RASA1 (RAS p21 protein activator 1, also known as p120RasGAP or p120GAP) is the prototypical Ras GTPase-activating protein that negatively regulates Ras signaling by stimulating the intrinsic GTPase activity of Ras, converting active Ras-GTP to inactive Ras-GDP. The protein contains a modular architecture with N-terminal tandem SH2 domains, an atypical SH3 domain, and central PH and C2 domains that mediate membrane recruitment via phosphotyrosine binding and lipid interactions. The C-terminal catalytic RasGAP domain contains an essential arginine finger (Arg-789) that stabilizes the transition state during GTP hydrolysis. RASA1 is recruited to activated receptor tyrosine kinases (including PDGFR, EGFR, and EphB4) via its SH2 domains, thereby constraining Ras-mediated RAF-MEK-ERK and PI3K-AKT signaling. Beyond its GAP activity, RASA1 serves as a signaling scaffold through interactions with p190RhoGAP (ARHGAP35) and DLC1, linking Ras and Rho pathway crosstalk. Germline loss-of-function mutations cause capillary malformation-arteriovenous malformation syndrome (CM-AVM1), highlighting its essential role in vascular development and endothelial cell function. The protein also has a documented anti-apoptotic function through caspase-mediated cleavage generating fragment N, which activates Akt to promote cell survival under stress conditions.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005096 GTPase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: RASA1 is the prototypical RasGAP, and GTPase activator activity is its defining core molecular function. Phylogenetic inference via IBA is well-supported by extensive experimental evidence demonstrating that RASA1 stimulates Ras GTPase activity (PMID:2123878, PMID:7478585, PMID:9219684). Reason: This is the primary molecular function of RASA1. The protein accelerates GTP hydrolysis on Ras proteins, converting active Ras-GTP to inactive Ras-GDP. This function is conserved across the RasGAP family and extensively validated experimentally. Supporting Evidence: PMID:2123878 Human ras GTPase-activating protein (GAP) is a cytoplasmic factor that stimulates the GTPase activity of normal N-ras p21 while having no stimulatory effect on the GTPase activity of oncogenic variants of N-ras p21. PMID:7478585 These results indicate that GAP acts as a negative regulation, rather than an effector, of Ras signaling in PC12 cells. file:human/RASA1/RASA1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:1902531 regulation of intracellular signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: RASA1 regulates intracellular signal transduction by constraining Ras-mediated RAF-MEK-ERK and PI3K-AKT signaling cascades. This broad BP term captures the regulatory role of RASA1 in these pathways. Reason: This annotation appropriately captures RASA1's role as a negative regulator of Ras-mediated signaling. The protein integrates signals from receptor tyrosine kinases and modulates downstream pathways. IBA annotation is consistent with conserved function across the RasGAP family. Supporting Evidence: PMID:2122974 Overexpression of GAP by 110-fold in NIH3T3 cells reduced the basal level of GTP complexed to Ras to 2.4%; upon challenge with PDGF, Ras was complexed to 6.6% GTP. |
| GO:0005096 GTPase activator activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation for GTPase activator activity. Consistent with the core molecular function of RASA1 as a RasGAP. Reason: Automated annotation is correct and consistent with experimental evidence. GTPase activator activity is the primary function of RASA1, well-supported by IBA and experimental annotations. |
| GO:0005102 signaling receptor binding | IEA GO_REF:0000117 | ACCEPT | Summary: RASA1 binds to activated receptor tyrosine kinases via its SH2 domains, including PDGFR, EGFR, and EphB4. This annotation reflects the recruitment of RASA1 to RTKs through phosphotyrosine recognition. Reason: RASA1 SH2 domains bind phosphotyrosine motifs on activated RTKs, which is essential for its membrane recruitment and subsequent GAP activity toward membrane-anchored Ras. While a more specific term like phosphotyrosine residue binding exists and is also annotated, this broader term remains accurate for describing RTK interactions. Supporting Evidence: PMID:30578106 We showed select VOGM-associated Eph-B4 mutations result in decreased binding of Eph-B4 to RASA1(see Figure 4 , panel E ) |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: RASA1 is primarily a cytoplasmic protein that is recruited to membranes upon RTK activation. Cytoplasmic localization is well-documented experimentally (PMID:8360177). Reason: This is consistent with experimental evidence and the known behavior of RASA1 as a cytosolic protein that translocates to membranes upon signaling. Supporting Evidence: PMID:8360177 Use of our antibodies allowed the specific localization of placental GAPs to cytotrophoblasts and in the syncytiotrophoblast barrier. |
