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Research report: Human RASA4 (CAPRI) – calcium-regulated Ras GTPase-activating protein (UniProt O43374)
Verification of identity and domain architecture
- Identity: The human gene RASA4 encodes the Ras GTPase-activating protein commonly known as CAPRI (calcium‑promoted Ras inactivator), matching the provided UniProt O43374 entry and synonyms. Reviews of RasGAP families explicitly list CAPRI as RASA4 and as a calcium-regulated Ras inhibitor (CAPRI/RASA4) (king2013nonredundantfunctionsfor pages 1-2, grewal2006molecularmechanismsinvolved pages 2-4). URL: https://doi.org/10.1126/scisignal.2003669 (2013-02) (king2013nonredundantfunctionsfor pages 1-2); https://doi.org/10.1002/bies.20503 (2006-12) (grewal2006molecularmechanismsinvolved pages 2-4)
- Domains and family: RASA4 belongs to the GAP1 family of RasGAPs and is a modular protein with N‑terminal C2 domains, a PH domain, and a C‑terminal catalytic RasGAP domain. C2 domains mediate calcium-dependent membrane association; PH domains support lipid binding and recruitment (notably PI(3,4,5)P3); the catalytic RasGAP module accelerates GTP hydrolysis on Ras by transition‑state stabilization (scheffzek2019rasspecificgtpaseactivatingproteinsstructures pages 1-3, grewal2006molecularmechanismsinvolved pages 2-4, king2013nonredundantfunctionsfor pages 1-2). URLs: https://doi.org/10.1101/cshperspect.a031500 (2019-08) (scheffzek2019rasspecificgtpaseactivatingproteinsstructures pages 1-3); https://doi.org/10.1002/bies.20503 (2006-12) (grewal2006molecularmechanismsinvolved pages 2-4); https://doi.org/10.1126/scisignal.2003669 (2013-02) (king2013nonredundantfunctionsfor pages 1-2)
| Feature | Summary | Evidence |
|---|---|---|
| Identity / Synonyms | RASA4 (CAPRI); UniProt O43374; "Calcium-promoted Ras inactivator" | (king2013nonredundantfunctionsfor pages 1-2, grewal2006molecularmechanismsinvolved pages 2-4) |
| Domain architecture | C2 – C2 – PH – RasGAP catalytic domain; C2 domains mediate Ca2+-dependent membrane binding; PH domain binds PIP3 and aids recruitment | (scheffzek2019rasspecificgtpaseactivatingproteinsstructures pages 1-3, xu2020rasinhibitorcapri pages 6-10, grewal2006molecularmechanismsinvolved pages 2-4) |
| Regulatory inputs | Activated/translocated by intracellular Ca2+ rises and PIP3 (GPCR/chemoattractant signals); translocation can be GPCR/Gi-dependent | (xu2020rasinhibitorcapri pages 6-10, xu2022rasinhibitorsgate pages 10-12, xu2022rasinhibitorsgate pages 14-14) |
| Catalytic function | Ras GTPase-activating protein — accelerates Ras GTP hydrolysis; dual GAP activity toward Rap reported in family-members/in vitro assays | (scheffzek2019rasspecificgtpaseactivatingproteinsstructures pages 1-3, king2013nonredundantfunctionsfor pages 1-2) |
| Primary targets | General Ras family (association with N‑Ras reported); possible activity toward Rap1 documented in literature | (xu2020rasinhibitorcapri pages 6-10, king2013nonredundantfunctionsfor pages 1-2) |
| Subcellular localization dynamics | Cytosolic at rest → rapid translocation to plasma membrane / leading edge upon Ca2+ or chemoattractant; colocalizes with active Ras and F-actin | (xu2020rasinhibitorcapri pages 6-10, grewal2006molecularmechanismsinvolved pages 2-4, xu2022rasinhibitorsgate pages 14-14) |
| Key cell types / contexts | Neutrophils and HL60 (chemotaxis studies); T cells (stimulus-dependent recruitment, e.g., CD28), macrophages (phagocytosis phenotypes reported) | (xu2020rasinhibitorcapri pages 6-10, king2013nonredundantfunctionsfor pages 2-3, xu2022rasinhibitorsgate pages 14-14) |
| Pathway roles | Gates GPCR-mediated chemotaxis adaptation; restrains Ras–MAPK/ERK signaling; limits PI3K–AKT–GSK3–cofilin signaling to control actin dynamics and cell sensitivity | (xu2022rasinhibitorsgate pages 10-12, xu2020rasinhibitorcapri pages 6-10, grewal2006molecularmechanismsinvolved pages 2-4) |
