{"gene":"RASA4","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2001,"finding":"CAPRI (RASA4) was identified as a Ca²⁺-dependent RasGAP that inactivates Ras following stimuli that elevate intracellular Ca²⁺. Ca²⁺ regulates CAPRI through a fast C2 domain-dependent translocation mechanism to the plasma membrane, where it switches off the Ras-MAPK pathway.","method":"Live-cell imaging of GFP-tagged CAPRI, real-time Ras activity assays, C2 domain mutational analysis","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 2 — original discovery with live imaging, domain mutagenesis, and real-time Ras activity readout in a single study; foundational paper","pmids":["11448776"],"is_preprint":false},{"year":2003,"finding":"CAPRI (RASA4) acts specifically at the plasma membrane to negatively regulate Ca²⁺-stimulated Ras activation, while RasGRP1 activates Ras at the Golgi apparatus in response to PLCγ1-generated DAG/Ca²⁺ signals. This establishes CAPRI as a spatially restricted negative regulator confining Ras-MAPK signaling to the Golgi in T cells.","method":"Fluorescence imaging of compartment-specific Ras biosensors in Jurkat T cells, overexpression and dominant-negative constructs, co-expression of CAPRI with RasGRP1","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches establishing spatial specificity of CAPRI action at plasma membrane vs Golgi; replicated in multiple cell types","pmids":["12845332"],"is_preprint":false},{"year":2005,"finding":"CAPRI (RASA4) acts as a low-pass Ca²⁺ filter: its C2 domain-dependent translocation to the plasma membrane is sustained and refractory to cytosolic Ca²⁺ oscillations, converting different intensities of Ca²⁺ stimulation into different durations of Ras activity. This requires integration of Ca²⁺ signals by C2 domains with agonist-evoked PH domain interactions at the plasma membrane. In contrast, the related protein RASAL tracks Ca²⁺ oscillations with repetitive membrane association, preserving frequency information.","method":"Real-time Ras activity assays correlated with live-cell CAPRI translocation imaging; domain swap/mutant analysis; Ca²⁺ manipulation experiments","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods correlating translocation dynamics with Ras deactivation; mechanistic domain analysis performed","pmids":["16009725"],"is_preprint":false},{"year":2006,"finding":"CAPRI (RASA4) translocates to the plasma membrane upon antigen stimulation (coinciding with elevated intracellular Ca²⁺) in mast cells (RBL cells), and overexpression of CAPRI suppresses antigen-induced degranulation, cytokine production, and ERK2 nuclear import. A GAP-related domain mutant (R472S) showed impaired membrane translocation and failed to suppress these responses, linking membrane localization to functional GAP activity in immune signaling.","method":"Overexpression and dominant mutant experiments in RBL mast cells; Ca²⁺ imaging; degranulation assay; ERK2 nuclear translocation imaging","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2/3 — single lab with functional readouts and mutant analysis, but single cell type","pmids":["16815298"],"is_preprint":false},{"year":2011,"finding":"CAPRI (RASA4) forms Ca²⁺-dependent homodimers both in vitro and in vivo. Dimerization requires a helix motif forming a hydrophobic face in the extreme C-terminal tail. Free Ca²⁺ at physiologically relevant concentrations is necessary and sufficient for dimer formation. Critically, monomeric CAPRI preferentially exhibits RasGAP activity, while dimeric CAPRI preferentially exhibits RapGAP activity, demonstrating that Ca²⁺-regulated dimerization switches CAPRI between dual GAP activities to coordinately regulate Ras and Rap1 signaling.","method":"In vitro dimerization assays, Co-IP from cells, deletion and point mutagenesis of C-terminal helix, in vivo RasGAP and RapGAP activity assays, Ca²⁺ titration experiments","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution of dimerization with mutagenesis, corroborated by in-cell Co-IP, and linked to differential enzymatic activity; multiple orthogonal methods in single study","pmids":["21460216"],"is_preprint":false},{"year":2001,"finding":"The PH domain of KIAA0538 (RASA4) lacks phosphoinositide binding activity due to an amino acid substitution at position 592 (Leu-592), unlike the related MRASAL whose PH domain binds PI(4,5)P₂ and PI(3,4,5)P₃. As a result, KIAA0538/RASA4 localizes to the cytosol rather than the plasma membrane under basal conditions, revealing that distinct phosphoinositide binding specificity of PH domains determines subcellular localization within the GAP1 family.","method":"Lipid-protein binding assays, site-directed mutagenesis of PH domain, subcellular fractionation and fluorescence microscopy in NIH3T3 cells","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — binding assays with mutagenesis and localization imaging, single lab","pmids":["11594756"],"is_preprint":false},{"year":2019,"finding":"TRPC3 channel-mediated Ca²⁺ influx sustains RASA4 localization at the plasma membrane