561 The result of late treatment showed that NOS inhibitor treatment decreased TEM8 expression, whereas NO donor and NaNO2 treatment increased TEM8, and decreased Tie2 expression control wound (Fig. 10). 1 UNIPROT:P01584 increases ANTXR1 UNIPROT:Q9H6X2 Protein 39e88046-bc00-11e5-8abe-001a4ae51246 10.1016/j.bbrc.2005.06.085 We have reported that IL-1β significantly raised the level of TEM-8 at the protein level, as revealed by Western blotting. 1 FPLX:VEGF activates ANTXR1 UNIPROT:Q9H6X2 ProteinFamily fd64bb62-bbdc-11e5-9b9d-001a4ae51247 PMC3289547 Importantly, TEM8 elevation in growth factor-starved cells could be inhibited by fibroblast growth factor (FGF), VEGF, or serum treatment, and the combination of all three resulted in the lowest TEM8 levels (Figures 1E and 1F;Figure S1D). 1 MESH:D012977 activates ANTXR1 UNIPROT:Q9H6X2 Phenotype 909a1210-f58d-11eb-9572-001a4a160176 30439561 The result of late treatment showed that NOS inhibitor treatment decreased TEM8 expression, whereas NO donor and NaNO2 treatment increased TEM8, and decreased Tie2 expression control wound (Fig. 10). 1 UNIPROT:Q8WXI3 inhibits ANTXR1 UNIPROT:Q9H6X2 Protein 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 Furthermore, ASB10 knockdown in ERα+MCF-7 cells significantly upregulated the TEM8 protein (Supplementary Fig.8n). 1 UNIPROT:Q8WXI3 increases ANTXR1 UNIPROT:Q9H6X2 Protein 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 The results of ubiquitylation assay showed that ASB10 knockdown decreased the ubiquitylation level of TEM8 (Fig.6e), whereas ASB10 overexpression increased it (Fig.6f). 1 MESH:D009362 activates ANTXR1 UNIPROT:Q9H6X2 Phenotype 8f3c6612-3555-11e9-8aa6-001a4a160176 PMC5771806 Overexpressing TEM8 in a preclinical breast cancer model increased tumor growth and metastasis (13). 1 UNIPROT:Q13464 increases ANTXR1 UNIPROT:Q9H6X2 Protein 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 These results indicated that inhibition of ROCK1 significantly suppressed the tumorigenesis and neovasculogenesis of TEM8-expressing TNBC in vivo, and that the combination of ROCK1 inhibition with chemotherapy could achieve a better therapeutic outcome.Fig. 1 UNIPROT:Q13464 activates ANTXR1 UNIPROT:Q9H6X2 Protein 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 Inhibition of ROCK1 with the ROCK1 specific inhibitor (ROCK1i) Y-27632 or shRNA transfection reversed the effects of TEM8 on tumor cell VM (Fig.4b, c), suggesting that ROCK1 was involved in the function of TEM8.Fig. 1 MESH:D000881 activates ANTXR1 UNIPROT:Q9H6X2 Phenotype a1bd9f4e-bc37-11e5-8d2d-001a4ae51247 PMC3422265 Anthrax toxin endocytosis is largely via the clathrin-mediated pathway, evidently for both TEM8 and CMG2[3],[32],[34]. 1 UNIPROT:O75581 inhibits ANTXR1 UNIPROT:Q9H6X2 Protein d80b94cc-bc3f-11e5-9b9d-001a4ae51247 10.1016/j.matbio.2007.01.007 Treatment with siRNA against LRP6 or expression of a dominant negative form (lacking the cytoplasmic domain) of LRP6 prevented the intracellular appearance of TEM8 and CMG2 after incubation of cells with PA. 1 CHEBI:75393 inhibits ANTXR1 UNIPROT:Q9H6X2 Chemical 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 Inhibition of ROCK1 with the ROCK1 specific inhibitor (ROCK1i) Y-27632 or shRNA transfection reversed the effects of TEM8 on tumor cell VM (Fig.4b, c), suggesting that ROCK1 was involved in the function of TEM8.Fig. 1 MESH:D000860 increases ANTXR1 UNIPROT:Q9H6X2 Phenotype 7d9b73fa-c463-11e5-a92e-001a4ae51246 PMC4718698 Consistent with this, we observed that Antxr1 expression in iliac artery endothelial cells is caused by fluid shear stress that is associated with arteriogenesis, but not by hypoxia that drives angiogenesis. 