STK3 (MST2) is a cytoplasmic serine/threonine protein kinase of the STE20 GCKII subfamily and the closer paralog of STK4 (MST1); together they are the mammalian orthologs of Drosophila Hippo. The protein has an N-terminal kinase domain, a linker containing a caspase-3 cleavage site, and a C-terminal SARAH coiled-coil domain. Through the SARAH domain STK3 forms homodimers, which allow trans-autophosphorylation of the activation loop (Thr-180), and heterodimers with SAV1 and the RASSF proteins, which respectively promote or restrain this activation. The SLMAP-STRIPAK PP2A complex dephosphorylates and inactivates it. Active STK3, scaffolded by SAV1, phosphorylates LATS1/2 and MOB1A/B, which leads to LATS-mediated phosphorylation and cytoplasmic retention of the transcriptional coactivators YAP1 and WWTR1/TAZ. STK3 is therefore the initiating kinase of hippo signaling, which restrains proliferation and tissue growth in animals and mediates contact inhibition. STK3 also phosphorylates SAV1 and NEK2A; NEK2A phosphorylation promotes NEK2A recruitment to centrosomes and centrosome disjunction. STK3 is cleaved by caspase-3 during apoptosis, and the released kinase fragment enters the nucleus and promotes cell death. It interacts with ATG8-family proteins through an LIR motif and phosphorylates LC3B. Kinases combining a kinase domain with a SARAH domain predate animals: they occur in amoebozoans and in unicellular holozoans. The Capsaspora ortholog coHpo restrains the Yorkie ortholog in the cytoplasm and limits a contractile cell state without affecting proliferation. Knockout of the choanoflagellate ortholog leaves rosette size unchanged. The kinase activity and the restraint of Yorkie/YAP are therefore ancestral, whereas control of proliferation, tissue size and apoptosis appears to be animal-specific.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | IDA PMID:8566796 Cloning and characterization of a member of the MST subfamil... | KEEP AS NON CORE | Summary: Mg2+ is the catalytic cofactor of the STK3 kinase domain; it is seen with AMP-PNP in the MST2 active site crystal structure, and the original 1995 characterization measured Mg-dependent autophosphorylation and substrate phosphorylation (abstract only). Reason: Correct, but metal-ion binding is a cofactor requirement of the kinase activity rather than a distinct function; retained as non-core. Supporting Evidence: PMID:23972470 the Mg2+ ion and AMP-PNP are clearly visible in the electron density map PMID:8566796 An in vitro kinase assay indicates that MST2 can phosphorylate an exogenous substrate, as well as itself, and phospho-amino-acid analysis indicates that it is a serine/threonine protein kinase file:human/STK3/STK3-uniprot.txt Name=Mg(2+); Xref=ChEBI:CHEBI:18420; |
| GO:0004672 protein kinase activity | IDA PMID:28087714 DLG5 connects cell polarity and Hippo signaling protein netw... | ACCEPT | Summary: In vitro kinase activity of MST1/2 was measured in the DLG5 study, which showed DLG5 inhibits MST1/2 kinase activity. Reason: Correct; protein kinase activity is the parent of the protein serine/threonine kinase activity that is the core function of STK3. Retained as accurate if general. Supporting Evidence: PMID:28087714 DLG5 inhibits the association between MST1/2 and large tumor suppressor homologs 1/2 (LATS1/2), uses its scaffolding function to link MST1/2 with MARK3, and inhibits MST1/2 kinase activity |
| GO:0004674 protein serine/threonine kinase activity | EXP PMID:11278283 MST, a physiological caspase substrate, highly sensitizes ap... | ACCEPT | Summary: STK3/MST2 is a STE20-family serine/threonine kinase: it autophosphorylates Thr-180 in trans within a SARAH-mediated dimer and phosphorylates LATS1/2, MOB1A/B, SAV1 and NEK2A. This EXP row is from the caspase-substrate study, which measured activation of MST kinase activity upon caspase cleavage (abstract only). Reason: Core molecular function of STK3, supported by many independent biochemical studies. Supporting Evidence: PMID:11278283 we show that MST1 and MST2 are direct substrates of caspase-3 both in vivo and in vitro PMID:8566796 An in vitro kinase assay indicates that MST2 can phosphorylate an exogenous substrate, as well as itself, and phospho-amino-acid analysis indicates that it is a serine/threonine protein kinase |
| GO:0004674 protein serine/threonine kinase activity | EXP PMID:15109305 Regulation of the MST1 kinase by autophosphorylation, by the... | ACCEPT | Summary: STK3/MST2 is a STE20-family serine/threonine kinase: it autophosphorylates Thr-180 in trans within a SARAH-mediated dimer and phosphorylates LATS1/2, MOB1A/B, SAV1 and NEK2A. The cited study shows recombinant MST1/2 autoactivation by activation-loop autophosphorylation (MST2 Thr-180). Reason: Core molecular function; direct in vitro evidence that includes MST2. Supporting Evidence: PMID:15109305 recombinant MST1/2 undergo a robust autoactivation in vitro, mediated by an intramolecular autophosphorylation of a single site |
| GO:0004674 protein serine/threonine kinase activity | EXP PMID:15688006 The Ste20-like kinase Mst2 activates the human large tumor s... | ACCEPT | Summary: STK3/MST2 is a STE20-family serine/threonine kinase: it autophosphorylates Thr-180 in trans within a SARAH-mediated dimer and phosphorylates LATS1/2, MOB1A/B, SAV1 and NEK2A. The cited study shows that MST2 phosphorylates and activates LATS1 and LATS2. Reason: Core molecular function; MST2 is the kinase named in the abstract. Supporting Evidence: PMID:15688006 human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2 |
| GO:0004674 protein serine/threonine kinase activity | EXP PMID:16930133 Association of mammalian sterile twenty kinases, Mst1 and Ms... | ACCEPT | Summary: STK3/MST2 is a STE20-family serine/threonine kinase: it autophosphorylates Thr-180 in trans within a SARAH-mediated dimer and phosphorylates LATS1/2, MOB1A/B, SAV1 and NEK2A. The cited study shows direct phosphorylation of SAV1 by MST1/2 in vitro. Reason: Core molecular function. Supporting Evidence: PMID:16930133 In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the PANTHER STE20/GCKII family; the target's own experimental annotations are among the descendant evidence, along with fly hippo and mouse orthologs. Reason: Kinase activity is the ancestral activity of the Hippo/MST clade; heterologous assays show the Capsaspora ortholog can phosphorylate Warts, consistent with deep conservation of the activity. Supporting Evidence: PMID:8566796 An in vitro kinase assay indicates that MST2 can phosphorylate an exogenous substrate, as well as itself, and phospho-amino-acid analysis indicates that it is a serine/threonine protein kinase PMID:38729842 these studies reveal ancient conservation of Hippo pathway kinase activity, showing that the ancestral Hippo pathway kinases were already competent to perform the biochemical activities that underlie the regulation of animal tissue size PMID:22832104 Interestingly, Co-Hpo also stimulated the phosphorylation of Dm-Wts and Dm-Yki, as revealed by phospho-specific antibodies against P-Dm-Wts-T1077 and P-Dm-Yki-S168, respectively |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:18328708 MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits ce... | ACCEPT | Summary: STK3/MST2 is a STE20-family serine/threonine kinase: it autophosphorylates Thr-180 in trans within a SARAH-mediated dimer and phosphorylates LATS1/2, MOB1A/B, SAV1 and NEK2A. The cited study identifies MOB1A/B as preferred MST1/MST2 substrates. Reason: Core molecular function. Supporting Evidence: PMID:18328708 The MOBKL1A and MOBKL1B polypeptides, homologs of the Drosophila MATS polypeptide, are identified as preferred MST1/MST2 substrates in vitro |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:18362890 Threonine 74 of MOB1 is a putative key phosphorylation site ... | ACCEPT | Summary: STK3/MST2 is a STE20-family serine/threonine kinase: it autophosphorylates Thr-180 in trans within a SARAH-mediated dimer and phosphorylates LATS1/2, MOB1A/B, SAV1 and NEK2A. The cited study shows MST2 phosphorylates MOB1 at Thr-74 in vitro. Reason: Core molecular function; MST2-specific. Supporting Evidence: PMID:18362890 Thr74, but not Thr181, is phosphorylated by MST2 in vitro |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:19525978 RASSF2 associates with and stabilizes the proapoptotic kinas... | ACCEPT | Summary: STK3/MST2 is a STE20-family serine/threonine kinase: it autophosphorylates Thr-180 in trans within a SARAH-mediated dimer and phosphorylates LATS1/2, MOB1A/B, SAV1 and NEK2A. The cited study shows RASSF2 is phosphorylated by co-immunoprecipitating MST1/2. Reason: Core molecular function. Supporting Evidence: PMID:19525978 We then showed that RASSF2 can be phosphorylated by a co-immunoprecipitating kinase that is likely to be MST1/2. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:29063833 SAV1 promotes Hippo kinase activation through antagonizing t... | ACCEPT | Summary: STK3/MST2 is a STE20-family serine/threonine kinase: it autophosphorylates Thr-180 in trans within a SARAH-mediated dimer and phosphorylates LATS1/2, MOB1A/B, SAV1 and NEK2A. The cited study (full text) uses MST2 kinase assays and defines Thr-180 trans-autophosphorylation and its antagonism by STRIPAK-PP2A. Reason: Core molecular function. Supporting Evidence: PMID:29063833 MST1 and MST2 can each form a constitutive homodimer through the SARAH domain, and kinase activation is achieved by trans-autophosphorylation of the activation loop PMID:29063833 SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:30622739 Architecture, substructures, and dynamic assembly of STRIPAK... | ACCEPT | Summary: STK3/MST2 is a STE20-family serine/threonine kinase: it autophosphorylates Thr-180 in trans within a SARAH-mediated dimer and phosphorylates LATS1/2, MOB1A/B, SAV1 and NEK2A. In the STRIPAK study MST2 knockdown reduces MOB1 Thr-35 phosphorylation. Reason: Core molecular function. Supporting Evidence: PMID:30622739 the knockdown of MST2 markedly decreased the phosphorylation of its substrate MOB1 (T35), leading to an enhanced YAP activity |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:8566796 Cloning and characterization of a member of the MST subfamil... | ACCEPT | Summary: STK3/MST2 is a STE20-family serine/threonine kinase: it autophosphorylates Thr-180 in trans within a SARAH-mediated dimer and phosphorylates LATS1/2, MOB1A/B, SAV1 and NEK2A. Original cloning paper: in vitro kinase assay with phospho-amino-acid analysis (abstract only). Reason: Core molecular function; the abstract explicitly reports Ser/Thr specificity of MST2. Supporting Evidence: PMID:8566796 An in vitro kinase assay indicates that MST2 can phosphorylate an exogenous substrate, as well as itself, and phospho-amino-acid analysis indicates that it is a serine/threonine protein kinase |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (Mst1/2 SARAH domain InterPro entry and EC 2.7.11.1). Reason: Consistent with experimental evidence. Supporting Evidence: PMID:8566796 An in vitro kinase assay indicates that MST2 can phosphorylate an exogenous substrate, as well as itself, and phospho-amino-acid analysis indicates that it is a serine/threonine protein kinase |
| GO:0005515 protein binding | IPI PMID:14729613 Identification of the E1A-regulated transcription factor p12... | REMOVE | Summary: IPI with RASSF1 (PMID:14729613). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:16930133 Association of mammalian sterile twenty kinases, Mst1 and Ms... | MODIFY | Summary: IPI with SAV1. The cited study shows that STK3 forms a SARAH-domain-mediated heterodimer with this partner. Reason: Generic protein binding is uninformative. The paper supports heterodimerization through the C-terminal SARAH coiled coils, which is the regulatory mode of these partners (SAV1 promotes, RASSF5 blocks, trans-autophosphorylation of the STK3 homodimer). Replaced with protein heterodimerization activity. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:16930133 Here we show that Mst and hSav heterodimerize in an interaction requiring the conserved C-terminal coiled-coil domains of both proteins. |
| GO:0005515 protein binding | IPI PMID:18347058 The RASSF1A tumor suppressor restrains anaphase-promoting co... | REMOVE | Summary: IPI with RASSF1 (PMID:18347058). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:18347058 We also identified the EWS family member FUS/TLS and a previously described RASSF1A-interacting protein, MST2, in the RASSF1A immunoprecipitates |
| GO:0005515 protein binding | IPI PMID:18362890 Threonine 74 of MOB1 is a putative key phosphorylation site ... | REMOVE | Summary: IPI with STK38 (PMID:18362890). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a STK3 substrate or kinase-cascade partner; the functional relationship is captured by protein serine/threonine kinase activity and hippo signaling annotations. Supporting Evidence: PMID:18362890 The phosphorylated MOB1 alone is capable to partially activate NDR1 in vitro, but MST2 is also required for the full activation. |
| GO:0005515 protein binding | IPI PMID:18362890 Threonine 74 of MOB1 is a putative key phosphorylation site ... | REMOVE | Summary: IPI with MOB1A (PMID:18362890). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a STK3 substrate or kinase-cascade partner; the functional relationship is captured by protein serine/threonine kinase activity and hippo signaling annotations. Supporting Evidence: PMID:18362890 The phosphorylated MOB1 alone is capable to partially activate NDR1 in vitro, but MST2 is also required for the full activation. |
| GO:0005515 protein binding | IPI PMID:20086174 Proapoptotic kinase MST2 coordinates signaling crosstalk bet... | REMOVE | Summary: IPI with AKT1 (PMID:20086174). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. Supporting Evidence: PMID:20086174 Raf-1 binds and inhibits MST2 kinase |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IPI with GABARAP (PMID:20562859). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. STK3 binds ATG8-family proteins through an LIR motif. No specific GO molecular function term for ATG8-family protein binding was found, and the binding itself is not a function, so the generic annotation is removed rather than modified. Supporting Evidence: PMID:20562859 including NEK9 and components of the Hippo kinase complex - STK3/MST2 and STK4/MST1 - implicated in cell growth control |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IPI with GABARAPL2 (PMID:20562859). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. STK3 binds ATG8-family proteins through an LIR motif. No specific GO molecular function term for ATG8-family protein binding was found, and the binding itself is not a function, so the generic annotation is removed rather than modified. Supporting Evidence: PMID:20562859 including NEK9 and components of the Hippo kinase complex - STK3/MST2 and STK4/MST1 - implicated in cell growth control |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IPI with STK4 (PMID:20562859). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:20562859 including NEK9 and components of the Hippo kinase complex - STK3/MST2 and STK4/MST1 - implicated in cell growth control |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IPI with RASSF5 (PMID:20562859). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:20562859 including NEK9 and components of the Hippo kinase complex - STK3/MST2 and STK4/MST1 - implicated in cell growth control |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IPI with MAP1LC3C (PMID:20562859). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. STK3 binds ATG8-family proteins through an LIR motif. No specific GO molecular function term for ATG8-family protein binding was found, and the binding itself is not a function, so the generic annotation is removed rather than modified. Supporting Evidence: PMID:20562859 including NEK9 and components of the Hippo kinase complex - STK3/MST2 and STK4/MST1 - implicated in cell growth control |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IPI with MAP1LC3B (PMID:20562859). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. STK3 binds ATG8-family proteins through an LIR motif. No specific GO molecular function term for ATG8-family protein binding was found, and the binding itself is not a function, so the generic annotation is removed rather than modified. Supporting Evidence: PMID:20562859 including NEK9 and components of the Hippo kinase complex - STK3/MST2 and STK4/MST1 - implicated in cell growth control |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IPI with GABARAPL1 (PMID:20562859). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. STK3 binds ATG8-family proteins through an LIR motif. No specific GO molecular function term for ATG8-family protein binding was found, and the binding itself is not a function, so the generic annotation is removed rather than modified. Supporting Evidence: PMID:20562859 including NEK9 and components of the Hippo kinase complex - STK3/MST2 and STK4/MST1 - implicated in cell growth control |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IPI with SAV1 (PMID:20562859). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:20562859 including NEK9 and components of the Hippo kinase complex - STK3/MST2 and STK4/MST1 - implicated in cell growth control |
| GO:0005515 protein binding | IPI PMID:20920251 Frequent epigenetic inactivation of RASSF2 in thyroid cancer... | REMOVE | Summary: IPI with RASSF2 (PMID:20920251). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:20920251 RASSF2 interacts with the proapoptotic kinases MST1 and MST2 and induces apoptosis in thyroid cancer cell lines |
| GO:0005515 protein binding | IPI PMID:20920251 Frequent epigenetic inactivation of RASSF2 in thyroid cancer... | REMOVE | Summary: IPI with STK4 (PMID:20920251). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:20920251 RASSF2 interacts with the proapoptotic kinases MST1 and MST2 and induces apoptosis in thyroid cancer cell lines |