of triple-negative breast cancer (MDA-MB-231) cells, where RASA4 inhibits the Ras-MAPK pathway. Blocking TRPC3 decreased plasma membrane-associated RASA4 and concomitantly activated MAPK pathways, establishing a TRPC3-RASA4-MAPK signaling cascade that promotes proliferation and apoptosis resistance.","method":"Subcellular fractionation and Western blot, immunocytochemistry, TRPC3 blocker (Pyr3) and dominant-negative TRPC3, proliferation and apoptosis assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2/3 — multiple complementary methods in a single lab establishing the signaling cascade; mechanistic link between Ca²⁺ influx and RASA4 membrane localization demonstrated","pmids":["31003514"],"is_preprint":false},{"year":2021,"finding":"CAPRI (RASA4) controls GPCR-stimulated Ras adaptation in human neutrophils. Neutrophils lacking CAPRI (capri⁻) show nonadaptive Ras activation in response to chemoattractants, with increased phosphorylation of AKT, GSK-3α/3β, and cofilin, and excessive actin polymerization. capri⁻ cells are defective in chemotaxis through high-concentration gradients but exhibit improved chemotaxis in low/subsensitive gradients due to enhanced sensitivity, demonstrating that CAPRI sets the sensitivity threshold for gradient sensing.","method":"CAPRI knockout in human neutrophil-like cells, real-time Ras activity biosensors, phosphoprotein analysis, chemotaxis assays across concentration gradients","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with multiple orthogonal mechanistic readouts (Ras activity, phosphoproteomics, functional chemotaxis); strong phenotypic evidence in human cells","pmids":["34675073"],"is_preprint":false},{"year":2021,"finding":"Treponema denticola interaction with human periodontal ligament (PDL) cells induces upregulation of RASA4 mRNA expression, leading to actin depolymerization and loss of cell adhesion, followed by increased MMP-2 activity. This effect is mediated by the T. denticola effector protein dentilisin, identifying a novel pathogen-triggered RASA4 transcriptional activation mechanism linked to actin cytoskeletal remodeling.","method":"Molecular cell assays including RASA4 mRNA quantification, actin dynamics imaging, MMP-2 activity assays, dentilisin mutant bacteria","journal":"Frontiers in Cellular and Infection Microbiology","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, mechanistic connection between RASA4 upregulation and cytoskeletal phenotype established but indirect; dentilisin specificity tested","pmids":["34094999"],"is_preprint":false},{"year":2014,"finding":"RASA4 isoform 2 (mapping to chromosome 7) undergoes recurrent, isoform-specific DNA hypermethylation in juvenile myelomonocytic leukemia (JMML), occurring in 51% of patients. Hypermethylation correlates with poor prognosis, PTPN11 mutation, and increased relapse risk after hematopoietic stem cell transplantation. Cases with monosomy 7 showed hypermethylation on the remaining RASA4 allele, suggesting epigenetic silencing as a two-hit mechanism.","method":"Quantitative high-resolution mass spectrometry-based methylation analysis in 125 JMML patients, correlation with clinical parameters","journal":"Epigenetics","confidence":"Medium","confidence_rationale":"Tier 3 — large clinical cohort establishing isoform-specific epigenetic silencing, but mechanistic downstream consequences not directly tested","pmids":["25147919"],"is_preprint":false}],"current_model":"RASA4 (CAPRI) is a Ca²⁺-dependent RasGAP of the GAP1 family that translocates to the plasma membrane via its C2 domains upon Ca²⁺ elevation to inactivate Ras and suppress the MAPK pathway; its PH domain lacks phosphoinositide binding (keeping it cytosolic at baseline), Ca²⁺-dependent homodimerization via a C-terminal hydrophobic helix switches its catalytic preference from RasGAP (monomer) to RapGAP (dimer), it functions as a low-pass Ca²⁺ filter to set the duration and sensitivity of Ras signaling, and it is regulated upstream by TRPC3-mediated Ca²⁺ influx in cancer cells and by GPCR-evoked Ca²⁺ in neutrophils where it controls Ras adaptation and chemotaxis range."},"narrative":{"teleology":[{"year":2001,"claim":"Discovery of RASA4 as a Ca²⁺-dependent RasGAP established the founding paradigm that calcium signals can directly terminate Ras-MAPK signaling through regulated membrane recruitment of a GAP.","evidence":"Live-cell GFP imaging, real-time Ras activity assays, and C2 domain mutagenesis in cultured cells; concurrent lipid-binding assays showing its PH domain lacks phosphoinositide binding","pmids":["11448776","11594756"],"confidence":"High","gaps":["No structural basis for C2 domain–membrane interaction resolved","Endogenous expression levels and tissue distribution not characterized","Role of PH domain during activated state unclear"]},{"year":2003,"claim":"Demonstration that RASA4 acts specifically at the plasma membrane to suppress Ras while RasGRP1 activates Ras at the Golgi resolved how opposing regulators spatially partition Ras signaling in T cells.","evidence":"Compartment-specific