| GO:0005829 cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: RASA1 resides in the cytosol before recruitment to membranes. ARBA annotation consistent with experimental data showing cytosolic localization. Reason: Cytosolic localization is the resting state of RASA1 before recruitment to membrane-associated Ras upon RTK activation. |
| GO:0019899 enzyme binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: RASA1 binds to multiple enzymes including tyrosine kinases and other signaling proteins. This is a generic term but captures documented interactions. Reason: While RASA1 does bind various enzymes, this is a very general annotation. More informative specific terms like GTPase binding are also present. This can be retained as a non-core annotation. |
| GO:0048731 system development | IEA GO_REF:0000117 | MODIFY | Summary: RASA1 is essential for vascular system development, as evidenced by the CM-AVM syndrome caused by loss-of-function mutations. However, this is an extremely broad developmental term. Reason: While RASA1 is indeed involved in development, particularly vascular development, this term is too broad. More specific vascular development terms are already annotated (blood vessel morphogenesis, vasculogenesis, angiogenesis). Proposed replacements: blood vessel development |
| GO:0005515 protein binding | IPI PMID:1314164 Phosphorylation sites in the PDGF receptor with different sp... | KEEP AS NON CORE | Summary: This annotation comes from studies of PDGF receptor phosphorylation sites that bind GAP. The study mapped specific phosphotyrosine residues on PDGFR that recruit GAP. Reason: Protein binding is an uninformative molecular function term. More specific annotations exist (e.g., GTPase binding, signaling receptor binding, phosphotyrosine residue binding). This can be retained as background evidence but does not represent a core function annotation. Supporting Evidence: PMID:1314164 Phosphorylation sites in the PDGF receptor with different specificities for binding GAP and PI3 kinase in vivo. |
| GO:0005515 protein binding | IPI PMID:1375321 GTPase-activating protein and phosphatidylinositol 3-kinase ... | KEEP AS NON CORE | Summary: Study demonstrating GAP and PI3K bind to distinct regions of PDGFR-beta, supporting SH2-mediated interactions with RTKs. Reason: Generic protein binding annotation. The underlying data supports more specific annotations for receptor binding via SH2 domains. Supporting Evidence: PMID:1375321 GTPase-activating protein and phosphatidylinositol 3-kinase bind to distinct regions of the platelet-derived growth factor receptor beta subunit. |
| GO:0005515 protein binding | IPI PMID:15504032 Tyrosine phosphorylation of caveolin-2 at residue 27: differ... | KEEP AS NON CORE | Summary: Study showing RASA1 interaction with phosphorylated caveolin-2 (CAV2). This represents a specific protein-protein interaction. Reason: Generic protein binding annotation from interaction studies. Not a core function descriptor. Supporting Evidence: PMID:15504032 Tyrosine phosphorylation of caveolin-2 at residue 27: differences in the spatial and temporal behavior of phospho-Cav-2 (pY19 and pY27). |
| GO:0005515 protein binding | IPI PMID:15574420 A novel role for Gab1 and SHP2 in epidermal growth factor-in... | KEEP AS NON CORE | Summary: Study on GAB1 and SHP2 in EGF-induced Ras activation, showing RASA1 involvement in the signaling complex. Reason: Generic protein binding annotation from signaling pathway studies. Supporting Evidence: PMID:15574420 2004 Dec 1. A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation. |
| GO:0005515 protein binding | IPI PMID:16273093 A quantitative protein interaction network for the ErbB rece... | KEEP AS NON CORE | Summary: Quantitative protein interaction study using protein microarrays for ErbB receptors, identifying RASA1 interactions. Reason: High-throughput interactome data supporting generic protein binding. Supporting Evidence: PMID:16273093 A quantitative protein interaction network for the ErbB receptors using protein microarrays. |
| GO:0005515 protein binding | IPI PMID:18761085 Capns1, a new binding partner of RasGAP-SH3 domain in K-Ras(... | KEEP AS NON CORE | Summary: Study identifying CAPNS1 (calpain small subunit 1) as a binding partner of RasGAP-SH3 domain, involved in cell survival and migration. Reason: Specific interaction data but annotated with generic protein binding term. Supporting Evidence: PMID:18761085 2008 Aug 13. Capns1, a new binding partner of RasGAP-SH3 domain in K-Ras(V12) oncogenic cells: modulation of cell survival and migration. |