| Knockdown / loss phenotypes | Elevated basal active Ras; nonadaptive (prolonged) Ras activation after stimulation; increased PIP3 and sustained AKT phosphorylation; excessive actin polymerization; altered chemotaxis (↑sensitivity at low chemoattractant, impaired migration at high) | (xu2020rasinhibitorcapri pages 6-10, xu2022rasinhibitorsgate pages 10-12, xu2022rasinhibitorsgate pages 14-14) |
| Selected quantitative / mechanistic notes | CAPRI loss in HL60/neutrophils → sustained AKT (T308/T473) phosphorylation and persistent PIP3 accumulation; membrane targeting requires both C2 and PH domains | (xu2020rasinhibitorcapri pages 6-10, xu2022rasinhibitorsgate pages 10-12) |
| Evidence summary | Consensus from structural/mechanistic reviews and cell-based studies: RASA4 is a Ca2+-regulated, membrane-recruited RasGAP that modulates Ras/PI3K/AKT and chemotactic adaptation in immune cells | (scheffzek2019rasspecificgtpaseactivatingproteinsstructures pages 1-3, xu2020rasinhibitorcapri pages 6-10, king2013nonredundantfunctionsfor pages 1-2) |
Table: Compact, evidence-linked summary of human RASA4/CAPRI covering identity, domains, regulation, catalytic activity, localization, key cell contexts, pathway roles, and knockdown phenotypes; useful as a quick reference with direct citations to the gathered evidence (pqac IDs).
Key concepts and definitions
- Primary biochemical function: RASA4 is a Ras-specific GAP that accelerates hydrolysis of GTP bound to Ras, thereby inactivating Ras signaling. The GAP mechanism involves stabilization of the GTP hydrolysis transition state by the conserved helical RasGAP catalytic domain (scheffzek2019rasspecificgtpaseactivatingproteinsstructures pages 1-3). URL: https://doi.org/10.1101/cshperspect.a031500 (2019-08) (scheffzek2019rasspecificgtpaseactivatingproteinsstructures pages 1-3)
- Regulation by Ca2+ and lipids: RASA4 is a calcium-regulated RasGAP. Elevations in intracellular Ca2+ prompt C2‑domain–dependent membrane translocation; PH domain interactions with PIP3 further facilitate membrane targeting. Membrane localization both brings RASA4 to Ras at the plasma membrane and is required for catalytic activation of the GAP domain (grewal2006molecularmechanismsinvolved pages 2-4, king2013nonredundantfunctionsfor pages 1-2, xu2022rasinhibitorsgate pages 10-12, xu2020rasinhibitorcapri pages 6-10). URLs: https://doi.org/10.1002/bies.20503 (2006-12) (grewal2006molecularmechanismsinvolved pages 2-4); https://doi.org/10.1126/scisignal.2003669 (2013-02) (king2013nonredundantfunctionsfor pages 1-2); https://doi.org/10.3389/fimmu.2022.1020117 (2022-10-18) (xu2022rasinhibitorsgate pages 10-12); https://doi.org/10.1101/2020.04.23.058131 (2020-04-24) (xu2020rasinhibitorcapri pages 6-10)
- Substrate specificity: RASA4 acts on Ras isoforms; direct association with N‑Ras was observed in chemoattractant‑stimulated neutrophil‑like cells. Some GAP1 family members (including RASA4) can show in vitro activity toward Rap1, although the primary physiological role of RASA4 is as a RasGAP in the contexts studied (xu2020rasinhibitorcapri pages 6-10, king2013nonredundantfunctionsfor pages 1-2). URLs: https://doi.org/10.1101/2020.04.23.058131 (2020-04-24) (xu2020rasinhibitorcapri pages 6-10); https://doi.org/10.1126/scisignal.2003669 (2013-02) (king2013nonredundantfunctionsfor pages 1-2)
Recent developments and latest research (emphasis 2022–2024)