Ras biosensors, co-expression of CAPRI with RasGRP1 in Jurkat T cells","pmids":["12845332"],"confidence":"High","gaps":["Whether RASA4 accesses Ras pools at endomembranes under any condition not tested","Stoichiometry relative to RasGRP1 at endogenous levels unknown"]},{"year":2005,"claim":"Identification of RASA4 as a low-pass Ca²⁺ filter—remaining membrane-bound and refractory to Ca²⁺ oscillations—explained how cells decode Ca²⁺ signal intensity into Ras signaling duration, contrasting with the oscillation-tracking behavior of the related protein RASAL.","evidence":"Correlated real-time translocation imaging with Ras activity readouts; domain-swap and mutant analysis under controlled Ca²⁺ regimes","pmids":["16009725"],"confidence":"High","gaps":["Molecular determinants distinguishing sustained versus oscillatory membrane binding not mapped at residue level","In vivo physiological consequences of low-pass filtering not demonstrated"]},{"year":2006,"claim":"Extension of RASA4 function to immune effector cells showed that its GAP-dependent membrane translocation suppresses antigen-induced degranulation, cytokine production, and ERK nuclear import in mast cells.","evidence":"Overexpression and GAP-dead mutant (R472S) analysis in RBL mast cells with degranulation and ERK translocation assays","pmids":["16815298"],"confidence":"Medium","gaps":["Loss-of-function (knockout/knockdown) not performed in mast cells","Endogenous RASA4 contribution relative to other RasGAPs not determined"]},{"year":2011,"claim":"Discovery that Ca²⁺-dependent homodimerization via a C-terminal hydrophobic helix switches RASA4 from a RasGAP (monomer) to a RapGAP (dimer) revealed how a single protein coordinately regulates two GTPase families through an oligomerization-based activity switch.","evidence":"In vitro dimerization reconstitution, in-cell co-immunoprecipitation, C-terminal helix mutagenesis, and parallel RasGAP/RapGAP activity assays with Ca²⁺ titration","pmids":["21460216"],"confidence":"High","gaps":["No high-resolution structure of monomer or dimer","Physiological contexts favoring dimer versus monomer not mapped in vivo","Rap1 substrates and downstream consequences of RapGAP activity not characterized"]},{"year":2014,"claim":"Recurrent isoform-specific DNA hypermethylation of RASA4 in juvenile myelomonocytic leukemia, correlating with poor prognosis and acting as a potential two-hit event with monosomy 7, implicated epigenetic silencing of RASA4 in myeloid malignancy.","evidence":"Quantitative methylation mass spectrometry in a 125-patient JMML cohort with clinical correlation","pmids":["25147919"],"confidence":"Medium","gaps":["Functional consequence of RASA4 silencing on Ras signaling in JMML blasts not directly tested","Causal versus correlative role of methylation not established","Whether restoring RASA4 expression rescues the phenotype unknown"]},{"year":2019,"claim":"Identification of TRPC3-mediated Ca²⁺ influx as the upstream signal sustaining RASA4 membrane localization in triple-negative breast cancer cells connected ion channel activity to Ras-MAPK suppression via RASA4.","evidence":"Subcellular fractionation, TRPC3 pharmacological blockade and dominant-negative constructs, proliferation and apoptosis assays in MDA-MB-231 cells","pmids":["31003514"],"confidence":"Medium","gaps":["Direct physical interaction between TRPC3 and RASA4 not demonstrated","Generalizability beyond a single breast cancer cell line not tested"]},{"year":2021,"claim":"Genetic knockout of RASA4 in neutrophils demonstrated it is required for Ras adaptation to chemoattractant, establishing that RASA4 sets the sensitivity threshold for gradient sensing and defines the chemotaxis operating range.","evidence":"CAPRI knockout in human neutrophil-like cells, Ras biosensors, phosphoprotein profiling (AKT, GSK-3, cofilin), chemotaxis across concentration gradients","pmids":["34675073"],"confidence":"High","gaps":["In vivo immune cell migration phenotype not assessed","Whether other RasGAPs partially compensate in specific tissues unknown","Direct measurement of Rap1 activity (via dimeric RASA4) in neutrophils not reported"]},{"year":null,"claim":"No high-resolution structure of RASA4 exists, the in vivo balance between monomeric RasGAP and dimeric RapGAP activities remains uncharacterized across tissues, and whether epigenetic silencing of RASA4 is functionally causative in myeloid malignancy has not been directly tested.