| GO:0005515 protein binding | IPI PMID:19151751 p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein ... | KEEP AS NON CORE | Summary: Study showing p120Ras-GAP binds DLC1 Rho-GAP tumor suppressor and inhibits its RhoA GTPase activity. This is a functionally important interaction mediating Ras-Rho crosstalk. Reason: Important interaction but annotated with generic term. The DLC1 interaction represents a key regulatory function linking Ras and Rho signaling. Supporting Evidence: PMID:19151751 p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities. |
| GO:0005515 protein binding | IPI PMID:20598684 Abi1/Hssh3bp1 pY213 links Abl kinase signaling to p85 regula... | KEEP AS NON CORE | Summary: Study on Abi1/Hssh3bp1 phosphorylation linking Abl kinase to PI3K regulation, with RASA1 involvement in the signaling complex. Reason: Generic protein binding from signaling pathway studies. Supporting Evidence: PMID:20598684 Epub 2010 Jun 23. Abi1/Hssh3bp1 pY213 links Abl kinase signaling to p85 regulatory subunit of PI-3 kinase in regulation of macropinocytosis in LNCaP cells. |
| GO:0005515 protein binding | IPI PMID:20808760 Tyrosine-phosphorylated caveolin-1 blocks bacterial uptake b... | KEEP AS NON CORE | Summary: Study on tyrosine-phosphorylated caveolin-1 and cytoskeletal rearrangements, with RASA1 interactions in the pathway. Reason: Generic protein binding annotation. Supporting Evidence: PMID:20808760 Tyrosine-phosphorylated caveolin-1 blocks bacterial uptake by inducing Vav2-RhoA-mediated cytoskeletal rearrangements. |
| GO:0005515 protein binding | IPI PMID:21664272 Adaptor protein Nck1 interacts with p120 Ras GTPase-activati... | KEEP AS NON CORE | Summary: Study showing NCK1 adaptor protein interacts with p120 RasGAP and regulates its activity. NCK1 can enhance GAP-mediated Ras GTPase stimulation. Reason: Important functional interaction data but annotated generically. UniProt notes that NCK1 interaction may enhance GAP activity toward Ras. Supporting Evidence: PMID:21664272 2011 Jun 2. Adaptor protein Nck1 interacts with p120 Ras GTPase-activating protein and regulates its activity. |
| GO:0005515 protein binding | IPI PMID:24412244 Charting the molecular links between driver and susceptibili... | KEEP AS NON CORE | Summary: Study charting molecular links between driver and susceptibility genes in colorectal cancer, identifying RASA1 interactions. Reason: Cancer interactome study with generic protein binding annotation. Supporting Evidence: PMID:24412244 Charting the molecular links between driver and susceptibility genes in colorectal cancer. |
| GO:0005515 protein binding | IPI PMID:24728074 Enhanced prediction of Src homology 2 (SH2) domain binding p... | KEEP AS NON CORE | Summary: Enhanced prediction of SH2 domain binding potentials using fluorescence polarization assays, characterizing RASA1 SH2 interactions. Reason: Methodological study providing protein binding data. Supporting Evidence: PMID:24728074 Epub 2014 Apr 12. Enhanced prediction of Src homology 2 (SH2) domain binding potentials using a fluorescence polarization-derived c-Met, c-Kit, ErbB, and androgen receptor interactome. |
| GO:0005515 protein binding | IPI PMID:28086240 ABL2 suppresses FLT3-ITD-induced cell proliferation through ... | KEEP AS NON CORE | Summary: Study on ABL2 suppression of FLT3-ITD-induced cell proliferation through AKT signaling regulation, with RASA1 involvement. Reason: Signaling pathway study with generic protein binding annotation. Supporting Evidence: PMID:28086240 ABL2 suppresses FLT3-ITD-induced cell proliferation through negative regulation of AKT signaling. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome | KEEP AS NON CORE | Summary: Reference map of the human binary protein interactome, large-scale interaction mapping including RASA1. Reason: High-throughput interactome study with generic annotation. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Interactome mapping study of neurodegenerative disease proteins, including RASA1 interactions. Reason: Large-scale interactome study with generic annotation. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. |
| GO:0005515 protein binding | IPI PMID:8382774 In vivo binding properties of SH2 domains from GTPase-activa... | KEEP AS NON CORE | Summary: Study of in vivo binding properties of SH2 domains from GAP and PI3K, characterizing phosphotyrosine recognition. Reason: SH2 domain binding study with generic protein binding annotation. Supporting Evidence: PMID:8382774 In vivo binding properties of SH2 domains from GTPase-activating protein and phosphatidylinositol 3-kinase. |
