count source_label source_id relationship target_label target_id entity_type solr_id publication_id sentences 8 PIB2_YEAST UNIPROT:P53191 activates FPLX:mTORC1 ProteinFamily 90906d44-4a30-11e8-93a4-001a4a160175 PMC5919408 In sharp contrast to ours and the previous observation by Strackaet al., Varlakhanovaet al. claim that Gtr/Ego and Pib2 work together to activate TORC1, rather than independently, based on the fact that both Pib2 and Gtr/Ego are required for glutamine and leucine-induced TORC1 activation [37].|||Crucially, in clear contrast tol-glutamine,d-glutamine did not effect a dose-dependent increase in Pib2-TORC1 interaction when added to immunoprecipitation buffers, providing further evidence for the physiological significance of Pib2-mediated TORC1 activation (Fig 5E,S5F Fig).|||However, these studies were unable to address several important questions surrounding such a role for Pib2, including whether the amino acid-dependent activation of TORC1 is achieved through the Pib2 and Gtr/Ego pathways alone (i.e., the effect of the simultaneous absence of Pib2 and the Gtr/Ego system on the activity and localization of TORC1); the nature of the molecular mechanism by which Pib2 modulates TORC1 activity; the identity of what senses glutamine; and how glutamine regulates TORC1 activity.|||Second, our data indicate that simultaneous depletion of Pib2 and the Gtr/Ego system abolishes TORC1 activity and completely compromises the vacuolar localization of TORC1.|||Forth, we very clearly show that Pib2-mediated TORC1 regulation is dependent on the concentration of glutamine by immunoprecipitation studies (Fig 5A–5C).|||Glutamine enhances the Pib2-TORC1 interaction To investigate the molecular mechanism underlying the amino acid dependent activation of TORC1 by Pib2, we examined the effect of nutrient conditions on the association between Pib2 and TORC1.|||Despite only a partial localization defect, mutations in the FYVE domain lead to the impairment of TORC1 activity, indicative of the direct involvement of PtdIns3P in Pib2-mediated TORC1 activation (Fig 3C). 5 PIB2_YEAST UNIPROT:P53191 activates FPLX:mTORC1 ProteinFamily 6a58f0c8-351e-11e8-8f56-001a4a160175 PMC5702048 If the pathways mediated by Pib2 and Gtr1/2 to activate TORC1 are independent of each other, there should be an intermediate TORC1 response to glutamine or leucine in cells lacking either Pib2 or Gtr1/2.|||Taken together, these data strongly suggest a novel dual mode of action of Pib2 on TORC1 activity: in the presence of Gtrs, Pib2 is an activator of TORC1, whereas in their absence it is an inhibitor.|||Overexpression of Pib2 in Δgtr1Δgtr2cells not only failed to rescue TORC1 activity in response to amino acids but also significantly dampened the basal response of TORC1, suggesting that Pib2 has an additional inhibitory function on TORC1 that is unmasked in the absence of the Gtrs.|||The mechanism of TORC1 activation by Pib2 and the Gtr1/2 may be explained by two overarching models: dependent and independent (Fig. S6). 4 PIB2_YEAST UNIPROT:P53191 activates FPLX:mTORC1 ProteinFamily 316501b0-5c18-11e7-af4d-001a4ae51247 PMC5466422 In this context, it will be interesting to elucidate how the activities of Pib2 and the EGO complex are coordinated to stimulate TORC1 in response to amino acids.|||Thus, like Gtr1, Pib2 is necessary to activate TORC1 in response to amino acids.|||Kog1 binding is, however, not essential for Pib2-mediated TORC1 activation, since cells expressing a fragment without these Kog1-binding domains (Pib2426-635) were as rapamycin-resistant as cells expressing full length Pib2 (FL,Figure 6G).|||Because gain-of-function alleles ofPIB2lead to rapamycin resistance, while loss-of-function alleles lead to sensitivity, our data suggest that Pib2 positively regulates TORC1 function. 3 PIB2_YEAST UNIPROT:P53191 activates GO:0038202 Phenotype 31142a46-d41b-11e5-b157-001a4ae51247 PMC4678020 We show that Pib2 increases TORC1 signaling and that full TORC1 signaling is required for LMP and cell death in bothS.|||The data presented here show that Pib2 naturally stimulates TORC1 signaling via a pathway that is independent of the EGO complex and its upstream regulators.|||While Pib2 stimulated TORC1 signaling, it may also inhibit TORC1 signaling by inhibiting functions of the EGO complex. 2 PIB2_YEAST UNIPROT:P53191 activates UNIPROT:Q9NR12 Protein 31142a46-d41b-11e5-b157-001a4ae51247 PMC4678020 Therefore Pib2 is well positioned to mediate LMP, membrane fusion, or other phenomena that could lead to death of calcineurin-deficient cells.|||Thus endogenous Pib2 promoted the onset of LMP, and overexpressed Pib2 delayed the onset of LMP, without any obvious effect on post-LMP survival times. 