| GO:0005515 protein binding | IPI PMID:20920251 Frequent epigenetic inactivation of RASSF2 in thyroid cancer... | REMOVE | Summary: IPI with RASSF6 (PMID:20920251). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:20920251 RASSF2 interacts with the proapoptotic kinases MST1 and MST2 and induces apoptosis in thyroid cancer cell lines |
| GO:0005515 protein binding | IPI PMID:20920251 Frequent epigenetic inactivation of RASSF2 in thyroid cancer... | REMOVE | Summary: IPI with RASSF3 (PMID:20920251). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:20920251 RASSF2 interacts with the proapoptotic kinases MST1 and MST2 and induces apoptosis in thyroid cancer cell lines |
| GO:0005515 protein binding | IPI PMID:20920251 Frequent epigenetic inactivation of RASSF2 in thyroid cancer... | REMOVE | Summary: IPI with RASSF5 (PMID:20920251). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:20920251 RASSF2 interacts with the proapoptotic kinases MST1 and MST2 and induces apoptosis in thyroid cancer cell lines |
| GO:0005515 protein binding | IPI PMID:20920251 Frequent epigenetic inactivation of RASSF2 in thyroid cancer... | REMOVE | Summary: IPI with RASSF4 (PMID:20920251). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:20920251 RASSF2 interacts with the proapoptotic kinases MST1 and MST2 and induces apoptosis in thyroid cancer cell lines |
| GO:0005515 protein binding | IPI PMID:20920251 Frequent epigenetic inactivation of RASSF2 in thyroid cancer... | REMOVE | Summary: IPI with SAV1 (PMID:20920251). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:20920251 RASSF2 interacts with the proapoptotic kinases MST1 and MST2 and induces apoptosis in thyroid cancer cell lines |
| GO:0005515 protein binding | IPI PMID:20920251 Frequent epigenetic inactivation of RASSF2 in thyroid cancer... | REMOVE | Summary: IPI with RASSF1 (PMID:20920251). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:20920251 RASSF2 interacts with the proapoptotic kinases MST1 and MST2 and induces apoptosis in thyroid cancer cell lines |
| GO:0005515 protein binding | IPI PMID:21104395 Mammalian MST2 kinase and human Salvador activate and reduce... | REMOVE | Summary: IPI with ESR1 (PMID:21104395). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. Supporting Evidence: PMID:21104395 The expression of hSAV and MST2 results in the phosphorylation of ERΞ± at serine residues 118 and 167 and represses ERΞ± expression. |
| GO:0005515 protein binding | IPI PMID:21199877 The tumor suppressor RASSF1A prevents dephosphorylation of t... | REMOVE | Summary: IPI with RASSF1 (PMID:21199877). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:21199877 In addition to preventing dephosphorylation, RASSF1A also stabilized the MST2 protein. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: IPI with RASSF5 (PMID:21988832). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: IPI with SAV1 (PMID:21988832). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:23386615 The tumor suppressor Mst1 promotes changes in the cellular r... | REMOVE | Summary: IPI with STK4 (PMID:23386615). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:23455922 Interlaboratory reproducibility of large-scale human protein... | REMOVE | Summary: IPI with RASSF2 (PMID:23455922). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:23455922 Interlaboratory reproducibility of large-scale human protein... | REMOVE | Summary: IPI with STK4 (PMID:23455922). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:23455922 Interlaboratory reproducibility of large-scale human protein... | REMOVE | Summary: IPI with RASSF3 (PMID:23455922). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:23455922 Interlaboratory reproducibility of large-scale human protein... | REMOVE | Summary: IPI with RASSF5 (PMID:23455922). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:23455922 Interlaboratory reproducibility of large-scale human protein... | REMOVE | Summary: IPI with RASSF4 (PMID:23455922). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:23455922 Interlaboratory reproducibility of large-scale human protein... | REMOVE | Summary: IPI with SAV1 (PMID:23455922). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:23972470 Structural basis for autoactivation of human Mst2 kinase and... | MODIFY | Summary: IPI with RASSF5. The cited study shows that STK3 forms a SARAH-domain-mediated heterodimer with this partner. Reason: Generic protein binding is uninformative. The paper supports heterodimerization through the C-terminal SARAH coiled coils, which is the regulatory mode of these partners (SAV1 promotes, RASSF5 blocks, trans-autophosphorylation of the STK3 homodimer). Replaced with protein heterodimerization activity. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:23972470 RASSF5 disrupts Mst2 homodimer and blocks Mst2 autoactivation. PMID:25004971 the three-dimensional structures of an MST1-RASSF5 SARAH heterodimer and an MST2 SARAH homodimer were determined by X-ray crystallography |
| GO:0005515 protein binding | IPI PMID:23972470 Structural basis for autoactivation of human Mst2 kinase and... | REMOVE | Summary: IPI with MOB1A (PMID:23972470). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a STK3 substrate or kinase-cascade partner; the functional relationship is captured by protein serine/threonine kinase activity and hippo signaling annotations. |
| GO:0005515 protein binding | IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... | REMOVE | Summary: IPI with RASSF2 (PMID:24255178). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:24255178 Mutation of the T-loop of MST2 (mammalian STE20-like protein kinase 2), which prevented autophosphorylation, disrupted its association with STRIPAK |
| GO:0005515 protein binding | IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... | REMOVE | Summary: IPI with STK4 (PMID:24255178). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:24255178 Mutation of the T-loop of MST2 (mammalian STE20-like protein kinase 2), which prevented autophosphorylation, disrupted its association with STRIPAK |
| GO:0005515 protein binding | IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... | REMOVE | Summary: IPI with SLMAP (PMID:24255178). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. Supporting Evidence: PMID:24255178 Mutation of the T-loop of MST2 (mammalian STE20-like protein kinase 2), which prevented autophosphorylation, disrupted its association with STRIPAK |
| GO:0005515 protein binding | IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... | REMOVE | Summary: IPI with MOB1B (PMID:24255178). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a STK3 substrate or kinase-cascade partner; the functional relationship is captured by protein serine/threonine kinase activity and hippo signaling annotations. Supporting Evidence: PMID:24255178 Mutation of the T-loop of MST2 (mammalian STE20-like protein kinase 2), which prevented autophosphorylation, disrupted its association with STRIPAK |
| GO:0005515 protein binding | IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... | REMOVE | Summary: IPI with RASSF3 (PMID:24255178). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:24255178 Mutation of the T-loop of MST2 (mammalian STE20-like protein kinase 2), which prevented autophosphorylation, disrupted its association with STRIPAK |
| GO:0005515 protein binding | IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... | REMOVE | Summary: IPI with RASSF5 (PMID:24255178). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:24255178 Mutation of the T-loop of MST2 (mammalian STE20-like protein kinase 2), which prevented autophosphorylation, disrupted its association with STRIPAK |
| GO:0005515 protein binding | IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... | REMOVE | Summary: IPI with RASSF4 (PMID:24255178). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:24255178 Mutation of the T-loop of MST2 (mammalian STE20-like protein kinase 2), which prevented autophosphorylation, disrupted its association with STRIPAK |
| GO:0005515 protein binding | IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... | REMOVE | Summary: IPI with SAV1 (PMID:24255178). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:24255178 Mutation of the T-loop of MST2 (mammalian STE20-like protein kinase 2), which prevented autophosphorylation, disrupted its association with STRIPAK |
| GO:0005515 protein binding | IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... | REMOVE | Summary: IPI with MOB1A (PMID:24255178). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a STK3 substrate or kinase-cascade partner; the functional relationship is captured by protein serine/threonine kinase activity and hippo signaling annotations. Supporting Evidence: PMID:24255178 Mutation of the T-loop of MST2 (mammalian STE20-like protein kinase 2), which prevented autophosphorylation, disrupted its association with STRIPAK |