| GO:0001726 ruffle | IEA GO_REF:0000107 | ACCEPT | Summary: RASA1 localizes to membrane ruffles, consistent with its recruitment to sites of active membrane dynamics where Ras signaling occurs. Reason: RASA1 is recruited to membrane domains with active signaling, including ruffles where RTKs and Ras are active. This annotation is consistent with the known membrane recruitment of RASA1 via SH2 and PH/C2 domains. |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: RASA1 is recruited to the plasma membrane upon RTK activation, where it accesses membrane-anchored Ras proteins. Reason: Plasma membrane localization is essential for RASA1 function as Ras is membrane-anchored. The PH and C2 domains facilitate membrane association, and SH2 domains recruit RASA1 to phosphorylated RTKs at the plasma membrane. |
| GO:0048013 ephrin receptor signaling pathway | TAS Reactome:R-HSA-2682334 | ACCEPT | Summary: RASA1 is recruited to phosphorylated EphB4 receptor and mediates downstream signaling effects. EphB4-RASA1 interaction is important for vascular development, and mutations affecting this interaction cause CM-AVM syndrome (PMID:30578106). Reason: RASA1 is a key component of EphB4 signaling, binding to phosphorylated EphB4 via SH2 domains. This interaction suppresses downstream Ras-ERK signaling in endothelial cells and is critical for vascular development. Mutations disrupting this interaction cause vascular malformations. Supporting Evidence: PMID:30578106 We showed select VOGM-associated Eph-B4 mutations result in decreased binding of Eph-B4 to RASA1(see Figure 4 , panel E ) PMID:22555806 Reduction of p120 RasGAP in HUVEC cells attenuated the inhibitory effect of EphB4 activation on the ERK pathway, whereas knockdown of PP2A in MCF7 cells attenuated EphB4 activation of the ERK pathway |
| GO:0001525 angiogenesis | IMP PMID:30578106 Mutations in Chromatin Modifier and Ephrin Signaling Genes i... | ACCEPT | Summary: RASA1 mutations cause vascular malformations including arteriovenous malformations (AVMs), indicating a role in angiogenesis. The study found RASA1-EPHB4 pathway mutations in vein of Galen malformations. Reason: RASA1 is essential for proper angiogenesis and vascular development. Loss of function causes CM-AVM syndrome characterized by abnormal blood vessel formation. The deep research confirms RASA1 deficiency leads to ERK hyperactivation and vascular malformation phenotypes. Supporting Evidence: PMID:30578106 Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. |
| GO:0005096 GTPase activator activity | IDA PMID:2123878 Purification, characterization, and western blot analysis of... | ACCEPT | Summary: Direct biochemical demonstration that purified human GAP stimulates the GTPase activity of normal Ras p21. This is foundational evidence for the core molecular function of RASA1. Reason: This is primary experimental evidence for the core function of RASA1. The study purified and characterized human GAP, demonstrating it stimulates GTPase activity of normal but not oncogenic Ras. Supporting Evidence: PMID:2123878 Human ras GTPase-activating protein (GAP) is a cytoplasmic factor that stimulates the GTPase activity of normal N-ras p21 while having no stimulatory effect on the GTPase activity of oncogenic variants of N-ras p21. |
| GO:0005737 cytoplasm | IDA PMID:8360177 Purification, characterization, and cellular localization of... | ACCEPT | Summary: Direct experimental evidence from immunolocalization studies showing GAP localizes to cytoplasm of trophoblast cells in human placenta. Reason: Primary experimental evidence for cytoplasmic localization from immunohistochemical studies. The protein was detected in cytoplasm of cytotrophoblasts and syncytiotrophoblasts. Supporting Evidence: PMID:8360177 Use of our antibodies allowed the specific localization of placental GAPs to cytotrophoblasts and in the syncytiotrophoblast barrier. |
| GO:0048013 ephrin receptor signaling pathway | IMP PMID:22555806 EphB4 promotes or suppresses Ras/MEK/ERK pathway in a contex... | ACCEPT | Summary: Study demonstrating RASA1 mediates EphB4-induced suppression of Ras/ERK pathway in endothelial cells. Knockdown of p120 RasGAP attenuated EphB4s inhibitory effect on ERK. Reason: Direct mutant phenotype evidence showing RASA1 is required for EphB4 signaling effects on the ERK pathway in endothelial cells. Supporting Evidence: PMID:22555806 Reduction of p120 RasGAP in HUVEC cells attenuated the inhibitory effect of EphB4 activation on the ERK pathway, whereas knockdown of PP2A in MCF7 cells attenuated EphB4 activation of the ERK pathway |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Cytosolic localization based on curation of immunofluorescence data, consistent with the known behavior of RASA1 as a cytosolic protein recruited to membranes upon signaling. Reason: Consistent with experimental evidence and known RASA1 biology. |