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of full-length RASA4 or its dimer","Tissue-specific ratio of monomer/dimer and its physiological regulation uncharacterized","Functional rescue experiments in JMML models needed to establish causality of RASA4 silencing"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,4,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,6,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,4,6,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,7]}],"complexes":[],"partners":["TRPC3"],"other_free_text":[]},"mechanistic_narrative":"RASA4 (CAPRI) is a Ca²⁺-responsive GTPase-activating protein of the GAP1 family that links intracellular calcium signaling to Ras/Rap1 inactivation at the plasma membrane. Upon Ca²⁺ elevation, its tandem C2 domains drive rapid translocation from the cytosol to the plasma membrane—where its PH domain, which lacks phosphoinositide binding at baseline, cooperates with agonist-dependent cues to sustain membrane retention—enabling RASA4 to function as a low-pass Ca²⁺ filter that converts signal intensity into Ras-MAPK signaling duration [PMID:11448776, PMID:16009725, PMID:11594756]. Ca²⁺-dependent homodimerization via a C-terminal hydrophobic helix switches RASA4 from a monomeric RasGAP to a dimeric RapGAP, coordinating the inactivation of both Ras and Rap1 [PMID:21460216]. In neutrophils, RASA4 mediates Ras adaptation to chemoattractant stimulation, setting the sensitivity threshold for gradient sensing and chemotaxis range [PMID:34675073], and in breast cancer cells its membrane localization is sustained by TRPC3-mediated Ca²⁺ influx to suppress MAPK-driven proliferation [PMID:31003514]."},"prefetch_data":{"uniprot":{"accession":"O43374","full_name":"Ras GTPase-activating protein 4","aliases":["Calcium-promoted Ras inactivator","Ras p21 protein activator 4","RasGAP-activating-like protein 2"],"length_aa":803,"mass_kda":90.5,"function":"Ca(2+)-dependent Ras GTPase-activating protein, that switches off the Ras-MAPK pathway following a stimulus that elevates intracellular calcium. Functions as an adaptor for Cdc42 and Rac1 during FcR-mediated phagocytosis","subcellular_location":"Cytoplasm, cytosol; Cell membrane","url":"https://www.uniprot.org/uniprotkb/O43374/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RASA4","classification":"Not Classified","n_dependent_lines":358,"n_total_lines":1046,"dependency_fraction":0.3422562141491396},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RASA4","total_profiled":1310},"omim":[{"mim_id":"607943","title":"RAS p21 PROTEIN ACTIVATOR 4; RASA4","url":"https://www.omim.org/entry/607943"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":223.0},{"tissue":"tongue","ntpm":76.1}],"url":"https://www.proteinatlas.org/search/RASA4"},"hgnc":{"alias_symbol":["KIAA0538","CAPRI","GAPL"],"prev_symbol":[]},"alphafold":{"accession":"O43374","domains":[{"cath_id":"2.60.40.150","chopping":"3-111_249-259","consensus_level":"high","plddt":91.3362,"start":3,"end":259},{"cath_id":"2.60.40.150","chopping":"120-241","consensus_level":"high","plddt":90.4788,"start":120,"end":241},{"cath_id":"1.10.506.10","chopping":"321-397_404-561","consensus_level":"high","plddt":88.7724,"start":321,"end":561},{"cath_id":"2.30.29.30","chopping":"568-716","consensus_level":"high","plddt":86.9584,"start":568,"end":716}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43374","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43374-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43374-F1-predicted_aligned_error_v6.png","plddt_mean":85.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RASA4","jax_strain_url":"https://www.jax.org/strain/search?query=RASA4"},"sequence":{"accession":"O43374","fasta_url":"https://rest.uniprot.org/uniprotkb/O43374.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43374/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43374"}},"corpus_meta":[{"pmid":"12784359","id":"PMC_12784359","title":"CAPRI: 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The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.","date":"1998","source":"DNA research : an international journal for rapid publication of reports on genes and genomes","url":"https://pubmed.ncbi.nlm.nih.gov/9628581","citation_count":156,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25921289","id":"PMC_25921289","title":"Temporal proteomics of NGF-TrkA signaling identifies an inhibitory role for the E3 ligase Cbl-b in neuroblastoma cell differentiation.","date":"2015","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/25921289","citation_count":61,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18320585","id":"PMC_18320585","title":"Identification of proteins interacting with protein arginine methyltransferase 8: the Ewing sarcoma (EWS) protein binds independent of its methylation state.","date":"2008","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/18320585","citation_count":42,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30655611","id":"PMC_30655611","title":"WDR76 is a RAS binding protein that functions as a tumor suppressor via RAS degradation.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30655611","citation_count":41,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"36215168","id":"PMC_36215168","title":"TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing.","date":"2023","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36215168","citation_count":25,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34675073","id":"PMC_34675073","title":"Ras inhibitor CAPRI enables neutrophil-like cells to chemotax through a higher-concentration range of gradients.