| GO:0005515 protein binding | IPI PMID:24366813 Interaction proteome of human Hippo signaling: modular contr... | REMOVE | Summary: IPI with RASSF2 (PMID:24366813). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:24366813 Active MST1/2 in complex with SAV1 phosphorylates LATS1/2 |
| GO:0005515 protein binding | IPI PMID:24366813 Interaction proteome of human Hippo signaling: modular contr... | REMOVE | Summary: IPI with STK4 (PMID:24366813). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:24366813 Active MST1/2 in complex with SAV1 phosphorylates LATS1/2 |
| GO:0005515 protein binding | IPI PMID:24366813 Interaction proteome of human Hippo signaling: modular contr... | REMOVE | Summary: IPI with RASSF6 (PMID:24366813). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:24366813 Active MST1/2 in complex with SAV1 phosphorylates LATS1/2 |
| GO:0005515 protein binding | IPI PMID:24366813 Interaction proteome of human Hippo signaling: modular contr... | REMOVE | Summary: IPI with RASSF3 (PMID:24366813). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:24366813 Active MST1/2 in complex with SAV1 phosphorylates LATS1/2 |
| GO:0005515 protein binding | IPI PMID:24366813 Interaction proteome of human Hippo signaling: modular contr... | REMOVE | Summary: IPI with RASSF5 (PMID:24366813). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:24366813 Active MST1/2 in complex with SAV1 phosphorylates LATS1/2 |
| GO:0005515 protein binding | IPI PMID:24366813 Interaction proteome of human Hippo signaling: modular contr... | REMOVE | Summary: IPI with RASSF4 (PMID:24366813). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:24366813 Active MST1/2 in complex with SAV1 phosphorylates LATS1/2 |
| GO:0005515 protein binding | IPI PMID:24366813 Interaction proteome of human Hippo signaling: modular contr... | REMOVE | Summary: IPI with SAV1 (PMID:24366813). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:24366813 Active MST1/2 in complex with SAV1 phosphorylates LATS1/2 |
| GO:0005515 protein binding | IPI PMID:24929361 Protein interaction switches coordinate Raf-1 and MST2/Hippo... | REMOVE | Summary: IPI with RAF1 (PMID:24929361). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. Supporting Evidence: PMID:24929361 These include Akt phosphorylation of MST2 and a feedback phosphorylation of Raf-1 Ser 259 by LATS1, which enables Raf-1 to suppress both MST2 and MEK signalling. |
| GO:0005515 protein binding | IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme... | REMOVE | Summary: IPI with RASSF2 (PMID:24981860). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme... | REMOVE | Summary: IPI with STK4 (PMID:24981860). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme... | REMOVE | Summary: IPI with RASSF5 (PMID:24981860). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme... | REMOVE | Summary: IPI with SAV1 (PMID:24981860). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI with TFPT (PMID:25416956). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI with RASSF2 (PMID:25416956). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI with TRAF1 (PMID:25416956). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI with SLMAP (PMID:25416956). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI with FAM9B (PMID:25416956). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI with GAD1 (PMID:25416956). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI with RASSF4 (PMID:25416956). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:28087714 DLG5 connects cell polarity and Hippo signaling protein netw... | REMOVE | Summary: IPI with LATS1, SAV1 (PMID:28087714). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. Supporting Evidence: PMID:28087714 DLG5 inhibits the association between MST1/2 and large tumor suppressor homologs 1/2 (LATS1/2), uses its scaffolding function to link MST1/2 with MARK3, and inhibits MST1/2 kinase activity |
| GO:0005515 protein binding | IPI PMID:28087714 DLG5 connects cell polarity and Hippo signaling protein netw... | REMOVE | Summary: IPI with MARK3 (PMID:28087714). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a STK3 substrate or kinase-cascade partner; the functional relationship is captured by protein serine/threonine kinase activity and hippo signaling annotations. Supporting Evidence: PMID:28087714 DLG5 inhibits the association between MST1/2 and large tumor suppressor homologs 1/2 (LATS1/2), uses its scaffolding function to link MST1/2 with MARK3, and inhibits MST1/2 kinase activity |
| GO:0005515 protein binding | IPI PMID:28087714 DLG5 connects cell polarity and Hippo signaling protein netw... | REMOVE | Summary: IPI with DLG5 (PMID:28087714). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. Supporting Evidence: PMID:28087714 DLG5 inhibits the association between MST1/2 and large tumor suppressor homologs 1/2 (LATS1/2), uses its scaffolding function to link MST1/2 with MARK3, and inhibits MST1/2 kinase activity |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: IPI with RASSF2 (PMID:28514442). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: IPI with SAV1 (PMID:28514442). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: IPI with RASSF1 (PMID:28514442). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:29063833 SAV1 promotes Hippo kinase activation through antagonizing t... | MODIFY | Summary: IPI with SAV1. The cited study shows that STK3 forms a SARAH-domain-mediated heterodimer with this partner. Reason: Generic protein binding is uninformative. The paper supports heterodimerization through the C-terminal SARAH coiled coils, which is the regulatory mode of these partners (SAV1 promotes, RASSF5 blocks, trans-autophosphorylation of the STK3 homodimer). Replaced with protein heterodimerization activity. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:29063833 Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. |
| GO:0005515 protein binding | IPI PMID:30622739 Architecture, substructures, and dynamic assembly of STRIPAK... | MODIFY | Summary: Self-interaction of STK3 reported in the STRIPAK structural study. STK3 forms a constitutive SARAH-mediated homodimer that is required for trans-autophosphorylation of Thr-180. Reason: Generic protein binding is uninformative; the self-interaction is SARAH-mediated homodimerization, which has a dedicated GO term and is functionally required for activation. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:23972470 Mst2 undergoes activation through transautophosphorylation at its activation loop, which requires SARAH-mediated homodimerization. PMID:29063833 MST1 and MST2 can each form a constitutive homodimer through the SARAH domain, and kinase activation is achieved by trans-autophosphorylation of the activation loop |
| GO:0005515 protein binding | IPI PMID:31857374 NIMA-related kinase 9-mediated phosphorylation of the microt... | REMOVE | Summary: IPI with GABARAP, MAP1LC3C (PMID:31857374). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. STK3 binds ATG8-family proteins through an LIR motif. No specific GO molecular function term for ATG8-family protein binding was found, and the binding itself is not a function, so the generic annotation is removed rather than modified. Supporting Evidence: PMID:31857374 GSTβpulldown assays using translated in vitro STK3 showed that STK3 interacted directly with several of the ATG8s, but most strongly with LC3C and GABARAP |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with TFPT (PMID:32296183). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with RASSF2 (PMID:32296183). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with TRAF1 (PMID:32296183). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with MOB1B (PMID:32296183). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a STK3 substrate or kinase-cascade partner; the functional relationship is captured by protein serine/threonine kinase activity and hippo signaling annotations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with MOB3B (PMID:32296183). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with SNIP1 (PMID:32296183). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with RASSF4 (PMID:32296183). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with SAV1 (PMID:32296183). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with PLEKHF2 (PMID:32296183). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI with RASSF1 (PMID:32296183). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | REMOVE | Summary: IPI with RASSF2 (PMID:32707033). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | REMOVE | Summary: IPI with STK4 (PMID:32707033). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | REMOVE | Summary: IPI with SLMAP (PMID:32707033). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | REMOVE | Summary: IPI with RASSF3 (PMID:32707033). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | REMOVE | Summary: IPI with RASSF5 (PMID:32707033). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | REMOVE | Summary: IPI with SAV1 (PMID:32707033). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: IPI with JPH3 (PMID:32814053). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. Interaction reported (often by high-throughput yeast two-hybrid or affinity purification-mass spectrometry) without a defined functional consequence for STK3. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI with RASSF2 (PMID:33961781). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI with RASSF6 (PMID:33961781). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI with SAV1 (PMID:33961781). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: IPI with STK4 (PMID:35271311). Reason: Generic protein binding is uninformative and is not used as a function annotation; removal does not dispute the reported interaction. The partner is a SARAH-domain protein (SAV1, RASSF1-6 or the paralog STK4); these interactions are real and regulate STK3 activation, but this row comes from a study that reports the interaction without characterising its mode, so it does not support a more specific term on its own. The SARAH heterodimerization activity is captured by MODIFY on rows from focused studies. |
| GO:0005524 ATP binding | IDA PMID:8566796 Cloning and characterization of a member of the MST subfamil... | ACCEPT | Summary: ATP is the phosphate donor for STK3 autophosphorylation and substrate phosphorylation; MST2 crystal structures contain bound AMP-PNP. Reason: Correct companion to the kinase activity. Supporting Evidence: PMID:8566796 An in vitro kinase assay indicates that MST2 can phosphorylate an exogenous substrate, as well as itself, and phospho-amino-acid analysis indicates that it is a serine/threonine protein kinase PMID:23972470 the Mg2+ ion and AMP-PNP are clearly visible in the electron density map |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro protein kinase domain and ATP-binding site signature. Reason: Correct companion to the kinase activity. Supporting Evidence: PMID:8566796 An in vitro kinase assay indicates that MST2 can phosphorylate an exogenous substrate, as well as itself, and phospho-amino-acid analysis indicates that it is a serine/threonine protein kinase |
| GO:0005634 nucleus | IDA PMID:21145499 The Crumbs complex couples cell density sensing to Hippo-dep... | KEEP AS NON CORE | Summary: Nuclear localization from the Crumbs/TAZ-YAP density-sensing study (abstract only). Full-length MST2 is predominantly cytoplasmic; the caspase-cleaved kinase fragment enters the nucleus in apoptosis. Reason: Experimental annotation that I cannot verify from the abstract; nuclear presence is plausible for a fraction of STK3 and for the caspase-cleaved form, but the Hippo-signaling function of STK3 is cytoplasmic. Supporting Evidence: PMID:11278283 During Fas-mediated apoptosis, cleaved MST translocates into the nucleus before nuclear fragmentation is initiated PMID:21145499 In high-density cell cultures, the Hippo pathway drives cytoplasmic localization of TAZ/YAP |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping (Nucleus) based on the same studies. Reason: As for the IDA row: true for a fraction (caspase-cleaved form), not the main site of action. Supporting Evidence: PMID:11278283 During Fas-mediated apoptosis, cleaved MST translocates into the nucleus before nuclear fragmentation is initiated |
| GO:0005737 cytoplasm | EXP PMID:29063833 SAV1 promotes Hippo kinase activation through antagonizing t... | ACCEPT | Summary: STK3 is cytoplasmic; immunostaining localizes full-length MST to the cytoplasm, RASSF2 is relocalized to the cytoplasm by MST2, and the Hippo kinase cascade operates in the cytoplasm. Reason: Correct and the main site of action. Supporting Evidence: PMID:11278283 Immunohistochemical analysis reveals that MST is localized in the cytoplasm. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: STK3 is cytoplasmic; immunostaining localizes full-length MST to the cytoplasm, RASSF2 is relocalized to the cytoplasm by MST2, and the Hippo kinase cascade operates in the cytoplasm. IBA from the Hippo/MST family node. Reason: Consistent with experimental data and with the conserved cytoplasmic sequestration mechanism (in Capsaspora, coHpo loss releases coYki to the nucleus). Supporting Evidence: PMID:11278283 Immunohistochemical analysis reveals that MST is localized in the cytoplasm. PMID:38517944 Loss of either kinase results in increased nuclear localization of coYki, showing that the regulatory activity of the Hippo kinase cascade is conserved. |
| GO:0005737 cytoplasm | IDA PMID:19525978 RASSF2 associates with and stabilizes the proapoptotic kinas... | ACCEPT | Summary: STK3 is cytoplasmic; immunostaining localizes full-length MST to the cytoplasm, RASSF2 is relocalized to the cytoplasm by MST2, and the Hippo kinase cascade operates in the cytoplasm. The cited study shows MST2-RASSF2 colocalization in the cytoplasm. Reason: Correct. Supporting Evidence: PMID:19525978 whereas RASSF2 alone is nuclear, the presence of MST1 or MST2 results in colocalization in the cytoplasm |
| GO:0005737 cytoplasm | IDA PMID:21145499 The Crumbs complex couples cell density sensing to Hippo-dep... | ACCEPT | Summary: STK3 is cytoplasmic; immunostaining localizes full-length MST to the cytoplasm, RASSF2 is relocalized to the cytoplasm by MST2, and the Hippo kinase cascade operates in the cytoplasm. Cytoplasmic localization in the Crumbs study (abstract only). Reason: Correct; consistent with other evidence. Supporting Evidence: PMID:11278283 Immunohistochemical analysis reveals that MST is localized in the cytoplasm. |
| GO:0005737 cytoplasm | IDA PMID:35429439 WWC proteins mediate LATS1/2 activation by Hippo kinases and... | ACCEPT | Summary: STK3 is cytoplasmic; immunostaining localizes full-length MST to the cytoplasm, RASSF2 is relocalized to the cytoplasm by MST2, and the Hippo kinase cascade operates in the cytoplasm. WWC proteins assemble SAV1-MST1/2 with LATS1/2 for activation (abstract only). Reason: Correct. Supporting Evidence: PMID:35429439 SAV1, in turn, brings in MST1/2 to phosphorylate and activate LATS1/2 |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: STK3 is cytoplasmic; immunostaining localizes full-length MST to the cytoplasm, RASSF2 is relocalized to the cytoplasm by MST2, and the Hippo kinase cascade operates in the cytoplasm. Combined IEA from mouse ortholog and UniProt subcellular location. Reason: Correct. Supporting Evidence: PMID:11278283 Immunohistochemical analysis reveals that MST is localized in the cytoplasm. |
| GO:0005813 centrosome | IDA PMID:21076410 Components of the Hippo pathway cooperate with Nek2 kinase t... | ACCEPT | Summary: Mst1/2 localize to centrosomes, where Mst2 phosphorylates Nek2A and promotes its centrosomal recruitment. Reason: Supported by the full-text study and by the TRIM69/PLK1 GO-CAM model, which places STK3 kinase activity at the centrosome. Supporting Evidence: PMID:21076410 Centrosomal localizations of Mst1/2 and hSav1 were not altered in cells depleted of Nek2 or C-Nap1 PMID:21076410 Our data suggest that Mst2 phosphorylates Nek2A thereby recruiting Nek2A to centrosomes and promoting phosphorylation and displacement of centrosomal linker proteins. |
| GO:0005813 centrosome | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping (centrosome). Reason: Consistent with experimental data. Supporting Evidence: PMID:21076410 Centrosomal localizations of Mst1/2 and hSav1 were not altered in cells depleted of Nek2 or C-Nap1 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2028589 | ACCEPT | Summary: Reactome reaction R-HSA-2028589 places STK3 in the cytosol (Hippo kinase cascade reactions and its caspase cleavage). Reason: Correct; the Hippo kinase reactions occur in the cytosol. Supporting Evidence: PMID:11278283 Immunohistochemical analysis reveals that MST is localized in the cytoplasm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2028591 | ACCEPT | Summary: Reactome reaction R-HSA-2028591 places STK3 in the cytosol (Hippo kinase cascade reactions and its caspase cleavage). Reason: Correct; the Hippo kinase reactions occur in the cytosol. Supporting Evidence: PMID:11278283 Immunohistochemical analysis reveals that MST is localized in the cytoplasm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2028635 | ACCEPT | Summary: Reactome reaction R-HSA-2028635 places STK3 in the cytosol (Hippo kinase cascade reactions and its caspase cleavage). Reason: Correct; the Hippo kinase reactions occur in the cytosol. Supporting Evidence: PMID:11278283 Immunohistochemical analysis reveals that MST is localized in the cytoplasm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2028673 | ACCEPT | Summary: Reactome reaction R-HSA-2028673 places STK3 in the cytosol (Hippo kinase cascade reactions and its caspase cleavage). Reason: Correct; the Hippo kinase reactions occur in the cytosol. Supporting Evidence: PMID:11278283 Immunohistochemical analysis reveals that MST is localized in the cytoplasm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2028675 | ACCEPT | Summary: Reactome reaction R-HSA-2028675 places STK3 in the cytosol (Hippo kinase cascade reactions and its caspase cleavage). Reason: Correct; the Hippo kinase reactions occur in the cytosol. Supporting Evidence: PMID:11278283 Immunohistochemical analysis reveals that MST is localized in the cytoplasm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2028697 | ACCEPT | Summary: Reactome reaction R-HSA-2028697 places STK3 in the cytosol (Hippo kinase cascade reactions and its caspase cleavage). Reason: Correct; the Hippo kinase reactions occur in the cytosol. Supporting Evidence: PMID:11278283 Immunohistochemical analysis reveals that MST is localized in the cytoplasm. |