- Chemotaxis adaptation gatekeeper in immune cells: A 2022 review synthesizes that CAPRI (RASA4) in human neutrophils controls GPCR‑mediated Ras adaptation and cell sensitivity; CAPRI is highly expressed in HL60 and human neutrophils, translocates to the leading edge in response to chemoattractants, and its recruitment depends on Ca2+ and PIP3 but not on GAP catalytic activity. CAPRI loss causes elevated basal Ras, nonadaptive Ras/Rap1 activation, excessive actin polymerization, and shifts chemotaxis to lower‑concentration ranges (xu2022rasinhibitorsgate pages 10-12). URL: https://doi.org/10.3389/fimmu.2022.1020117 (2022-10-18) (xu2022rasinhibitorsgate pages 10-12)
- Mechanistic details from cell studies consistent with the above: CAPRI translocation is GPCR/Gi dependent; ΔC2 and ΔPH mutants are defective in membrane targeting; loss of CAPRI sustains PI3K activity (PIP3 accumulation), leads to persistent AKT phosphorylation (T308/T473) and cofilin changes. CAPRI associates with N‑Ras and colocalizes with active Ras and F‑actin at the leading edge (xu2020rasinhibitorcapri pages 6-10). URL: https://doi.org/10.1101/2020.04.23.058131 (2020-04-24) (xu2020rasinhibitorcapri pages 6-10)
Cellular and subcellular localization
- Localization dynamics: RASA4 is largely cytosolic at rest and translocates to the plasma membrane/leading edge upon calcium influx or GPCR stimulation. 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 (grewal2006molecularmechanismsinvolved pages 2-4, king2013nonredundantfunctionsfor pages 1-2, xu2020rasinhibitorcapri pages 6-10, xu2022rasinhibitorsgate pages 10-12). URLs: https://doi.org/10.1002/bies.20503 (2006-12) (grewal2006molecularmechanismsinvolved pages 2-4); https://doi.org/10.1126/scisignal.2003669 (2013-02) (king2013nonredundantfunctionsfor pages 1-2); https://doi.org/10.1101/2020.04.23.058131 (2020-04-24) (xu2020rasinhibitorcapri pages 6-10); https://doi.org/10.3389/fimmu.2022.1020117 (2022-10-18) (xu2022rasinhibitorsgate pages 10-12)
Pathways and precise roles
- Ras–MAPK/ERK: By inactivating Ras at the plasma membrane, RASA4 limits MAPK/ERK pathway activation following receptor stimulation. Early work and reviews place CAPRI as a Ca2+-dependent attenuator of the Ras–MAPK cascade (grewal2006molecularmechanismsinvolved pages 2-4). URL: https://doi.org/10.1002/bies.20503 (2006-12) (grewal2006molecularmechanismsinvolved pages 2-4)
- GPCR chemotaxis and PI3K–AKT–GSK3: In neutrophil-like cells, CAPRI restrains Ras-driven PI3K signaling, thereby modulating PIP3, AKT phosphorylation, GSK3 regulation, cofilin phosphorylation, actin polymerization, and adaptation to chemoattractant gradients (xu2020rasinhibitorcapri pages 6-10, xu2022rasinhibitorsgate pages 10-12). URLs: https://doi.org/10.1101/2020.04.23.058131 (2020-04-24) (xu2020rasinhibitorcapri pages 6-10); https://doi.org/10.3389/fimmu.2022.1020117 (2022-10-18) (xu2022rasinhibitorsgate pages 10-12)
Immune-cell contexts and applications
- Neutrophils/HL60: CAPRI is required for proper adaptation to high chemoattractant concentrations. Knockdown results: elevated basal Ras, prolonged Ras activation after stimulation, increased PIP3 and sustained AKT phosphorylation, excessive actin polymerization; chemotaxis impaired at high concentration but improved at low/subsensitive ranges, indicating CAPRI gates the usable concentration window for chemotaxis (xu2020rasinhibitorcapri pages 6-10, xu2022rasinhibitorsgate pages 10-12). URLs: https://doi.org/10.1101/2020.04.23.058131 (2020-04-24) (xu2020rasinhibitorcapri pages 6-10); https://doi.org/10.3389/fimmu.2022.1020117 (2022-10-18) (xu2022rasinhibitorsgate pages 10-12)
- T cells and lymphoid expression: RASA4 is enriched in lymphoid organs (spleen, lymph nodes), and multiple RasGAPs co-exist in T cells. Stimulus-dependent recruitment to the plasma membrane has been described (e.g., CD28-dependent), supporting a role in tuning Ras/ERK during T‑cell activation and adhesion; RASA4 is discussed alongside RASA2/3 in T‑cell signaling frameworks (king2013nonredundantfunctionsfor pages 2-3, xu2022rasinhibitorsgate pages 14-14). URLs: https://doi.org/10.1126/scisignal.2003669 (2013-02) (king2013nonredundantfunctionsfor pages 2-3); https://doi.org/10.3389/fimmu.2022.1020117 (2022-10-18) (xu2022rasinhibitorsgate pages 14-14)