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34675073","citation_count":14,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34752201","id":"PMC_34752201","title":"RASA4 inhibits the HIFα signaling pathway to suppress proliferation of cervical cancer cells.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34752201","citation_count":8,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11594756","id":"PMC_11594756","title":"Distinct phosphoinositide binding specificity of the GAP1 family proteins: characterization of the pleckstrin homology domains of MRASAL and KIAA0538.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11594756","citation_count":5,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42910,"output_tokens":771,"usd":0.070148},"stage2":{"model":"","input_tokens":0,"output_tokens":0,"usd":0.0},"total_usd":0.31637,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":50168,"output_tokens":3542,"usd":0.101817},"round2_rules_fired":"R1","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6704,"output_tokens":2510,"usd":0.144405}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"CAPRI (RASA4) was identified as a Ca2+-dependent RasGAP that inactivates Ras following stimuli that elevate intracellular Ca2+. The protein translocates to the plasma membrane via a fast C2 domain-dependent mechanism upon Ca2+ elevation, where it switches off the Ras-MAPK pathway.\",\n      \"method\": \"Live-cell imaging of GFP-tagged CAPRI translocation; biochemical assays monitoring Ras-MAPK pathway activity; domain deletion/mutation analysis of C2 domain\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original discovery paper with multiple orthogonal methods (live imaging, signaling assays, domain mutants), founding mechanistic study\",\n      \"pmids\": [\"11448776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CAPRI acts as a low-pass filter of Ca2+ signals, converting different intensities of Ca2+ stimulation into different durations of Ras activity. Unlike RASAL, CAPRI shows a sustained Ca2+-triggered translocation refractory to cytosolic Ca2+ oscillations, dependent on both C2 domain Ca2+ integration and agonist-evoked plasma membrane interaction sites for its pleckstrin homology (PH) domain.\",\n      \"method\": \"Real-time Ras activity assay; live-cell imaging of CAPRI translocation correlated with H-Ras deactivation; domain analysis (C2 and PH domains)\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (real-time Ras assay, live imaging, domain analysis), directly extends mechanistic understanding of CAPRI\",\n      \"pmids\": [\"16009725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CAPRI forms Ca2+-dependent homodimers in vitro and in vivo via a hydrophobic helix motif in the extreme C-terminal tail. Monomeric CAPRI preferentially acts as a RasGAP, whereas dimeric CAPRI preferentially acts as a RapGAP, demonstrating that Ca2+-regulated dimerization switches CAPRI between its dual GAP activities to coordinate Ras and Rap1 signaling.\",\n      \"method\": \"Co-immunoprecipitation; deletion and point mutations of C-terminal helix; in vivo GAP activity assays for Ras and Rap1; physiologically relevant Ca2+ concentration experiments\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro and in vivo reconstitution of dimerization, mutagenesis pinpointing dimerization domain, dual GAP activity assays,\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to identify papers about the canonical RASA4 protein (also known as CAPRI - Ca²⁺-promoted Ras inactivator).\n\n**Classification:**\n- Papers about protein-protein docking experiments named \"CAPRI\" (Critical Assessment of PRedicted Interactions): EXCLUDE (alias collision - different use of \"CAPRI\")\n- Papers about CAPRI clinical trials (cancer treatments): EXCLUDE (alias collision)\n- Papers about Mycoplasma mycoides subsp. capri: EXCLUDE (symbol collision - different organism/context)\n- Papers about the canonical RASA4/CAPRI protein: KEEP\n\n**KEEP papers:**\n- PMID:11448776 - CAPRI: Ca²⁺-dependent Ras inactivator identification\n- PMID:16009725 - CAPRI vs RASAL temporal filtering of Ca²⁺\n- PMID:21460216 - Ca²⁺-dependent monomer/dimer switching of CAPRI\n- PMID:12845332 - PLCγ/RasGRP1/CAPRI in Ras compartmentalization\n- PMID:16815298 - CAPRI plasma membrane shuttling in mast cells\n- PMID:25147919 - RASA4 DNA hypermethylation in JMML\n- PMID:34675073 - CAPRI in neutrophil chemotaxis\n- PMID:31003514 - TRPC3/RASA4/MAPK in TNBC\n- PMID:34094999 - RASA4 in T. denticola-induced actin remodeling\n- PMID:34752201 - RASA4 and HIFα in cervical cancer\n- PMID:11594756 - PH domain phosphoinositide binding of GAP1 family (KIAA0538 = RASA4)\n- PMID:16169070 - protein interaction network (RASA4 interactions)\n- PMID:23602568 - CMGC kinase interactome (may include RASA4)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"CAPRI (RASA4) was identified as a Ca²⁺-dependent RasGAP that inactivates Ras following stimuli that elevate intracellular Ca²⁺. Ca²⁺ regulates CAPRI through a fast C2 domain-dependent translocation mechanism to the plasma membrane, where it switches off the Ras-MAPK pathway.