| GO:0006468 protein phosphorylation | IDA PMID:8566796 Cloning and characterization of a member of the MST subfamil... | ACCEPT | Summary: MST2 autophosphorylates and phosphorylates exogenous substrates in vitro (abstract only). Reason: Correct, general process for a protein kinase. Supporting Evidence: PMID:8566796 An in vitro kinase assay indicates that MST2 can phosphorylate an exogenous substrate, as well as itself, and phospho-amino-acid analysis indicates that it is a serine/threonine protein kinase |
| GO:0006606 protein import into nucleus | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine-learning rule assigning protein import into nucleus. Reason: STK3 does not carry out nuclear import. The best-characterized output of STK3 is the opposite, retention of YAP/TAZ in the cytoplasm through LATS1/2. A role in FOXO nuclear translocation was described for MST1 in the cited FOXO study and, at most, would be regulation of import, not import itself. Supporting Evidence: PMID:17974916 Mst2 stimulates YAP2 phosphorylation indirectly in vivo, perhaps by activating Lats2. PMID:16751106 MST1 phosphorylates FOXO proteins at a conserved site within the forkhead domain that disrupts their interaction with 14-3-3 proteins, promotes FOXO nuclear translocation |
| GO:0006606 protein import into nucleus | IGI PMID:16751106 A conserved MST-FOXO signaling pathway mediates oxidative-st... | UNDECIDED | Summary: IGI with STK4 from the MST-FOXO oxidative stress study. The abstract describes MST1 phosphorylating FOXO and promoting its nuclear translocation; MST2 is not mentioned in the abstract and the full text is not cached. Reason: I cannot see whether the full text tested MST2 (the IGI with STK4 suggests MST1/MST2 were examined together). If retained, the effect described (kinase-mediated release of FOXO from 14-3-3, promoting nuclear entry) is better captured as positive regulation of protein import into nucleus than as import itself. Supporting Evidence: PMID:16751106 MST1 phosphorylates FOXO proteins at a conserved site within the forkhead domain that disrupts their interaction with 14-3-3 proteins, promotes FOXO nuclear translocation |
| GO:0006915 apoptotic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA rule assigning apoptotic process. Reason: STK3 is cleaved by caspase-3 and its kinase fragment promotes apoptosis; a genuine but secondary, animal-specific role. Supporting Evidence: PMID:11278283 we show that MST1 and MST2 are direct substrates of caspase-3 both in vivo and in vitro PMID:11278283 These findings suggest that MST1 and MST2 play a role in apoptosis both upstream and downstream of caspase activation. |
| GO:0006915 apoptotic process | TAS PMID:11278283 MST, a physiological caspase substrate, highly sensitizes ap... | KEEP AS NON CORE | Summary: MST1 and MST2 are caspase-3 substrates; the cleaved kinase translocates to the nucleus and sensitizes cells to death-receptor apoptosis (abstract only). Reason: Supported, but not the core Hippo function; apoptosis is an animal-specific output. Supporting Evidence: PMID:11278283 we show that MST1 and MST2 are direct substrates of caspase-3 both in vivo and in vitro PMID:11278283 These findings suggest that MST1 and MST2 play a role in apoptosis both upstream and downstream of caspase activation. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO from the SARAH domain. Reason: Correct, general. The specific process, hippo signaling, is annotated separately. Supporting Evidence: file:human/STK3/STK3-uniprot.txt InterPro; IPR011524; SARAH_dom. PMID:15688006 These results indicate that Mst2-like kinases regulate Lats kinase activities in an evolutionarily conserved regulatory pathway. |
| GO:0010468 regulation of gene expression | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Inferred by inter-ontology logic from the transcription regulator activator activity annotation. Reason: STK3 does regulate gene expression, but indirectly, through LATS1/2-mediated inhibition of YAP/TAZ (Mst2 represses YAP-TEAD reporter activity). The MF row it is derived from is itself an over-annotation. Broad and non-core. Supporting Evidence: PMID:17974916 Coexpression of Lats2 or Mst2, but not the kinase-inactive mutants, resulted in a dose-dependent inhibition of the reporter |
| GO:0032991 protein-containing complex | IDA PMID:19962960 Role of the tumor suppressor RASSF2 in regulation of MST1 ki... | KEEP AS NON CORE | Summary: Protein-containing complex from the RASSF2-MST1 study (abstract only). MST2 also forms complexes with RASSF2, SAV1, MOB1/NDR1 and STRIPAK. Reason: Correct but uninformative; no specific complex term is supported by the cited abstract, which reports a RASSF2-MST1 complex. Supporting Evidence: PMID:19962960 RASSF2 activates MST1 kinase activity through formation of a RASSF2-MST1 complex |
| GO:0035329 hippo signaling | IBA GO_REF:0000033 | ACCEPT | Summary: STK3/MST2 is the initiating kinase of the hippo pathway: with SAV1 it phosphorylates and activates LATS1/2 and MOB1, leading to YAP/TAZ phosphorylation and cytoplasmic retention. GO:0035329 explicitly names STK3/MST2. IBA from the PANTHER Hippo/MST node (PTN001220914); STK3 appears among its own sources, which reflects its own experimental grounding. Reason: Core process. The Hpo-Wts-Yki cascade predates animals: Capsaspora Hippo engages Warts and Yorkie, and coHpo loss makes coYki nuclear. Supporting Evidence: PMID:15688006 human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2 PMID:38517944 Loss of either kinase results in increased nuclear localization of coYki, showing that the regulatory activity of the Hippo kinase cascade is conserved. PMID:22832104 Interestingly, Co-Hpo also stimulated the phosphorylation of Dm-Wts and Dm-Yki, as revealed by phospho-specific antibodies against P-Dm-Wts-T1077 and P-Dm-Yki-S168, respectively |
| GO:0035329 hippo signaling | IDA PMID:15688006 The Ste20-like kinase Mst2 activates the human large tumor s... | ACCEPT | Summary: STK3/MST2 is the initiating kinase of the hippo pathway: with SAV1 it phosphorylates and activates LATS1/2 and MOB1, leading to YAP/TAZ phosphorylation and cytoplasmic retention. GO:0035329 explicitly names STK3/MST2. Cited study: Mst2 phosphorylates and activates LATS1/2 (abstract only). Reason: Core process. Supporting Evidence: PMID:15688006 human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2 PMID:15688006 These results indicate that Mst2-like kinases regulate Lats kinase activities in an evolutionarily conserved regulatory pathway. |
| GO:0035329 hippo signaling | IDA PMID:20412773 The Hippo pathway regulates Wnt/beta-catenin signaling. | ACCEPT | Summary: STK3/MST2 is the initiating kinase of the hippo pathway: with SAV1 it phosphorylates and activates LATS1/2 and MOB1, leading to YAP/TAZ phosphorylation and cytoplasmic retention. GO:0035329 explicitly names STK3/MST2. Cited study (Hippo-Wnt crosstalk, abstract only) used Hippo pathway perturbation. Reason: Core process; defer to curator for the experimental detail. Supporting Evidence: PMID:20412773 Abrogation of TAZ levels or Hippo signaling enhances Wnt3A-stimulated DVL phosphorylation, nuclear beta-Catenin, and Wnt target gene expression. PMID:15688006 human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2 |
| GO:0035329 hippo signaling | IDA PMID:29063833 SAV1 promotes Hippo kinase activation through antagonizing t... | ACCEPT | Summary: STK3/MST2 is the initiating kinase of the hippo pathway: with SAV1 it phosphorylates and activates LATS1/2 and MOB1, leading to YAP/TAZ phosphorylation and cytoplasmic retention. GO:0035329 explicitly names STK3/MST2. Cited study shows SAV1 promotes MST1/2 activation by antagonizing STRIPAK-PP2A. Reason: Core process. Supporting Evidence: PMID:29063833 SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. PMID:29063833 Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. |