| GO:0003924 GTPase activity | TAS Reactome:R-HSA-8981353 | REMOVE | Summary: Reactome annotation indicating RASA1 involvement in GTPase reactions. However, RASA1 itself does not have intrinsic GTPase activity - it stimulates the GTPase activity of Ras proteins. Reason: This annotation is misleading. RASA1 is a GTPase activating protein (GAP) that stimulates the GTPase activity of Ras, but RASA1 itself is not a GTPase. The correct annotation is GTPase activator activity (GO:0005096), not GTPase activity. This appears to be a misannotation based on the Reactome pathway context. |
| GO:0005096 GTPase activator activity | EXP PMID:7478585 Regulation of the Ras signaling pathway by GTPase-activating... | ACCEPT | Summary: Experimental study demonstrating GAP acts as a negative regulator of Ras signaling in PC12 cells by downregulating Ras function through stimulation of GTPase activity. Reason: Direct experimental evidence for GAP function in cells. The study showed overexpression of GAP inhibits NGF-induced differentiation by downregulating Ras, and this effect is bypassed by oncogenic Ras or Raf, confirming GAP acts upstream of Ras. Supporting Evidence: PMID:7478585 These results indicate that GAP acts as a negative regulation, rather than an effector, of Ras signaling in PC12 cells. |
| GO:0005515 protein binding | IPI PMID:30578106 Mutations in Chromatin Modifier and Ephrin Signaling Genes i... | KEEP AS NON CORE | Summary: Study of VOGM mutations showing RASA1 binds to EphB4 receptor and mutations disrupt this interaction. Reason: Generic protein binding annotation. The specific interaction with EphB4 is more appropriately captured by ephrin receptor signaling pathway and signaling receptor binding annotations. Supporting Evidence: PMID:30578106 2018 Dec 18. Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation. |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:15542850 Partial cleavage of RasGAP by caspases is required for cell ... | ACCEPT | Summary: Important study showing RASA1 partial cleavage by caspase-3 generates fragment N, which activates Akt and prevents apoptosis amplification. This mechanism allows cells to survive mild stress conditions. Reason: Well-documented anti-apoptotic function of RASA1. The caspase-mediated cleavage generating fragment N is essential for cell survival under stress conditions. Cells expressing uncleavable RASA1 cannot survive mild stress. Supporting Evidence: PMID:15542850 Partial cleavage of RasGAP is required for cell survival under stress conditions because cells expressing an uncleavable RasGAP mutant cannot activate Akt, cannot prevent amplification of caspase 3 activity, and eventually undergo apoptosis. |
| GO:0001784 phosphotyrosine residue binding | IPI PMID:20624904 Tarp regulates early Chlamydia-induced host cell survival th... | ACCEPT | Summary: Protein microarray study demonstrating RASA1 SH2 domains bind phosphotyrosine motifs on bacterial effector protein Tarp, confirming the phosphotyrosine recognition function of RASA1 SH2 domains. Reason: This is an important molecular function annotation that accurately describes the binding specificity of RASA1 SH2 domains. The tandem SH2 domains recognize phosphotyrosine motifs on RTKs and other signaling proteins, which is essential for RASA1 recruitment and function. Supporting Evidence: PMID:20624904 Most notably, the tyrosine kinase ABL2 (ARG) and the GTPase-activating protein RASA1 interacted with Tarp peptides (Fig |
| GO:0048514 blood vessel morphogenesis | IMP PMID:23687085 A novel RASA1 mutation causing capillary malformation-arteri... | ACCEPT | Summary: Study of a novel RASA1 mutation causing CM-AVM syndrome presenting during pregnancy, demonstrating the essential role of RASA1 in blood vessel development and morphogenesis. Reason: RASA1 mutations cause vascular malformations, demonstrating its essential role in blood vessel morphogenesis. This is a core biological process for RASA1, directly linked to its role in ephrin receptor signaling. Supporting Evidence: PMID:23687085 Capillary malformation-arteriovenous malformation (CM-AVM) is a newly recognized clinical entity caused by mutation of the RASA1 gene, which encodes p120-RasGAP. |
| GO:0000281 mitotic cytokinesis | ISS GO_REF:0000024 | UNDECIDED | Summary: Annotation transferred based on sequence similarity. There is limited direct evidence for RASA1 involvement in mitotic cytokinesis in the literature reviewed. Reason: While RASA1 affects cell proliferation through Ras signaling, direct involvement in cytokinesis is not well-documented in available literature. This may be a secondary effect of Ras pathway modulation rather than a direct role in cytokinesis machinery. Requires further evaluation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-186798 | ACCEPT | Summary: Reactome annotation for GAP binding to PDGF-beta receptors, indicating cytosolic localization consistent with RASA1 biology. Reason: Consistent with known cytosolic localization of RASA1 before membrane recruitment. Multiple lines of evidence support cytosolic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-4093331 | ACCEPT | Summary: Reactome annotation for Ras:GTP binding to p120-RasGAP, indicating cytosolic localization. Reason: Consistent with cytosolic localization. Duplicate cytosol annotations from different Reactome pathways are acceptable. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-4093339 | ACCEPT | Summary: Reactome annotation for p120-RasGAP activating GTP hydrolysis on RAS. Reason: Consistent cytosol annotation from Reactome pathway data. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5218845 | ACCEPT | Summary: Reactome annotation from sphingosine kinase pathway, indicating cytosol localization. Reason: Consistent cytosol annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5658231 | ACCEPT | Summary: Reactome annotation for RAS GAPs stimulating RAS GTPase activity. Reason: Consistent cytosol annotation from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5658435 | ACCEPT | Summary: Reactome annotation for RAS GAPs binding RAS:GTP. Reason: Consistent cytosol annotation from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8849094 | ACCEPT | Summary: Reactome annotation for ARHGAP35 binding RASA1. Reason: Consistent cytosol annotation from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8981353 | ACCEPT | Summary: Reactome annotation for RASA1 stimulating RAS GTPase activity. Reason: Consistent cytosol annotation from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8981355 | ACCEPT | Summary: Reactome annotation for RASA1 binding RAS:GTP. Reason: Consistent cytosol annotation from Reactome. |
| GO:0005515 protein binding | IPI PMID:8618896 Phosphotyrosine-independent binding of a 62-kDa protein to t... | KEEP AS NON CORE | Summary: Study on phosphotyrosine-independent binding of a 62-kDa protein (SQSTM1) to SH2 domain of p56lck, with interactions involving RASA1. Reason: Generic protein binding annotation from interaction studies. Supporting Evidence: PMID:8618896 Phosphotyrosine-independent binding of a 62-kDa protein to the src homology 2 (SH2) domain of p56lck and its regulation by phosphorylation of Ser-59 in the lck unique N-terminal region. |
| GO:0019870 potassium channel inhibitor activity | NAS PMID:1553544 GAP domains responsible for ras p21-dependent inhibition of ... | KEEP AS NON CORE | Summary: Study showing GAP SH2-SH3 domains are responsible for Ras p21-dependent inhibition of muscarinic atrial K+ channel currents. This suggests an effector-like function of GAP mediated by its N-terminal region. Reason: This is an interesting secondary function of RASA1 related to its SH2-SH3 domains acting as effector modules. However, it is not a core GAP function and may represent a context-specific role in cardiac cells. The annotation is NAS (non-traceable author statement), so evidence is indirect. Supporting Evidence: PMID:1553544 Through the use of isolated atrial cell membranes and genetically engineered GAP deletion mutants, the src homology regions (SH2-SH3) at the amino terminus of GAP have been identified as the domains responsible for this effect. |
| GO:0051020 GTPase binding | IPI PMID:2122974 Modulation of guanine nucleotides bound to Ras in NIH3T3 cel... | ACCEPT | Summary: Study demonstrating GAP modulates guanine nucleotides bound to Ras in NIH3T3 cells, showing overexpression of GAP reduces Ras-GTP levels. This supports GTPase (Ras) binding activity. Reason: RASA1 binds to GTP-bound Ras via its GAP domain to stimulate GTP hydrolysis. GTPase binding is a core function essential for the GAP catalytic mechanism. Supporting Evidence: PMID:2122974 Overexpression of GAP by 110-fold in NIH3T3 cells reduced the basal level of GTP complexed to Ras to 2.4%; upon challenge with PDGF, Ras was complexed to 6.6% GTP |
| GO:0001570 vasculogenesis | ISS GO_REF:0000024 | ACCEPT | Summary: Annotation transferred based on sequence similarity. RASA1 is involved in vascular development, and vasculogenesis (de novo blood vessel formation) is likely affected in RASA1 mutants. Reason: Consistent with known role of RASA1 in vascular development. While most evidence is for angiogenesis and blood vessel morphogenesis, RASA1 knockout mice have severe vascular defects suggesting involvement in early vasculogenesis as well. |
| GO:0043524 negative regulation of neuron apoptotic process | ISS GO_REF:0000024 | ACCEPT | Summary: Annotation transferred based on sequence similarity. The deep research notes that RASA1 knockout embryos display extensive neuronal death, suggesting a neuroprotective role. Reason: Consistent with the anti-apoptotic function of RASA1 (via fragment N generation) and the observation that RASA1-/- embryos show neuronal death. This is likely a cell type-specific manifestation of the general anti-apoptotic function. |
