RAS p21 protein activator 2, GTPase-activating protein (GAP) for RAS family small GTPases. Member of GAP1 family of RasGAPs characterized by tandem C2 domains (Ca2+ and phospholipid binding), pleckstrin homology (PH) domain (binds PIP3 with high affinity), and C-terminal RasGAP catalytic domain. Functions as tumor suppressor by negatively regulating RAS signaling: catalyzes GTP hydrolysis on RAS proteins (HRAS, KRAS, NRAS, R-Ras) via arginine-finger mechanism (Arg-511), converting active RAS-GTP to inactive RAS-GDP. Cytoplasmic protein with regulated membrane association - PH domain recruitment to PIP3-enriched membranes brings RASA2 to sites of active RAS signaling. Loss of RASA2 leads to hyperactive RAS-MAPK and RAS-PI3K pathways, promoting cell proliferation, survival, and tumorigenesis. Recurrent inactivating mutations identified in ~5% of melanomas; loss associated with enhanced ERK signaling, increased proliferation/migration, and worse patient outcomes. Rare germline mutations cause Noonan syndrome (Rasopathy) due to elevated developmental RAS activity. In T cells, RASA2 acts as brake on TCR signaling - RASA2-deficient T cells show ~2-fold increased proliferation, enhanced activation markers (CD69, CD154), heightened antigen sensitivity, and improved tumor cell killing. Expression in immune cells, endothelium, and various tissues. Part of negative feedback mechanisms restraining growth factor receptor signaling cascades.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005096 GTPase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: RASA2/GAP1m is a Ras GTPase-activating protein that accelerates hydrolysis of Ras-GTP to Ras-GDP, thereby downregulating RAS output. This is the core molecular function of the protein, supported by phylogenetic inference and extensive literature. Reason: Core enzymatic function of RASA2. The protein contains a conserved RasGAP catalytic domain with an arginine finger residue (Arg-397 in human) that is essential for stimulating GTP hydrolysis. This function is well-established across the GAP1 family of RasGAPs. Supporting Evidence: PMID:8812506 We have previously isolated a novel Ras GTPase-activating protein (Ras GAP), Gap1m, from rat brain. Gap1m is considered to be a negative regulator of the Ras signaling pathways, like other Ras GAPs, neurofibromin, which is a gene product of the neurofibromatosis type I gene, and p120GAP. Reactome:R-HSA-5658435 GAP proteins stimulate RAS GTPase activity by inserting a conserved arginine residue into the RAS active site, promoting a conformational change in the active site to allow GTP hydrolysis (Ahamdian et al, 2003; Scheffzek et al, 1997; Ahamdian et al, 1997). file:human/RASA2/RASA2-deep-research-openai.md See deep research file for comprehensive analysis |
| GO:1902531 regulation of intracellular signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: RASA2 regulates intracellular signal transduction by negatively regulating the RAS-RAF-MEK-ERK cascade and RAS-PI3K signaling. Loss of RASA2 leads to hyperactive MAPK signaling. Reason: Core regulatory function. RASA2 functions as an intracellular checkpoint that limits RAS/MAPK signaling. In T cells, RASA2 deficiency results in enhanced MAPK signaling and increased T cell activation. Supporting Evidence: file:human/RASA2/RASA2-deep-research-falcon.md RASA2 negatively regulates the RAS-RAF-MEK-ERK cascade by accelerating Ras GTP hydrolysis; its lipid-binding domains coordinate membrane recruitment, ensuring spatial coupling of Ras inactivation with effector engagement. |
| GO:0005096 GTPase activator activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation of GTPase activator activity based on combined computational evidence. Consistent with the experimentally validated RasGAP function of RASA2. Reason: Core enzymatic function. Duplicates the IBA annotation with computational evidence, which is consistent with the known function. Supporting Evidence: file:human/RASA2/RASA2-uniprot.txt Inhibitory regulator of the Ras-cyclic AMP pathway. |
| GO:0005543 phospholipid binding | IEA GO_REF:0000002 | ACCEPT | Summary: RASA2 contains PH and C2 domains that bind membrane phospholipids. The PH domain binds PIP3 with high affinity, and the tandem C2 domains bind calcium and phospholipids for membrane targeting. Reason: Important accessory function for membrane localization. The PH domain enables recruitment to PIP3-enriched membranes where active RAS signaling occurs. The C2 domains provide additional lipid-binding capacity. Supporting Evidence: file:human/RASA2/RASA2-deep-research-falcon.md PH and C2 domains confer lipid-dependent membrane association of RasGAPs, coordinating with the catalytic domain to accelerate Ras GTP hydrolysis at the plasma membrane/inner leaflet signalling sites. file:human/RASA2/RASA2-uniprot.txt Binds inositol tetrakisphosphate (IP4). |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: RASA2 is a cytoplasmic protein with regulated membrane association. It is recruited to the plasma membrane via PH domain binding to PIP3 upon growth factor stimulation. Reason: Core localization. UniProt explicitly states cytoplasmic localization. The cytoplasmic pool is recruited to membranes in response to signaling. Supporting Evidence: file:human/RASA2/RASA2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, perinuclear region. |
| GO:0008270 zinc ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: RASA2 contains a Btk-type zinc finger domain (residues 708-744) with four conserved cysteine residues (Cys-716, Cys-727, Cys-728, Cys-738) that coordinate a zinc ion. Reason: Structural requirement for protein stability. The Btk-type zinc finger is a conserved structural element in the GAP1 family. Supporting Evidence: file:human/RASA2/RASA2-uniprot.txt ZN_FING 708..744 /note="Btk-type" |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: RASA2 participates in intracellular signal transduction as a negative regulator of RAS signaling pathways, including RAS-MAPK and RAS-PI3K cascades. Reason: Core function in signal transduction. RASA2 terminates RAS signaling by catalyzing GTP hydrolysis, which is a fundamental intracellular signaling mechanism. Supporting Evidence: PMID:8699317 Ras, ras gene product, is a GTP binding protein which controls the signal transduction by GTP hydrolysis. |