\",\n      \"method\": \"Live-cell imaging of GFP-tagged CAPRI, real-time Ras activity assays, C2 domain mutational analysis\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original discovery with live imaging, domain mutagenesis, and real-time Ras activity readout in a single study; foundational paper\",\n      \"pmids\": [\"11448776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CAPRI (RASA4) acts specifically at the plasma membrane to negatively regulate Ca²⁺-stimulated Ras activation, while RasGRP1 activates Ras at the Golgi apparatus in response to PLCγ1-generated DAG/Ca²⁺ signals. This establishes CAPRI as a spatially restricted negative regulator confining Ras-MAPK signaling to the Golgi in T cells.\",\n      \"method\": \"Fluorescence imaging of compartment-specific Ras biosensors in Jurkat T cells, overexpression and dominant-negative constructs, co-expression of CAPRI with RasGRP1\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches establishing spatial specificity of CAPRI action at plasma membrane vs Golgi; replicated in multiple cell types\",\n      \"pmids\": [\"12845332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CAPRI (RASA4) acts as a low-pass Ca²⁺ filter: its C2 domain-dependent translocation to the plasma membrane is sustained and refractory to cytosolic Ca²⁺ oscillations, converting different intensities of Ca²⁺ stimulation into different durations of Ras activity. This requires integration of Ca²⁺ signals by C2 domains with agonist-evoked PH domain interactions at the plasma membrane. In contrast, the related protein RASAL tracks Ca²⁺ oscillations with repetitive membrane association, preserving frequency information.\",\n      \"method\": \"Real-time Ras activity assays correlated with live-cell CAPRI translocation imaging; domain swap/mutant analysis; Ca²⁺ manipulation experiments\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods correlating translocation dynamics with Ras deactivation; mechanistic domain analysis performed\",\n      \"pmids\": [\"16009725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CAPRI (RASA4) translocates to the plasma membrane upon antigen stimulation (coinciding with elevated intracellular Ca²⁺) in mast cells (RBL cells), and overexpression of CAPRI suppresses antigen-induced degranulation, cytokine production, and ERK2 nuclear import. A GAP-related domain mutant (R472S) showed impaired membrane translocation and failed to suppress these responses, linking membrane localization to functional GAP activity in immune signaling.\",\n      \"method\": \"Overexpression and dominant mutant experiments in RBL mast cells; Ca²⁺ imaging; degranulation assay; ERK2 nuclear translocation imaging\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — single lab with functional readouts and mutant analysis, but single cell type\",\n      \"pmids\": [\"16815298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CAPRI (RASA4) forms Ca²⁺-dependent homodimers both in vitro and in vivo. Dimerization requires a helix motif forming a hydrophobic face in the extreme C-terminal tail. Free Ca²⁺ at physiologically relevant concentrations is necessary and sufficient for dimer formation. Critically, monomeric CAPRI preferentially exhibits RasGAP activity, while dimeric CAPRI preferentially exhibits RapGAP activity, demonstrating that Ca²⁺-regulated dimerization switches CAPRI between dual GAP activities to coordinately regulate Ras and Rap1 signaling.\",\n      \"method\": \"In vitro dimerization assays, Co-IP from cells, deletion and point mutagenesis of C-terminal helix, in vivo RasGAP and RapGAP activity assays, Ca²⁺ titration experiments\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution of dimerization with mutagenesis, corroborated by in-cell Co-IP, and linked to differential enzymatic activity; multiple orthogonal methods in single study\",\n      \"pmids\": [\"21460216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The PH domain of KIAA0538 (RASA4) lacks phosphoinositide binding activity due to an amino acid substitution at position 592 (Leu-592), unlike the related MRASAL whose PH domain binds PI(4,5)P₂ and PI(3,4,5)P₃. As a result, KIAA0538/RASA4 localizes to the cytosol rather than the plasma membrane under basal conditions, revealing that distinct phosphoinositide binding specificity of PH domains determines subcellular localization within the GAP1 family.\",\n      \"method\": \"Lipid-protein binding assays, site-directed mutagenesis of PH domain, subcellular fractionation and fluorescence microscopy in NIH3T3 cells\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding assays with mutagenesis and localization imaging, single lab\",\n      \"pmids\": [\"11594756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPC3 channel-mediated Ca²⁺ influx sustains RASA4 localization at the plasma membrane of triple-negative breast cancer (MDA-MB-231) cells, where RASA4 inhibits the Ras-MAPK pathway. Blocking TRPC3 decreased plasma membrane-associated RASA4 and concomitantly activated MAPK pathways, establishing a TRPC3-RASA4-MAPK signaling cascade that promotes proliferation and apoptosis resistance.