| GO:0001953 negative regulation of cell-matrix adhesion | IDA PMID:8344248 The N-terminal region of GAP regulates cytoskeletal structur... | ACCEPT | Summary: Study showing expression of GAP-N (N-terminal SH2-SH3 region) correlates with impaired ability to adhere to fibronectin, demonstrating a role in regulating cell-matrix adhesion. Reason: Direct experimental evidence showing RASA1 N-terminal domain expression affects cell adhesion to extracellular matrix. This reflects the effector function of RASA1 N-terminal region via interactions with p190RhoGAP and effects on Rho signaling. Supporting Evidence: PMID:8344248 The expression of GAP-N in Rat-2 cells correlated with changes in the cytoskeleton and in cell adhesion, typified by the disruption of action stress fibres, a reduction in focal contacts, and an impaired ability to adhere to fibronectin. |
| GO:0007162 negative regulation of cell adhesion | IDA PMID:8344248 The N-terminal region of GAP regulates cytoskeletal structur... | ACCEPT | Summary: Same study as above showing GAP-N expression reduces cell adhesion. Reason: Directly supported by experimental evidence from the McGlade et al. study. RASA1 N-terminal region affects cell adhesion through interactions with p190RhoGAP and modulation of Rho/Rac signaling. Supporting Evidence: PMID:8344248 The expression of GAP-N in Rat-2 cells correlated with changes in the cytoskeleton and in cell adhesion, typified by the disruption of action stress fibres, a reduction in focal contacts, and an impaired ability to adhere to fibronectin. |
| GO:0008360 regulation of cell shape | NAS PMID:9113414 Ras-GTPase activating protein (GAP) a putative effector for ... | KEEP AS NON CORE | Summary: Review discussing GAP as a putative Ras effector, noting its N-terminal domain functions in processes associated with cell shape. Reason: Cell shape regulation is a downstream consequence of RASA1's effects on cytoskeleton via p190RhoGAP/Rho pathway interactions. This is a secondary rather than core function. Supporting Evidence: PMID:9113414 Ras-GTPase activating protein (GAP): a putative effector for Ras. |
| GO:0030833 regulation of actin filament polymerization | IDA PMID:8344248 The N-terminal region of GAP regulates cytoskeletal structur... | ACCEPT | Summary: Study showing GAP-N expression leads to disruption of actin stress fibers, indicating regulation of actin polymerization. Reason: Direct experimental evidence that RASA1 N-terminal region affects actin cytoskeleton organization. This is mediated through interactions with p190RhoGAP and effects on Rho signaling, which controls actin dynamics. Supporting Evidence: PMID:8344248 The expression of GAP-N in Rat-2 cells correlated with changes in the cytoskeleton and in cell adhesion, typified by the disruption of action stress fibres, a reduction in focal contacts, and an impaired ability to adhere to fibronectin |
| GO:0051252 regulation of RNA metabolic process | NAS PMID:9113414 Ras-GTPase activating protein (GAP) a putative effector for ... | MARK AS OVER ANNOTATED | Summary: Review mentioning GAP association with p62, an RNA binding protein, suggesting potential involvement in RNA metabolism. Reason: While RASA1 does bind p62/G3BP (an RNA-binding protein), direct involvement in RNA metabolic processes is not well-established as a primary function. This appears to be an over-annotation based on protein interaction data rather than demonstrated functional involvement in RNA metabolism. Supporting Evidence: PMID:9113414 Ras-GTPase activating protein (GAP): a putative effector for Ras. |
| GO:0005515 protein binding | IPI PMID:15077193 Overexpression of FAK promotes Ras activity through the form... | KEEP AS NON CORE | Summary: Study on FAK promoting Ras activity through FAK/p120RasGAP complex formation in malignant astrocytoma cells. Reason: Generic protein binding annotation from interaction studies. Supporting Evidence: PMID:15077193 Overexpression of FAK promotes Ras activity through the formation of a FAK/p120RasGAP complex in malignant astrocytoma cells. |
| GO:0005515 protein binding | IPI PMID:9219684 The Ras-RasGAP complex structural basis for GTPase activatio... | KEEP AS NON CORE | Summary: Landmark structural study of the Ras-RasGAP complex at 2.5 angstrom resolution, providing structural basis for GTPase activation. Reason: While this is a foundational structural study, the generic protein binding annotation does not capture the functional significance. The GTPase binding and GTPase activator activity annotations better represent this interaction. Supporting Evidence: PMID:9219684 An arginine side chain (arginine-789) of GAP-334 is supplied into the active site of Ras to neutralize developing charges in the transition state. |