- Mast cells: CAPRI shuttling to the plasma membrane in mast cells has been linked to regulation of activation in response to calcium‑mobilizing stimuli, consistent with its general Ca2+-dependent inhibitory action on Ras–MAPK (grewal2006molecularmechanismsinvolved pages 2-4). URL: https://doi.org/10.1002/bies.20503 (2006-12) (grewal2006molecularmechanismsinvolved pages 2-4)
Statistics and quantitative findings (from recent cell studies)
- In neutrophil-like HL60 cells lacking CAPRI, investigators report increased basal Ras activity and stronger, prolonged Ras responses after chemoattractant; signaling readouts include sustained phosphorylation of AKT at T308/T473 and persistent PIP3 accumulation, consistent with failure of adaptation. These effects co-occur with excessive actin polymerization and altered chemotaxis performance across gradient ranges. While precise fold-changes vary by experiment, the qualitative direction and persistence of signaling changes are consistent across studies (xu2020rasinhibitorcapri pages 6-10, xu2022rasinhibitorsgate pages 10-12). URLs: https://doi.org/10.1101/2020.04.23.058131 (2020-04-24) (xu2020rasinhibitorcapri pages 6-10); https://doi.org/10.3389/fimmu.2022.1020117 (2022-10-18) (xu2022rasinhibitorsgate pages 10-12)
Expert opinions and authoritative reviews
- Family-level perspective: Authoritative reviews of RasGAP structures and mechanisms emphasize that accessory domains, including C2 and PH domains in GAP1-family members like RASA4, dictate subcellular targeting and regulatory control of catalytic activity, and that membrane recruitment is central to function. These reviews also note that some RasGAPs can affect Rap, but RASA4’s physiological role is best supported as a calcium-regulated RasGAP at membranes (scheffzek2019rasspecificgtpaseactivatingproteinsstructures pages 1-3, king2013nonredundantfunctionsfor pages 1-2). URLs: https://doi.org/10.1101/cshperspect.a031500 (2019-08) (scheffzek2019rasspecificgtpaseactivatingproteinsstructures pages 1-3); https://doi.org/10.1126/scisignal.2003669 (2013-02) (king2013nonredundantfunctionsfor pages 1-2)
Disease and translational context
- Cancer and disease associations: At the level of principle, loss of function or downregulation of RasGAPs can contribute to aberrant Ras signaling in cancers; reviews place CAPRI/RASA4 within the cytoplasmic GAPs that modulate oncogenic cascades. However, compared with NF1 or RASA1, specific recurrent genetic alterations in RASA4 in human tumors are less well documented, and recent targeted 2023–2024 reports are limited in the present evidence set (scheffzek2019rasspecificgtpaseactivatingproteinsstructures pages 1-3). URL: https://doi.org/10.1101/cshperspect.a031500 (2019-08) (scheffzek2019rasspecificgtpaseactivatingproteinsstructures pages 1-3)
Notes on gene symbol ambiguity and paralogs
- The human genome encodes a close paralog, RASA4B, which appears in some databases. The present report is restricted to RASA4 (UniProt O43374) and does not conflate with RASA4B. Evidence summarized above explicitly refers to CAPRI/RASA4 in human immune cells and to the GAP1 family mechanisms (king2013nonredundantfunctionsfor pages 1-2). URL: https://doi.org/10.1126/scisignal.2003669 (2013-02) (king2013nonredundantfunctionsfor pages 1-2)
Conclusions