| GO:0035329 hippo signaling | IDA PMID:30622739 Architecture, substructures, and dynamic assembly of STRIPAK... | ACCEPT | Summary: STK3/MST2 is the initiating kinase of the hippo pathway: with SAV1 it phosphorylates and activates LATS1/2 and MOB1, leading to YAP/TAZ phosphorylation and cytoplasmic retention. GO:0035329 explicitly names STK3/MST2. MST2 knockdown reduces MOB1 phosphorylation and increases YAP activity. Reason: Core process. Supporting Evidence: PMID:30622739 the knockdown of MST2 markedly decreased the phosphorylation of its substrate MOB1 (T35), leading to an enhanced YAP activity |
| GO:0035329 hippo signaling | IEA GO_REF:0000120 | ACCEPT | Summary: STK3/MST2 is the initiating kinase of the hippo pathway: with SAV1 it phosphorylates and activates LATS1/2 and MOB1, leading to YAP/TAZ phosphorylation and cytoplasmic retention. GO:0035329 explicitly names STK3/MST2. Combined IEA. Reason: Core process. Supporting Evidence: PMID:15688006 human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2 |
| GO:0035329 hippo signaling | TAS PMID:19484742 Mammalian NDR/LATS protein kinases in hippo tumor suppressor... | ACCEPT | Summary: STK3/MST2 is the initiating kinase of the hippo pathway: with SAV1 it phosphorylates and activates LATS1/2 and MOB1, leading to YAP/TAZ phosphorylation and cytoplasmic retention. GO:0035329 explicitly names STK3/MST2. Review of NDR/LATS kinases in hippo signaling. Reason: Core process. Supporting Evidence: PMID:19484742 MST kinases directly phosphorylate NDR/LATS kinases. |
| GO:0035329 hippo signaling | TAS Reactome:R-HSA-2028269 | ACCEPT | Summary: STK3/MST2 is the initiating kinase of the hippo pathway: with SAV1 it phosphorylates and activates LATS1/2 and MOB1, leading to YAP/TAZ phosphorylation and cytoplasmic retention. GO:0035329 explicitly names STK3/MST2. Reactome Signaling by Hippo. Reason: Core process. Supporting Evidence: PMID:15688006 human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2 |
| GO:0035332 positive regulation of hippo signaling | IDA PMID:22292086 Mammalian ste20-like kinase and SAV1 promote 3T3-L1 adipocyt... | MODIFY | Summary: Acts-upstream annotation from the adipocyte/PPARgamma study. STK3 is the core kinase of the hippo pathway rather than a regulator of it. Reason: A core pathway kinase is better annotated to the pathway itself; positive regulation of hippo signaling describes upstream activators (e.g. NF2, KIBRA/WWC, SAV1). The study's MST2-dependent effects are part of hippo signaling. Proposed replacements: hippo signaling Supporting Evidence: PMID:22292086 This binding required the kinase activity of MST2 and was mediated by the WW domains of SAV1 and the PPYY motif of PPARΞ³. PMID:15688006 human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2 |
| GO:0035332 positive regulation of hippo signaling | IEA GO_REF:0000117 | MODIFY | Summary: ARBA rule assigning positive regulation of hippo signaling. Reason: As above: STK3 is the hippo kinase itself and is better annotated to hippo signaling. Proposed replacements: hippo signaling Supporting Evidence: PMID:15688006 human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2 |
| GO:0035556 intracellular signal transduction | IDA PMID:8566796 Cloning and characterization of a member of the MST subfamil... | ACCEPT | Summary: Original characterization of MST2 as a Ste20-like signaling kinase (abstract only). Reason: Correct general parent of hippo signaling. Supporting Evidence: PMID:8566796 An in vitro kinase assay indicates that MST2 can phosphorylate an exogenous substrate, as well as itself, and phospho-amino-acid analysis indicates that it is a serine/threonine protein kinase |
| GO:0042802 identical protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | MODIFY | Summary: Identical protein binding (self) from the autophagy interaction network (AP-MS). STK3 forms a constitutive SARAH-mediated homodimer. Reason: Self-binding of STK3 is SARAH-mediated homodimerization, required for trans-autophosphorylation and activation; protein homodimerization activity is the informative term. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:23972470 Mst2 undergoes activation through transautophosphorylation at its activation loop, which requires SARAH-mediated homodimerization. PMID:20562859 including NEK9 and components of the Hippo kinase complex - STK3/MST2 and STK4/MST1 - implicated in cell growth control |
| GO:0042802 identical protein binding | IPI PMID:23972470 Structural basis for autoactivation of human Mst2 kinase and... | MODIFY | Summary: The MST2 structural study shows SARAH-mediated homodimerization required for trans-autophosphorylation, which RASSF5 blocks. Reason: Protein homodimerization activity is the precise term for what was shown. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:23972470 Mst2 undergoes activation through transautophosphorylation at its activation loop, which requires SARAH-mediated homodimerization. PMID:23972470 RASSF5 disrupts Mst2 homodimer and blocks Mst2 autoactivation. |
| GO:0043065 positive regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from the Hippo/MST node; MST1/2 promote apoptosis when activated or caspase-cleaved. Reason: Supported for STK3 in animal cells, but a secondary output. It is unlikely to be the ancestral function: no apoptosis phenotype has been reported for Hippo kinases in unicellular holozoans. Supporting Evidence: PMID:11278283 MST highly sensitizes the cells to death receptor-mediated apoptosis by accelerating caspase-3 activation |
| GO:0043065 positive regulation of apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from STK4/MST1. Reason: As for the IBA row; directly supported for STK3 by the caspase-substrate study. Supporting Evidence: PMID:11278283 MST highly sensitizes the cells to death receptor-mediated apoptosis by accelerating caspase-3 activation |
| GO:0043408 regulation of MAPK cascade | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from a broad STE20 kinase node whose donors include several MAP4K-type GCK kinases. Reason: STK3 is linked to MAPK signaling mainly through crosstalk with Raf-1 (Raf-1 binds and inhibits MST2; LATS1 feeds back on Raf-1). Plausible but peripheral. Supporting Evidence: PMID:20086174 Raf-1 binds and inhibits MST2 kinase PMID:24929361 These include Akt phosphorylation of MST2 and a feedback phosphorylation of Raf-1 Ser 259 by LATS1, which enables Raf-1 to suppress both MST2 and MEK signalling. |
| GO:0043539 protein serine/threonine kinase activator activity | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA rule assigning protein serine/threonine kinase activator activity. Reason: STK3 activates LATS1/2 and NDR1 by phosphorylating them (and MOB1), a catalytic mechanism already captured by protein serine/threonine kinase activity. The activator activity term (GO:0043539) is for molecular function regulators that act by binding, e.g. MOB1 for LATS/NDR. Using both terms double-counts the same activity. Supporting Evidence: PMID:15688006 human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2 PMID:18362890 The phosphorylated MOB1 alone is capable to partially activate NDR1 in vitro, but MST2 is also required for the full activation. |
| GO:0043539 protein serine/threonine kinase activator activity | TAS PMID:20412773 The Hippo pathway regulates Wnt/beta-catenin signaling. | MARK AS OVER ANNOTATED | Summary: TAS from the Hippo-Wnt crosstalk study (abstract only), presumably for MST2 activation of LATS kinases. Reason: As above: activation of LATS1/2 by STK3 is by phosphorylation, which is kinase activity, not a binding-mediated activator activity. Supporting Evidence: PMID:15688006 human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2 |
| GO:0045926 negative regulation of growth | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA rule assigning negative regulation of growth. Reason: Hippo signaling restricts tissue growth in animals, but growth control is an animal-specific co-option. In Capsaspora, loss of coHpo does not change proliferation. Supporting Evidence: PMID:38729842 The deep conservation of cytoskeletal regulation by the Hippo pathway indicates an ancestral role for the Hippo pathway in cytoskeletal regulation, implying a subsequent co-option of the pathway to constrain proliferation and tissue size in animals. PMID:38517944 In adherent growth conditions, coWts-/- and coHpo-/- cells proliferated at similar rates as WT cells |
| GO:0050821 protein stabilization | IMP PMID:22292086 Mammalian ste20-like kinase and SAV1 promote 3T3-L1 adipocyt... | KEEP AS NON CORE | Summary: MST2 together with SAV1 stabilizes PPARgamma protein in differentiating adipocytes (full text). Separately, MST1/2 stabilize SAV1 through binding, independent of kinase activity. Reason: Supported but cell-type-specific and peripheral to the core function. Supporting Evidence: PMID:22292086 Overexpression of MST2 and SAV1 increased PPARΞ³ levels by stabilizing the protein PMID:16930133 catalytically inactive Mst mutants that retained the ability to bind to hSav were still able to increase its abundance |
