RAS p21 protein activator 4 (CAPRI - Calcium-Promoted Ras Inactivator), calcium-regulated GTPase-activating protein for RAS and RAP1 small GTPases. Member of GAP1 family with two tandem C2 domains (Ca2+ and phospholipid binding), central GAP-related domain (GRD) for catalytic activity, and C-terminal pleckstrin homology (PH) domain with Bruton's tyrosine kinase (Btk) motif. Unique calcium sensor that links intracellular Ca2+ signals to Ras inactivation. Cytosolic protein at rest that rapidly translocates to inner plasma membrane upon Ca2+ elevation via C2 domain binding to anionic phospholipids (phosphatidylserine). PH domain atypical - does not bind phosphoinositides due to LeuβArg substitution. Dual substrate specificity: catalyzes GTP hydrolysis on Ras family GTPases (H-Ras, N-Ras, K-Ras) and Rap1 via arginine-finger mechanism. Oligomerization state regulates substrate preference - monomeric form predominantly RasGAP, while Ca2+-induced homodimers exhibit enhanced Rap1GAP activity. Functions as negative regulator of Ras-MAPK and Rap1-integrin signaling pathways. Critical for immune cell function: in neutrophils, enables chemotaxis through high-concentration gradients by mediating GPCR-induced Ras adaptation - loss causes hyperactive Ras-GTP, excessive F-actin polymerization, and defective directional migration. In macrophages, essential for FcΞ³ receptor-mediated phagocytosis - CAPRI acts as adaptor linking FcΞ³R calcium signals to coordinated regulation of Ras (inactivation) and Cdc42/Rac1 (activation) for phagosome formation. CAPRI-knockout mice show ~80% lethality to Salmonella infection due to impaired bacterial clearance. Tumor suppressor-like function - loss leads to prolonged Ras-MAPK signaling. Downregulated in cervical cancer (~AUC 0.986 diagnostic value); forced expression suppresses proliferation by inactivating HIF-1Ξ±/survivin pathway. Somatic mutations (e.g. D111N in DLBCL) associated with enhanced ERK/MAPK activation and cancer progression. Broadly expressed with high levels in immune organs (spleen, lymph nodes). Acts as amplitude sensor for Ca2+ bursts, translating calcium signal intensity into proportional Ras inactivation. Provides negative feedback loop preventing overactivation of growth and immune signaling pathways.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005096 GTPase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: RASA4/CAPRI is a Ras GTPase-activating protein that accelerates GTP hydrolysis on Ras family GTPases. Phylogenetic analysis supports conservation of this core enzymatic function across species (PMID:11448776). Reason: Core enzymatic function well established through experimental evidence and phylogenetic conservation. CAPRI catalyzes Ras-GTP hydrolysis, serving as a critical negative regulator of Ras signaling. Supporting Evidence: PMID:11448776 Here, we describe the identification of CAPRI (Ca(2+)-promoted Ras inactivator), a Ca(2+)-dependent Ras GTPase-activating protein (GAP) that switches off the Ras-MAPK pathway following a stimulus that elevates intracellular Ca(2+). |
| GO:1902531 regulation of intracellular signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: RASA4/CAPRI regulates intracellular signal transduction by controlling Ras-MAPK pathway activity in response to calcium signals (PMID:11448776, PMID:16009725). Reason: Core regulatory function. CAPRI integrates calcium signals with Ras signaling, functioning as a key modulator of intracellular signal transduction pathways. Supporting Evidence: PMID:11448776 CAPRI regulates Ca(2+)-dependent inactivation of the Ras-MAPK pathway. PMID:16009725 CAPRI seems to low-pass filter the Ca2+ signal, converting different intensities of stimulation into different durations of Ras activity in contrast to the preservation of Ca2+ frequency information by RASAL, suggesting sophisticated modes of Ca2+-regulated Ras deactivation. |
| GO:0005096 GTPase activator activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation based on RasGAP domain presence. Consistent with experimental evidence demonstrating CAPRI GAP activity (PMID:11448776, PMID:16009725). Reason: Correct automated annotation. The RasGAP domain (residues 318-546) confers GTPase activator activity, which has been experimentally validated. Supporting Evidence: file:human/RASA4/RASA4-uniprot.txt FT DOMAIN 318..546 /note="Ras-GAP" |