\",\n      \"method\": \"Subcellular fractionation and Western blot, immunocytochemistry, TRPC3 blocker (Pyr3) and dominant-negative TRPC3, proliferation and apoptosis assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — multiple complementary methods in a single lab establishing the signaling cascade; mechanistic link between Ca²⁺ influx and RASA4 membrane localization demonstrated\",\n      \"pmids\": [\"31003514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CAPRI (RASA4) controls GPCR-stimulated Ras adaptation in human neutrophils. Neutrophils lacking CAPRI (capri⁻) show nonadaptive Ras activation in response to chemoattractants, with increased phosphorylation of AKT, GSK-3α/3β, and cofilin, and excessive actin polymerization. capri⁻ cells are defective in chemotaxis through high-concentration gradients but exhibit improved chemotaxis in low/subsensitive gradients due to enhanced sensitivity, demonstrating that CAPRI sets the sensitivity threshold for gradient sensing.\",\n      \"method\": \"CAPRI knockout in human neutrophil-like cells, real-time Ras activity biosensors, phosphoprotein analysis, chemotaxis assays across concentration gradients\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with multiple orthogonal mechanistic readouts (Ras activity, phosphoproteomics, functional chemotaxis); strong phenotypic evidence in human cells\",\n      \"pmids\": [\"34675073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Treponema denticola interaction with human periodontal ligament (PDL) cells induces upregulation of RASA4 mRNA expression, leading to actin depolymerization and loss of cell adhesion, followed by increased MMP-2 activity. This effect is mediated by the T. denticola effector protein dentilisin, identifying a novel pathogen-triggered RASA4 transcriptional activation mechanism linked to actin cytoskeletal remodeling.\",\n      \"method\": \"Molecular cell assays including RASA4 mRNA quantification, actin dynamics imaging, MMP-2 activity assays, dentilisin mutant bacteria\",\n      \"journal\": \"Frontiers in Cellular and Infection Microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mechanistic connection between RASA4 upregulation and cytoskeletal phenotype established but indirect; dentilisin specificity tested\",\n      \"pmids\": [\"34094999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RASA4 isoform 2 (mapping to chromosome 7) undergoes recurrent, isoform-specific DNA hypermethylation in juvenile myelomonocytic leukemia (JMML), occurring in 51% of patients. Hypermethylation correlates with poor prognosis, PTPN11 mutation, and increased relapse risk after hematopoietic stem cell transplantation. Cases with monosomy 7 showed hypermethylation on the remaining RASA4 allele, suggesting epigenetic silencing as a two-hit mechanism.\",\n      \"method\": \"Quantitative high-resolution mass spectrometry-based methylation analysis in 125 JMML patients, correlation with clinical parameters\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — large clinical cohort establishing isoform-specific epigenetic silencing, but mechanistic downstream consequences not directly tested\",\n      \"pmids\": [\"25147919\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RASA4 (CAPRI) is a Ca²⁺-dependent RasGAP of the GAP1 family that translocates to the plasma membrane via its C2 domains upon Ca²⁺ elevation to inactivate Ras and suppress the MAPK pathway; its PH domain lacks phosphoinositide binding (keeping it cytosolic at baseline), Ca²⁺-dependent homodimerization via a C-terminal hydrophobic helix switches its catalytic preference from RasGAP (monomer) to RapGAP (dimer), it functions as a low-pass Ca²⁺ filter to set the duration and sensitivity of Ras signaling, and it is regulated upstream by TRPC3-mediated Ca²⁺ influx in cancer cells and by GPCR-evoked Ca²⁺ in neutrophils where it controls Ras adaptation and chemotaxis range.\"\n}\n```","stage2_raw":"\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"RASA4 (CAPRI) is a Ca²⁺-responsive GTPase-activating protein of the GAP1 family that links intracellular calcium signaling to Ras/Rap1 inactivation at the plasma membrane. Upon Ca²⁺ elevation, its tandem C2 domains drive rapid translocation from the cytosol to the plasma membrane—where its PH domain, which lacks phosphoinositide binding at baseline, cooperates with agonist-dependent cues to sustain membrane retention—enabling RASA4 to function as a low-pass Ca²⁺ filter that converts signal intensity into Ras-MAPK signaling duration [PMID:11448776, PMID:16009725, PMID:11594756]. Ca²⁺-dependent homodimerization via a C-terminal hydrophobic helix switches RASA4 from a monomeric RasGAP to a dimeric RapGAP, coordinating the inactivation of both Ras and Rap1 [PMID:21460216]. In neutrophils, RASA4 mediates Ras adaptation to chemoattractant stimulation, setting the sensitivity threshold for gradient sensing and chemotaxis range [PMID:34675073], and in breast cancer cells its membrane localization is sustained by TRPC3-mediated Ca²⁺ influx to suppress MAPK-driven proliferation [PMID:31003514].