| GO:0046580 negative regulation of Ras protein signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: RASA2 is a bona fide negative regulator of Ras signaling, converting active RAS-GTP to inactive RAS-GDP. This is the primary biological function of the protein. Reason: Core biological process. This term accurately captures the primary regulatory role of RASA2 in attenuating RAS signaling cascades. Supporting Evidence: PMID:8812506 Gap1m is considered to be a negative regulator of the Ras signaling pathways, like other Ras GAPs, neurofibromin, which is a gene product of the neurofibromatosis type I gene, and p120GAP. Reactome:R-HSA-5658435 The human genome encodes at least 10 proteins that bind RAS and activate its intrinsic GTPase activity, resulting in the formation of inactive RAS:GDP and attenuating RAS signaling (reviewed in King et al, 2013). |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: RASA2 binds zinc ions via its Btk-type zinc finger domain. This is a more general term than GO:0008270 (zinc ion binding). Reason: Redundant with the more specific zinc ion binding annotation. The metal ion binding is structural rather than catalytic. Supporting Evidence: file:human/RASA2/RASA2-uniprot.txt ZN_FING 708..744 /note="Btk-type" with BINDING sites for Zn(2+) at residues 716, 727, 728, 738. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: RASA2 localizes to the perinuclear region of the cytoplasm according to UniProt annotation. Reason: This represents a specific sublocalization within the cytoplasm. While valid, this may represent a steady-state localization rather than the functional site (plasma membrane upon recruitment). Supporting Evidence: file:human/RASA2/RASA2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, perinuclear region. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: RASA2 was identified in protein interaction studies (BioPlex 3.0). The term protein binding is uninformative as it does not specify the binding partner or functional consequence. Reason: Protein binding is too generic. RASA2 specifically binds RAS proteins (its substrates), and has been shown to interact with NOLC1 and potentially p53. A more informative term would be small GTPase binding (GO:0031267; the former Ras GTPase binding term has been merged into it). Proposed replacements: small GTPase binding Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. file:human/RASA2/RASA2-uniprot.txt Q15283; Q14978: NOLC1; NbExp=2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5658231 | ACCEPT | Summary: RASA2 is localized in the cytosol and is recruited to membranes to stimulate RAS GTPase activity. Reactome pathway includes RASA2 as a cytosolic GAP. Reason: Consistent with UniProt annotation of cytoplasmic localization. The cytosol represents the soluble pool of RASA2 before membrane recruitment. Supporting Evidence: Reactome:R-HSA-5658231 The intrinsic GTPase activity of RAS proteins is stimulated by the GAP proteins, of which there are at least 10 in the human genome (reviewed in King et al, 2013). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5658435 | ACCEPT | Summary: Duplicate cytosol annotation from Reactome pathway describing RAS GAP binding to RAS-GTP. Reason: Consistent localization annotation. RASA2 is a cytosolic protein that is recruited to membranes where RAS is tethered. Supporting Evidence: Reactome:R-HSA-5658435 These identified RAS GAP proteins are RASA1 (also known as p120 GAP), NF1, the GAP1 family (RASA2, RASA3, RASA4 and RASAL1) and the SYNGAP family (SYNGAP1, DAB2IP, RASAL2 and RASAL3). |
| GO:0005096 GTPase activator activity | TAS PMID:8812506 cDNA cloning and chromosomal mapping of a novel human GAP (G... | ACCEPT | Summary: Original cloning paper for human GAP1M/RASA2 establishing it as a novel Ras GTPase-activating protein distinct from p120GAP and NF1. Reason: Core enzymatic function established in the original characterization of human RASA2. The paper identifies GAP1M as a novel Ras GAP. Supporting Evidence: PMID:8812506 We have previously isolated a novel Ras GTPase-activating protein (Ras GAP), Gap1m, from rat brain. |
| GO:0007165 signal transduction | TAS PMID:8699317 [Heterogeneity of GTPase-activating proteins for Ras in the ... | ACCEPT | Summary: Review paper describing the heterogeneity of Ras GAPs and their roles in regulating Ras signal transduction, including Gap1m (RASA2). Reason: RASA2 participates in signal transduction by negatively regulating the Ras signaling pathway. This is a general but accurate process annotation. Supporting Evidence: PMID:8699317 The proto-oncogene ras is an essential gene for the growth and the differentiation for various types of cells. Ras, ras gene product, is a GTP binding protein which controls the signal transduction by GTP hydrolysis. |
| GO:0007165 signal transduction | TAS PMID:8812506 cDNA cloning and chromosomal mapping of a novel human GAP (G... | ACCEPT | Summary: Duplicate signal transduction annotation based on the original cloning paper. Reason: Valid annotation. RASA2 functions in signal transduction as a negative regulator of the Ras pathway. Supporting Evidence: PMID:8812506 Gap1m is considered to be a negative regulator of the Ras signaling pathways, like other Ras GAPs, neurofibromin, which is a gene product of the neurofibromatosis type I gene, and p120GAP. |
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