1 MESH:D000860 activates ANTXR1 UNIPROT:Q9H6X2 Phenotype fd64bb62-bbdc-11e5-9b9d-001a4ae51247 PMC3289547 Neither coculture with tumor cells nor exposure to hypoxia induced TEM8 (Figures S1B and S1C). 1 MESH:D008024 activates ANTXR1 UNIPROT:Q9H6X2 Phenotype f2dc4150-bc05-11e5-9b9d-001a4ae51247 PMC2886593 Alternatively, Hek293 and other cell lines examined could express an endogenous ligand eliciting TEM8 constant endocytosis and recycling. 1 UNIPROT:Q99717 activates ANTXR1 UNIPROT:Q9H6X2 Protein 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 The in vivo xenograft experiments also showed that SMAD5 knockdown suppressed TEM8-enhanced tumor growth (Fig.4j), and the enrichment of BTICs (Fig.4k), as well as the increase in tumor VM density (Fig.4l). 1 UNIPROT:O95467 inhibits ANTXR1 UNIPROT:Q9H6X2 Protein 62b6c41a-ae93-11ec-b4ed-0050569a1f61 PMCPMC8292527 GNAS knockdown reversed TEM8-induced increase of active RhoC (Fig.3iand Supplementary Fig.6b), whereas GNAS overexpression further enhanced RhoC activation (Fig.3jand Supplementary Fig.6d). 1 UNIPROT:P58335 inhibits ANTXR1 UNIPROT:Q9H6X2 Protein 7e556b6c-ae94-11ec-ae7b-0050569a1f61 PMC8716333 This analysis showed that the combined elimination of CMG-2 and TEM-8 completely prevented intoxication of all tissues examined.To determine the role of TEM-8 and CMG-2 in intoxication of leukocytes, single-cell suspensions of CD45-positive leukocytes from spleens were analyzed by flow cytometry. 1 CHEBI:42191 inhibits ANTXR1 UNIPROT:Q9H6X2 Chemical 3ba09f66-c468-11e5-8491-001a4ae51247 PMC3859190 An excess of EDTA (5 mM) was added to the TEM8-mCit destined for the 192 inhibitor-positive control wells to chelate metal and thereby prevent the interaction of TEM8 with PA in those wells, whereas inhibitor-negative control wells contained additional NaCl (10 mM) to provide equivalent sodium concentrations while not chelating divalent cations. 1 MESH:D010712 activates ANTXR1 UNIPROT:Q9H6X2 Phenotype 3ba09f66-c468-11e5-8491-001a4ae51247 PMC3859190 Final TEM8 and PA concentrations were sufficient to promote quantitative binding of TEM8 in the absence of effective inhibitors, based on the previously reported Kd(130 nM in the presence of magnesium).24Fluorescence intensities at donor and acceptor wavelengths were used to calculate the observed FRET ratio; comparison of the mean and standard deviation of the FRET in the positive and negative controls was used to calculate Z′. 1 MESH:D010712 phosphorylatesProtein ANTXR1 UNIPROT:Q9H6X2 Phenotype 6ab9bf24-c47e-11e5-9da3-001a4ae51247 PMC2824395 We next investigated whether PA also triggered the phosphorylation of TEM8 isoform 1 (TEM8-1,Fig. S1A). 1 MESH:D010712 activates ANTXR1 UNIPROT:Q9H6X2 Phenotype bedfe476-bc3a-11e5-ac4e-001a4ae51246 10.1016/j.mam.2009.06.002 In a fibroblast line PA binding to TEM8 has been shown to induce cell spreading by promoting TEM8 anchorage to the actin cytoskeleton (Werner et al., 2006). 