| GO:0005543 phospholipid binding | IEA GO_REF:0000002 | ACCEPT | Summary: RASA4 contains two C2 domains (C2A and C2B) that bind phospholipids in a calcium-dependent manner, mediating membrane translocation (PMID:11448776, PMID:16009725). Reason: Critical for CAPRI function. C2 domains mediate Ca2+-dependent phospholipid binding required for membrane translocation and activation. Supporting Evidence: PMID:11448776 Analysis of the spatio-temporal dynamics of CAPRI indicates that Ca(2+) regulates the GAP by a fast C2 domain-dependent translocation mechanism. file:human/RASA4/RASA4-deep-research-falcon.md C2 domains sense Ca2+ and bind phospholipids; PH domain binding to PIP3 further promotes recruitment. Membrane association is necessary for GAP activity and for interaction with Ras. |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: RASA4 is localized to the cytosol at resting calcium levels, consistent with UniProt subcellular location annotation and experimental evidence (PMID:16009725). Reason: Core resting localization confirmed by imaging studies. Supporting Evidence: file:human/RASA4/RASA4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol. Localized to the cytosol as a result of its lack of phosphoinositide binding activity. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: RASA4/CAPRI translocates to the plasma membrane upon calcium elevation, where it inactivates Ras. This is a dynamic, activity-dependent localization (PMID:16009725). Reason: Activity-dependent localization essential for GAP function. CAPRI must translocate to the plasma membrane to access and inactivate membrane-associated Ras. Supporting Evidence: file:human/RASA4/RASA4-deep-research-falcon.md RASA4 is largely cytosolic at rest and translocates to the plasma membrane/leading edge upon calcium influx or GPCR stimulation. file:human/RASA4/RASA4-uniprot.txt Upon agonist-stimulated calcium mobilization, utilizes the C2A and C2B domains to associate with the plasma membrane. |
| GO:0008270 zinc ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: RASA4 contains a Btk-type zinc finger motif (residues 675-711) that coordinates zinc ions, as annotated based on UniProt keyword mapping. Reason: Domain-based annotation. The Btk zinc finger motif is a conserved structural element present in GAP1 family members. Supporting Evidence: file:human/RASA4/RASA4-uniprot.txt FT ZN_FING 675..711 /note="Btk-type" |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: RASA4 participates in intracellular signal transduction by regulating Ras-MAPK signaling. This is a broader term encompassing its negative regulatory role (PMID:11448776). Reason: Accurate annotation. CAPRI functions in intracellular signal transduction by modulating Ras activity downstream of calcium signals. Supporting Evidence: PMID:11448776 CAPRI regulates Ca(2+)-dependent inactivation of the Ras-MAPK pathway. |
| GO:0046580 negative regulation of Ras protein signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: RASA4/CAPRI is a negative regulator of Ras signaling. By accelerating Ras-GTP hydrolysis, it switches off the Ras-MAPK pathway (PMID:11448776, PMID:12845332). Reason: Core function. This is the primary biological role of CAPRI - to negatively regulate Ras signaling in response to calcium signals. Supporting Evidence: PMID:11448776 a Ca(2+)-dependent Ras GTPase-activating protein (GAP) that switches off the Ras-MAPK pathway following a stimulus that elevates intracellular Ca(2+). PMID:12845332 Ca(2+) positively regulated Ras on the Golgi apparatus through RasGRP1, the same second messenger negatively regulated Ras on the plasma membrane by means of the Ras GTPase-activating protein CAPRI. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: RASA4 binds calcium ions through its C2 domains and zinc through its Btk-type zinc finger. This is a parent term covering both binding activities. Reason: Accurate parent term covering calcium and zinc binding capabilities essential for CAPRI function and structure. Supporting Evidence: file:human/RASA4/RASA4-uniprot.txt Binds 3 Ca(2+) ions per C2 domain. |
| GO:0071277 cellular response to calcium ion | IEA GO_REF:0000002 | ACCEPT | Summary: RASA4/CAPRI is a calcium sensor that responds to intracellular calcium elevation by translocating to the plasma membrane and activating its GAP function (PMID:11448776, PMID:16009725). Reason: Core regulatory mechanism. CAPRI is defined by its calcium-dependent activation and translocation, making this annotation central to its identity. Supporting Evidence: file:human/RASA4/RASA4-deep-research-falcon.md RASA4 (CAPRI) is a calcium-regulated, membrane-recruited RasGAP that inactivates Ras at the plasma membrane to tune receptor-driven signaling. PMID:16009725 CAPRI is a novel low-pass filter for Ca2+, dependent on predominantly Ca2+-independent interactions between the plasma membrane and the PH domain after receptor activation. |
| GO:0005096 GTPase activator activity | IDA PMID:16009725 CAPRI and RASAL impose different modes of information proces... | ACCEPT | Summary: Direct experimental evidence for CAPRI GTPase activator activity demonstrated using live-cell imaging of Ras-GTP levels with GFP-RBD reporter assays (PMID:16009725). Reason: Strong direct evidence. Real-time imaging showed CAPRI translocation correlates with Ras-GTP deactivation at the plasma membrane. Supporting Evidence: PMID:16009725 The experiments confirmed that CAPRI has little basal GAP activity in resting cells and is acutely regulated by Ca2+ mobilization. The assays also showed that CAPRI specifically deactivates Ras at the plasma membrane. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5658231 | ACCEPT | Summary: Reactome pathway annotation places RASA4 in the cytosol as part of the RAS GAP regulatory pathway, consistent with its resting localization. Reason: Consistent with experimental evidence showing cytosolic localization at rest. Supporting Evidence: PMID:16009725 CAPRI has no detectable GAP activity at resting Ca2+, suggesting it exists in a closed conformation in the cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5658435 | ACCEPT | Summary: Reactome pathway annotation for RAS GAP binding to RAS:GTP places RASA4 in the cytosol prior to membrane translocation. Reason: Consistent with experimental evidence showing cytosolic resting localization. Supporting Evidence: PMID:16009725 CAPRI has no detectable GAP activity at resting Ca2+, suggesting it exists in a closed conformation in the cytosol. |
| GO:0005829 cytosol | IDA PMID:16009725 CAPRI and RASAL impose different modes of information proces... | ACCEPT | Summary: Direct imaging evidence shows GFP-CAPRI localized to cytosol at rest, with translocation to plasma membrane upon calcium elevation (PMID:16009725). Reason: Strong direct evidence from live-cell imaging studies. Supporting Evidence: PMID:16009725 CAPRI has no detectable GAP activity at resting Ca2+, suggesting it exists in a closed conformation in the cytosol. We believe that conformational changes must occur to facilitate the activation of Ras GAP function upon translocation. |
| GO:0005886 plasma membrane | IDA PMID:16009725 CAPRI and RASAL impose different modes of information proces... | ACCEPT | Summary: Direct imaging evidence demonstrates GFP-CAPRI translocation to plasma membrane upon agonist stimulation, with sustained association at the membrane (PMID:16009725). Reason: Strong direct evidence from TIRFM and confocal imaging studies showing activity-dependent membrane localization. Supporting Evidence: PMID:16009725 This demonstrated long-term association of GFP-CAPRI with the plasma membrane at supra-maximal doses of agonist (Fig. 1, A and B). file:human/RASA4/RASA4-deep-research-falcon.md RASA4 is largely cytosolic at rest and translocates to the plasma membrane/leading edge upon calcium influx or GPCR stimulation. |
| GO:0071277 cellular response to calcium ion | IMP PMID:16009725 CAPRI and RASAL impose different modes of information proces... | ACCEPT | Summary: Mutant phenotype analysis shows CAPRI translocation and GAP activity depend on calcium signaling. C2 domain mutations abolish calcium-dependent membrane translocation (PMID:16009725). Reason: Strong mutant phenotype evidence. Domain deletion and mutation studies confirm calcium-dependent regulation of CAPRI function. Supporting Evidence: file:human/RASA4/RASA4-deep-research-falcon.md Elevations in intracellular Ca2+ prompt C2-domain-dependent membrane translocation; PH domain interactions with PIP3 further facilitate membrane targeting. PMID:16009725 The GRD/PH/Btk domains of CAPRI are required to mediate the novel properties of the protein as a Ca2+ sensor, with the PH domain being critical. |
| GO:0034260 negative regulation of GTPase activity | IMP PMID:11448776 CAPRI regulates Ca(2+)-dependent inactivation of the Ras-MAP... | ACCEPT | Summary: Mutant phenotype evidence shows CAPRI expression leads to calcium-dependent reduction in Ras-GTP levels, demonstrating negative regulation of Ras GTPase cycle (PMID:11448776). Reason: Core GAP function. CAPRI stimulates GTP hydrolysis, effectively negatively regulating the GTPase by converting active Ras-GTP to inactive Ras-GDP. Supporting Evidence: PMID:11448776 a Ca(2+)-dependent Ras GTPase-activating protein (GAP) that switches off the Ras-MAPK pathway following a stimulus that elevates intracellular Ca(2+). |
| GO:0034260 negative regulation of GTPase activity | IDA PMID:12845332 Phospholipase Cgamma activates Ras on the Golgi apparatus by... | ACCEPT | Summary: Direct assay evidence shows CAPRI negatively regulates Ras at the plasma membrane in response to calcium, while RasGRP1 activates Ras on Golgi (PMID:12845332). Reason: Direct evidence from compartmentalized Ras signaling studies showing CAPRI-mediated negative regulation at plasma membrane. Supporting Evidence: PMID:12845332 Ca(2+) positively regulated Ras on the Golgi apparatus through RasGRP1, the same second messenger negatively regulated Ras on the plasma membrane by means of the Ras GTPase-activating protein CAPRI. |
| GO:0005096 GTPase activator activity | IDA PMID:11448776 CAPRI regulates Ca(2+)-dependent inactivation of the Ras-MAP... | ACCEPT | Summary: Original identification of CAPRI as a calcium-dependent Ras GTPase-activating protein through functional assays (PMID:11448776). Reason: Foundational evidence establishing CAPRI as a Ras GAP. Supporting Evidence: PMID:11448776 Here, we describe the identification of CAPRI (Ca(2+)-promoted Ras inactivator), a Ca(2+)-dependent Ras GTPase-activating protein (GAP) that switches off the Ras-MAPK pathway following a stimulus that elevates intracellular Ca(2+). |
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