2 PIB2_YEAST UNIPROT:P53191 activates FPLX:mTORC1 ProteinFamily 25038f2a-c676-11ee-b346-0050569a791b 10.1016/j.celrep.2023.113599 These results indicate that serine can activate TORC1 by either the Gtr or Pib2 pathway.|||Altogether, these data demonstrate that cysteine-induced TORC1 activation is primarily mediated by the Pib2 pathway. 2 PIB2_YEAST UNIPROT:P53191 activates FPLX:mTORC1 ProteinFamily 2b7fc588-3407-11e8-b868-001a4a160176 PMC5492174 "The Pib2-mediated TORC1 activation machinery primarily responded to glutamine.|||The sensing event induces association between Pib2 and TORC1, which, in turn, somewhat promotes activation of TORC1." 1 PIB2_YEAST UNIPROT:P53191 phosphorylatesProtein UNIPROT:O43934 Protein 5fcbaa79-dc58-11ea-8a0a-001a4a160176 30527664 " (D) Gtr1 and Pib2 are required for phosphorylation of ET and VT reporters in response to glutamine." 1 PIB2_YEAST UNIPROT:P53191 activates UNIPROT:Q944G5 Protein 1b55e82d-f540-11eb-ae3d-001a4a160175 29787763 Alternatively, we do not exclude the possibility that loss of Pib2 may inactivate Gtr1, at least to some extent, thereby synthetically restoring mitophagy innpr2-null cells. 1 PIB2_YEAST UNIPROT:P53191 inhibits UNIPROT:P16066 Protein 6a58f0c8-351e-11e8-8f56-001a4a160175 PMC5702048 We also observed that Pib2 inactivates Npr1 in parallel to TORC1. 1 PIB2_YEAST UNIPROT:P53191 activates GO:0061025 Phenotype 31142a46-d41b-11e5-b157-001a4ae51247 PMC4678020 Therefore Pib2 is well positioned to mediate LMP, membrane fusion, or other phenomena that could lead to death of calcineurin-deficient cells. 1 PIB2_YEAST UNIPROT:P53191 inhibits GO:0051179 Phenotype 90906d44-4a30-11e8-93a4-001a4a160175 PMC5919408 This finding is underscored by our localization studies, which indicate that the double depletion of Gtr1 and Pib2 causes a complete defect in TORC1 localization to the vacuole (Fig 4D). 1 PIB2_YEAST UNIPROT:P53191 activates GO:0008219 Phenotype 31142a46-d41b-11e5-b157-001a4ae51247 PMC4678020 Because Pib2 and all of the tested derivatives were unable to increase the rate of cell death in wild-type cells, Pib2 is not likely to function as a dose-dependent toxin that directly induces LMP and subsequent cell death. 1 PIB2_YEAST UNIPROT:P53191 inhibits GO:0008219 Phenotype 31142a46-d41b-11e5-b157-001a4ae51247 PMC4678020 Interestingly, overexpression of GFP-Pib2 in wild-type cells also slowed the rate of cell death to levels approaching those ofpib2∆cells (Figure 2A). 1 PIB2_YEAST UNIPROT:P53191 inhibits FPLX:mTORC1 ProteinFamily 25038f2a-c676-11ee-b346-0050569a791b 10.1016/j.celrep.2023.113599 Although there are some reports that the absence of either the Pib2 or Gtr pathway prevents phase 1 (acute and transient) TORC1 activation by amino acids,26,50our results suggest that different amino acids exhibit different dependencies on the Gtr and Pib2 pathways in the activation of TORC1. 1 PIB2_YEAST UNIPROT:P53191 activates FPLX:mTORC1 ProteinFamily 4a600518-3509-11e9-8aa6-001a4a160176 PMC6249832 These amino acids are required for reactivation of TORC1 by EGO Complex and Pib2. 1 PIB2_YEAST UNIPROT:P53191 activates FPLX:mTORC1 ProteinFamily 31142a46-d41b-11e5-b157-001a4ae51247 PMC4678020 Thus Pib2 and EGO complexes seem to activate TORC1 independently and additively, with full TORC1 activity being necessary for LMP and cell death in the conditions studied here. 1 PIB2_YEAST UNIPROT:P53191 inhibits FPLX:mTORC1 ProteinFamily 788ad1e8-c87f-11ee-9aaa-0050569a1f61 10.1007/s00294-018-00929-9 In contrast, we have reported that a spontaneous mutation in the C-terminus of Pib2 can lead to cell overgrowth, suggesting that Pib2 may suppress TORC1 under our low amino acid conditions, further supported by re-expressing wild-type Pib2 (Teng et al.2013). 1 PIB2_YEAST UNIPROT:P53191 inhibits FPLX:mTORC1 ProteinFamily 90906d44-4a30-11e8-93a4-001a4a160175 PMC5919408 This finding is underscored by our localization studies, which indicate that the double depletion of Gtr1 and Pib2 causes a complete defect in TORC1 localization to the vacuole (Fig 4D). 1 UNIPROT:P04406 activates PIB2_YEAST UNIPROT:P53191 Protein 1cc63fd0-ca01-11e5-9b70-001a4ae51247 PMC1237094 "This was done by constructing the following expression vectors: GFP-PpAtg9 behind the GAPDH promoter in pIB2 (pTC1), PpAtg9-GFP behind the endogenous PpAtg9 promoter (pTC2), GFP-PpAtg9 behind the GAPDH promoter in pGAPz (pWD17), and mRFP-PpAtg9 behind the GAPDH promoter in pGAPz (pAJM6)." 1 FPLX:mTORC1 activates PIB2_YEAST UNIPROT:P53191 ProteinFamily 90906d44-4a30-11e8-93a4-001a4a160175 PMC5919408 It is unlikely that residual Pib2 observed on the vacuole membrane is caused by binding to Gtr/Ego–anchored TORC1, as Tor1 is localized to the vacuole in Δvps34cells [22].