1 MESH:D010712 activates ANTXR1 UNIPROT:Q9H6X2 Phenotype f2dc4150-bc05-11e5-9b9d-001a4ae51247 PMC2886593 After 1h, PA increased TEM8 localization in late endosomes as evidenced by immunofluorescence staining using anti-Lamp-1 or syntaxin 8 antibodies (Supplementary Fig. 1). 1 MESH:D010712 inhibits ANTXR1 UNIPROT:Q9H6X2 Phenotype 4ae7ada0-c483-11e5-9cc6-001a4ae51246 PMC3252584 In reverse, binding of PA abolished the interaction of TEM8 with actin (Abramiet al, 2010a), again similarly to integrins (Campbell and Humphries, 2011). 1 MESH:D010712 inhibits ANTXR1 UNIPROT:Q9H6X2 Phenotype f2dc4150-bc05-11e5-9b9d-001a4ae51247 PMC2886593 PA addition reduced TEM8 internalization rate, with maximal receptor accumulation occurring at 30min (Fig. 5A, B). 1 UNIPROT:Q9H6X2 activates ANTXR1 UNIPROT:Q9H6X2 Protein 909a1210-f58d-11eb-9572-001a4a160176 30439561 The result of late treatment showed that NOS inhibitor treatment decreased TEM8 expression, whereas NO donor and NaNO2 treatment increased TEM8, and decreased Tie2 expression control wound (Fig. 10). 1 UNIPROT:Q9H6X2 decreases ANTXR1 UNIPROT:Q9H6X2 Protein 31ac9eb6-c476-11e5-85e4-001a4ae51246 PMC4716791 Suppression of TEM-8 expression reduces the growth rate of HaCaT keratinocytes To determine the effect of reduced TEM-8 expression on keratinocyte cell growth, HaCaT keratinocytes were transfected with ribozyme transgenes specifically targeted to the TEM-8 transcript to reduce TEM-8 transcript levels within HaCaT cells, as assessed by RT-PCR (Fig. 2A). 1 FPLX:FGF activates ANTXR1 UNIPROT:Q9H6X2 ProteinFamily fd64bb62-bbdc-11e5-9b9d-001a4ae51247 PMC3289547 Importantly, TEM8 elevation in growth factor-starved cells could be inhibited by fibroblast growth factor (FGF), VEGF, or serum treatment, and the combination of all three resulted in the lowest TEM8 levels (Figures 1E and 1F;Figure S1D). 1 FPLX:FGF inhibits ANTXR1 UNIPROT:Q9H6X2 ProteinFamily fd64bb62-bbdc-11e5-9b9d-001a4ae51247 PMC3289547 Importantly, TEM8 elevation in growth factor-starved cells could be inhibited by fibroblast growth factor (FGF), VEGF, or serum treatment, and the combination of all three resulted in the lowest TEM8 levels (Figures 1E and 1F;Figure S1D). 1 UNIPROT:P04198 increases ANTXR1 UNIPROT:Q9H6X2 Protein 01dec922-7218-11ee-add2-0050569a791b PMC10409967 N-Myc increases TEM8 expression to induce growth and angiogenesis in prostate cancer cells, and is associated with therapy resistance (Li et al.2021a,b,c,d,e,f). 1 UNIPROT:P04198 activates ANTXR1 UNIPROT:Q9H6X2 Protein 4ba310c8-ae96-11ec-ae7b-0050569a1f61 PMC8440287 Furthermore, our results showed that N-Myc promoted the proliferation rate of prostate cancer cells by regulating TEM8. 1 UNIPROT:P04198 activates ANTXR1 UNIPROT:Q9H6X2 Protein 46c84234-ea2c-11ee-b346-0050569a791b 10.1016/j.prp.2022.154083 Moreover, N-Myc regulates FSCN1 to facilitate prostate cancer progression[33], and modulates TEM8 to exacerbate angiogenesis[34]. 1 MESH:D006391 activates ANTXR1 UNIPROT:Q9H6X2 Phenotype 24d4c448-c471-11e5-85e4-001a4ae51246 PMC2671253 Of relevance, low levels of VEGFR1 have been found in infantile hemangioma caused by mutations in the genes encoding VEGFR2 and TEM8. 1 FPLX:E3:Ub:ligase ubiquitinatesProtein ANTXR1 UNIPROT:Q9H6X2 ProteinFamily f2dc4150-bc05-11e5-9b9d-001a4ae51247 PMC2886593 Cell surface receptors bind the toxin and re-localize to lipid rafts where they undergo endocytosis via a mechanism dependent on clathrin-coated vesicles and on TEM8 ubiquitination by the E3 ligase Cbl[1].