| GO:0035556 intracellular signal transduction | NAS PMID:1581965 Molecular cloning of cDNAs encoding the GAP-associated prote... | KEEP AS NON CORE | Summary: Study on p190, a GAP-associated protein with implications for signaling from Ras to the nucleus. Reason: Broad biological process term. More specific annotations for signaling pathways are present (ephrin receptor signaling pathway, regulation of intracellular signal transduction). This can be retained as non-core. Supporting Evidence: PMID:1581965 Molecular cloning of cDNAs encoding the GAP-associated protein p190: implications for a signaling pathway from ras to the nucleus. |
| GO:0005102 signaling receptor binding | IPI PMID:2157284 Binding of GAP to activated PDGF receptors | ACCEPT | Summary: Study demonstrating binding of GAP to activated PDGF receptors, showing SH2-mediated recruitment to RTKs. Reason: RASA1 binds to activated receptor tyrosine kinases via SH2 domains. This is essential for its membrane recruitment and access to membrane-bound Ras. Supporting Evidence: PMID:2157284 Binding of GAP to activated PDGF receptors. |
| GO:0005102 signaling receptor binding | IPI PMID:2176151 The tyrosine phosphorylated carboxyterminus of the EGF recep... | ACCEPT | Summary: Study showing tyrosine phosphorylated C-terminus of EGF receptor is a binding site for GAP and PLC-gamma. Reason: Direct evidence for RASA1 binding to EGFR, supporting signaling receptor binding annotation. Supporting Evidence: PMID:2176151 The tyrosine phosphorylated carboxyterminus of the EGF receptor is a binding site for GAP and PLC-gamma. |
| GO:0005515 protein binding | IPI PMID:1689011 Phosphorylation of GAP and GAP-associated proteins by transf... | KEEP AS NON CORE | Summary: Study on phosphorylation of GAP and GAP-associated proteins by transforming and mitogenic tyrosine kinases. Reason: Generic protein binding annotation from early signaling studies. Supporting Evidence: PMID:1689011 Phosphorylation of GAP and GAP-associated proteins by transforming and mitogenic tyrosine kinases. |
| GO:0005515 protein binding | IPI PMID:8649363 A Ras-GTPase-activating protein SH3-domain-binding protein. | KEEP AS NON CORE | Summary: Study identifying G3BP as a Ras-GTPase-activating protein SH3-domain-binding protein. Reason: Identifies specific G3BP interaction via SH3 domain but annotated with generic protein binding term. Supporting Evidence: PMID:8649363 A Ras-GTPase-activating protein SH3-domain-binding protein. |
| GO:0005737 cytoplasm | NAS PMID:2821624 A cytoplasmic protein stimulates normal N-ras p21 GTPase, bu... | ACCEPT | Summary: Early study identifying a cytoplasmic protein (GAP) that stimulates normal N-ras p21 GTPase but not oncogenic mutants. Reason: Consistent with cytoplasmic localization of RASA1. This foundational study first characterized GAP as a cytoplasmic factor. Supporting Evidence: PMID:2821624 A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. |
| GO:0007165 signal transduction | IDA PMID:1756860 Identification of amino acid residues of Ras protein that ar... | KEEP AS NON CORE | Summary: Study identifying Ras residues essential for signal transduction but not for GAP-mediated GTPase enhancement, demonstrating RASA1 role in Ras signaling regulation. Reason: Very broad BP term. More specific signaling annotations are present. This can be retained as non-core general annotation. Supporting Evidence: PMID:1756860 The Val45 and Gly48 residues should be included by definition in the effector region responsible for the signal transduction, while only a subset of the effector-region residues is required for enhancement of the GTPase activity by GAP. |
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Download this section (compressed HTML)Q: What is the relative contribution of RasGAP activity versus the scaffold/effector functions of the N-terminal SH2-SH3-SH2 region to RASA1's role in vascular development?
Q: Do the anti-apoptotic effects of RASA1 fragment N contribute to the vascular phenotypes seen in CM-AVM syndrome, or are these independent of the GAP domain mutations typically observed?
Q: How does the interaction between RASA1 SH3 domain and DLC1 RhoGAP contribute to endothelial cell function and vascular morphogenesis?
Experiment: Domain-specific rescue experiments in RASA1-/- endothelial cells to determine which domains (GAP domain alone vs. full-length vs. N-terminal region) are sufficient to rescue vascular phenotypes.
Experiment: Phosphoproteomics analysis comparing EphB4-stimulated endothelial cells with and without RASA1 to identify complete downstream signaling changes.
Experiment: Live imaging of RASA1 membrane recruitment dynamics in endothelial cells during angiogenic sprouting to understand spatiotemporal regulation.
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