| GO:0051262 protein tetramerization | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO from IPR036674, the p53-like tetramerisation domain superfamily, a fold-level match of the SARAH helix. The STK3 SARAH domain forms homodimers and 1:1 heterodimers with SAV1 and RASSF SARAH domains. In the one documented STK3-containing tetramer (2:2 SAV1-MST2), the dimer-of-dimers contact is made by SAV1 WW domains, not by STK3. Reason: The InterPro2GO mapping is a fold artefact: membership of a p53-tetramerisation-like structural superfamily does not imply tetramerization. STK3's own oligomerization module is a dimerization module, captured by protein homodimerization activity and protein heterodimerization activity. This matches the coHpo review, which removed the same row. Human STK3 differs in that a SAV1-MST2 heterotetramer does exist, so the term is over-stated rather than flatly wrong; the tetramerization interface belongs to SAV1. Supporting Evidence: file:human/STK3/STK3-uniprot.txt InterPro; IPR036674; p53_tetramer_sf. PMID:23972470 Mst2 undergoes activation through transautophosphorylation at its activation loop, which requires SARAH-mediated homodimerization. PMID:25004971 the three-dimensional structures of an MST1-RASSF5 SARAH heterodimer and an MST2 SARAH homodimer were determined by X-ray crystallography PMID:29063833 Two SAV1-MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. PMID:17517604 In cross-linking experiments, the major population of the free Rassf5 SARAH domain formed tetramers in solution. However, when the Mst1 SARAH domain was added, dimers were formed |
| GO:0060243 negative regulation of cell growth involved in contact inhibition | IDA PMID:17974916 Inactivation of YAP oncoprotein by the Hippo pathway is invo... | KEEP AS NON CORE | Summary: The YAP cell-density study (full text) shows Mst2 represses YAP-TEAD activity, partly through Lats2, and that the Hippo pathway mediates contact inhibition through YAP. Reason: Supported for the pathway, though the contact-inhibition experiments centre on YAP and SAV1-deficient cells. Contact inhibition of proliferation is an animal-specific output of the ancestral STK3-LATS-YAP module. Supporting Evidence: PMID:17974916 Coexpression of Lats2 or Mst2, but not the kinase-inactive mutants, resulted in a dose-dependent inhibition of the reporter PMID:17974916 Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact. |
| GO:0071539 protein localization to centrosome | IDA PMID:21076410 Components of the Hippo pathway cooperate with Nek2 kinase t... | ACCEPT | Summary: Mst2 phosphorylates Nek2A, promoting Nek2A recruitment to centrosomes and centrosome disjunction (full text). A GO-CAM model (TRIM69 activation of STK3) uses this process for STK3. Reason: Well supported for STK3 kinase activity acting on a centrosomal substrate (STK3 phosphorylates NEK2A, which is then recruited), and captured as a distinct core function; it is a cell-cycle role separate from the YAP/TAZ output of hippo signaling. Supporting Evidence: PMID:21076410 Our data suggest that Mst2 phosphorylates Nek2A thereby recruiting Nek2A to centrosomes and promoting phosphorylation and displacement of centrosomal linker proteins. PMID:21076410 Together, this shows that phosphorylation of Nek2A by Mst2 is necessary for centrosome splitting. |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The Hippo pathway restricts Wnt/beta-catenin signaling through TAZ binding DVL in the cytoplasm. IBA from the Hippo/MST node. Reason: An indirect crosstalk effect via LATS-phosphorylated TAZ; plausible but not a core STK3 function. Supporting Evidence: PMID:20412773 Here, we show that the Hippo pathway restricts Wnt/beta-Catenin signaling by promoting an interaction between TAZ and DVL in the cytoplasm. |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: The Hippo pathway restricts Wnt/beta-catenin signaling through TAZ binding DVL in the cytoplasm. ARBA rule. Reason: Indirect, via TAZ. Supporting Evidence: PMID:20412773 Here, we show that the Hippo pathway restricts Wnt/beta-Catenin signaling by promoting an interaction between TAZ and DVL in the cytoplasm. |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IMP PMID:20412773 The Hippo pathway regulates Wnt/beta-catenin signaling. | KEEP AS NON CORE | Summary: The Hippo pathway restricts Wnt/beta-catenin signaling through TAZ binding DVL in the cytoplasm. IMP from the cited study (abstract only), in which Hippo signaling perturbation enhanced Wnt3A responses. Reason: Defer to the curator on the experimental detail; the effect is indirect (TAZ-DVL). Supporting Evidence: PMID:20412773 Here, we show that the Hippo pathway restricts Wnt/beta-Catenin signaling by promoting an interaction between TAZ and DVL in the cytoplasm. PMID:20412773 Abrogation of TAZ levels or Hippo signaling enhances Wnt3A-stimulated DVL phosphorylation, nuclear beta-Catenin, and Wnt target gene expression. |
| GO:0106310 protein serine kinase activity | EXP PMID:15688006 The Ste20-like kinase Mst2 activates the human large tumor s... | ACCEPT | Summary: Mst2 phosphorylation of LATS1 on Ser/Thr sites; Rhea serine reaction in UniProt is evidenced by this paper. Reason: Correct; a child of the Ser/Thr kinase activity term. Supporting Evidence: PMID:15688006 human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2 |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-mapped IEA (RHEA:17989, serine phosphorylation). Reason: Correct. Supporting Evidence: PMID:15688006 human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2 |
| GO:0140537 transcription regulator activator activity | IGI PMID:22292086 Mammalian ste20-like kinase and SAV1 promote 3T3-L1 adipocyt... | MARK AS OVER ANNOTATED | Summary: IGI with SAV1 from the adipocyte study (full text): MST2 kinase activity stimulates SAV1 binding to PPARgamma and increases PPARgamma transactivation. The authors state the mechanism is unresolved. Reason: GO:0140537 requires direct binding to, or modification of, the transcription regulator. The study shows the PPARgamma interaction is via SAV1 WW domains and does not show that MST2 binds or phosphorylates PPARgamma. The effect is real but indirect, and a cell-type-specific, animal-only output. Supporting Evidence: PMID:22292086 This binding required the kinase activity of MST2 and was mediated by the WW domains of SAV1 and the PPYY motif of PPARΞ³. PMID:22292086 MST2 and SAV1 significantly increased PPARΞ³ transactivation PMID:22292086 stimulation of PPARΞ³ transactivation activity by MST2 and SAV1 requires other mechanism, such as recruitment of co-activators or phosphorylation |
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Download this section (compressed HTML)Q: Which functions of STK3 are ancestral? Can human STK3 replace Capsaspora coHpo or S. rosetta hippo, restoring cytoplasmic coYki and normal cell shape? And conversely, can the unicellular kinases rescue YAP/TAZ localization in MST1/2-deficient human cells, as the Acanthamoeba Hippo ortholog does?
Q: Is SARAH-mediated homodimerization and SAV1 heterodimerization conserved in coHpo and S. rosetta hippo? In particular, do unicellular SAV1 orthologs form the WW-mediated 2:2 heterotetramer described for human SAV1-MST2?
Q: Which functions of the paralog pair STK3/STK4 are specific to STK3? Many annotations, such as FOXO nuclear translocation, PRDX1 phosphorylation and ATG8-family binding, rest on MST1 data or on joint MST1/2 knockdowns, and STK3 binds ATG8-family proteins much more strongly than STK4.
Q: Is the STK3-NEK2A centrosome disjunction role Hippo-independent, and does it predate animals? Choanoflagellates and Capsaspora have centrosomes, while fungal Hippo-like kinases that lost SARAH act in mitotic exit and septation.
Experiment: Express human STK3 in Capsaspora coHpo-/- cells, and express coHpo in MST1/MST2 double-knockout human cells. Score Yorkie/YAP nuclear localization, LATS/Warts hydrophobic-motif phosphorylation and, in Capsaspora, the contractile elongated-cell phenotype.
Hypothesis: The restraint of Yorkie/YAP by Hippo kinases is ancestral and interchangeable across holozoans.
Type: cross-species complementation
Experiment: Compare STK3-only and STK4-only knockout cells, each rescued with wild-type, kinase-dead or SARAH-deleted constructs, for LATS/MOB1 phosphorylation, ATG8-dependent autophagy flux and centrosome disjunction.
Hypothesis: STK3 has paralog-specific functions not shared with STK4.
Type: genetic loss-of-function and rescue
Experiment: Purify SARAH domains of human STK3, Capsaspora coHpo and S. rosetta hippo and measure their oligomeric state (SEC-MALS, AUC) alone and with the cognate SAV1/RASSF SARAH domains.
Hypothesis: SARAH-mediated dimerization is an ancestral regulatory mechanism.
Type: biophysical characterization
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