- RASA4 (CAPRI) is a calcium-regulated, membrane-recruited RasGAP that inactivates Ras at the plasma membrane to tune receptor-driven signaling. Its C2 and PH domains coordinate Ca2+ and phosphoinositide inputs to control translocation and catalytic activation, and in immune cells it functions as a gatekeeper of GPCR-mediated Ras adaptation, thereby governing PI3K–AKT signaling, actin dynamics, and chemotactic range. Recent work (2022) consolidates RASA4’s role in neutrophil chemotaxis and signaling adaptation; additional cell-type–specific roles in T cells and mast cells are consistent with its regulatory logic and membrane recruitment mechanisms (xu2022rasinhibitorsgate pages 10-12, xu2020rasinhibitorcapri pages 6-10, grewal2006molecularmechanismsinvolved pages 2-4, king2013nonredundantfunctionsfor pages 1-2, scheffzek2019rasspecificgtpaseactivatingproteinsstructures pages 1-3). URLs: https://doi.org/10.3389/fimmu.2022.1020117 (2022-10-18) (xu2022rasinhibitorsgate pages 10-12); https://doi.org/10.1101/2020.04.23.058131 (2020-04-24) (xu2020rasinhibitorcapri pages 6-10); https://doi.org/10.1002/bies.20503 (2006-12) (grewal2006molecularmechanismsinvolved pages 2-4); https://doi.org/10.1126/scisignal.2003669 (2013-02) (king2013nonredundantfunctionsfor pages 1-2); https://doi.org/10.1101/cshperspect.a031500 (2019-08) (scheffzek2019rasspecificgtpaseactivatingproteinsstructures pages 1-3)
References
(king2013nonredundantfunctionsfor pages 1-2): Philip D. King, Beth A. Lubeck, and Philip E. Lapinski. Nonredundant functions for ras gtpase-activating proteins in tissue homeostasis. Science Signaling, 6:re1-re1, Feb 2013. URL: https://doi.org/10.1126/scisignal.2003669, doi:10.1126/scisignal.2003669. This article has 94 citations and is from a domain leading peer-reviewed journal.
(grewal2006molecularmechanismsinvolved pages 2-4): Thomas Grewal and Carlos Enrich. Molecular mechanisms involved in ras inactivation: the annexin a6–p120gap complex. BioEssays, 28:1211-1220, Dec 2006. URL: https://doi.org/10.1002/bies.20503, doi:10.1002/bies.20503. This article has 74 citations and is from a peer-reviewed journal.
(scheffzek2019rasspecificgtpaseactivatingproteinsstructures pages 1-3): Klaus Scheffzek and Giridhar Shivalingaiah. Ras-specific gtpase-activating proteins-structures, mechanisms, and interactions. Cold Spring Harbor perspectives in medicine, 9 3:a031500, Aug 2019. URL: https://doi.org/10.1101/cshperspect.a031500, doi:10.1101/cshperspect.a031500. This article has 104 citations and is from a peer-reviewed journal.
(xu2020rasinhibitorcapri pages 6-10): Xuehua Xu, Xi Wen, Amer Moosa, Smit Bhimani, and Tian Jin. Ras inhibitor capri enables neutrophils to chemotax through a higher-concentration range of gradients. bioRxiv, Apr 2020. URL: https://doi.org/10.1101/2020.04.23.058131, doi:10.1101/2020.04.23.058131. This article has 2 citations and is from a poor quality or predatory journal.
(xu2022rasinhibitorsgate pages 10-12): Xuehua Xu and Tian Jin. Ras inhibitors gate chemoattractant concentration range for chemotaxis through controlling gpcr-mediated adaptation and cell sensitivity. Frontiers in Immunology, Oct 2022. URL: https://doi.org/10.3389/fimmu.2022.1020117, doi:10.3389/fimmu.2022.1020117. This article has 3 citations and is from a peer-reviewed journal.
(xu2022rasinhibitorsgate pages 14-14): Xuehua Xu and Tian Jin. Ras inhibitors gate chemoattractant concentration range for chemotaxis through controlling gpcr-mediated adaptation and cell sensitivity. Frontiers in Immunology, Oct 2022. URL: https://doi.org/10.3389/fimmu.2022.1020117, doi:10.3389/fimmu.2022.1020117. This article has 3 citations and is from a peer-reviewed journal.
(king2013nonredundantfunctionsfor pages 2-3): Philip D. King, Beth A. Lubeck, and Philip E. Lapinski. Nonredundant functions for ras gtpase-activating proteins in tissue homeostasis. Science Signaling, 6:re1-re1, Feb 2013. URL: https://doi.org/10.1126/scisignal.2003669, doi:10.1126/scisignal.2003669. This article has 94 citations and is from a domain leading peer-reviewed journal.