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Discovery of RASA4 as a Ca²⁺-dependent RasGAP established the founding paradigm that calcium signals can directly terminate Ras-MAPK signaling through regulated membrane recruitment of a GAP.\",\n      \"evidence\": \"Live-cell GFP imaging, real-time Ras activity assays, and C2 domain mutagenesis in cultured cells; concurrent lipid-binding assays showing its PH domain lacks phosphoinositide binding\",\n      \"pmids\": [\"11448776\", \"11594756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural basis for C2 domain–membrane interaction resolved\",\n        \"Endogenous expression levels and tissue distribution not characterized\",\n        \"Role of PH domain during activated state unclear\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstration that RASA4 acts specifically at the plasma membrane to suppress Ras while RasGRP1 activates Ras at the Golgi resolved how opposing regulators spatially partition Ras signaling in T cells.\",\n      \"evidence\": \"Compartment-specific Ras biosensors, co-expression of CAPRI with RasGRP1 in Jurkat T cells\",\n      \"pmids\": [\"12845332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether RASA4 accesses Ras pools at endomembranes under any condition not tested\",\n        \"Stoichiometry relative to RasGRP1 at endogenous levels unknown\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of RASA4 as a low-pass Ca²⁺ filter—remaining membrane-bound and refractory to Ca²⁺ oscillations—explained how cells decode Ca²⁺ signal intensity into Ras signaling duration, contrasting with the oscillation-tracking behavior of the related protein RASAL.\",\n      \"evidence\": \"Correlated real-time translocation imaging with Ras activity readouts; domain-swap and mutant analysis under controlled Ca²⁺ regimes\",\n      \"pmids\": [\"16009725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular determinants distinguishing sustained versus oscillatory membrane binding not mapped at residue level\",\n        \"In vivo physiological consequences of low-pass filtering not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extension of RASA4 function to immune effector cells showed that its GAP-dependent membrane translocation suppresses antigen-induced degranulation, cytokine production, and ERK nuclear import in mast cells.\",\n      \"evidence\": \"Overexpression and GAP-dead mutant (R472S) analysis in RBL mast cells with degranulation and ERK translocation assays\",\n      \"pmids\": [\"16815298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Loss-of-function (knockout/knockdown) not performed in mast cells\",\n        \"Endogenous RASA4 contribution relative to other RasGAPs not determined\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that Ca²⁺-dependent homodimerization via a C-terminal hydrophobic helix switches RASA4 from a RasGAP (monomer) to a RapGAP (dimer) revealed how a single protein coordinately regulates two GTPase families through an oligomerization-based activity switch.\",\n      \"evidence\": \"In vitro dimerization reconstitution, in-cell co-immunoprecipitation, C-terminal helix mutagenesis, and parallel RasGAP/RapGAP activity assays with Ca²⁺ titration\",\n      \"pmids\": [\"21460216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of monomer or dimer\",\n        \"Physiological contexts favoring dimer versus monomer not mapped in vivo\",\n        \"Rap1 substrates and downstream consequences of RapGAP activity not characterized\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Recurrent isoform-specific DNA hypermethylation of RASA4 in juvenile myelomonocytic leukemia, correlating with poor prognosis and acting as a potential two-hit event with monosomy 7, implicated epigenetic silencing of RASA4 in myeloid malignancy.\",\n      \"evidence\": \"Quantitative methylation mass spectrometry in a 125-patient JMML cohort with clinical correlation\",\n      \"pmids\": [\"25147919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of RASA4 silencing on Ras signaling in JMML blasts not directly tested\",\n        \"Causal versus correlative role of methylation not established\",\n        \"Whether restoring RASA4 expression rescues the phenotype unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of TRPC3-mediated Ca²⁺ influx as the upstream signal sustaining RASA4 membrane localization in triple-negative breast cancer cells connected ion channel activity to Ras-MAPK suppression via RASA4.\",\n      \"evidence\": \"Subcellular fractionation, TRPC3 pharmacological blockade and dominant-negative constructs, proliferation and apoptosis assays in MDA-MB-231 cells\",\n      \"pmids\": [\"31003514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction between TRPC3 and RASA4 not demonstrated\",\n        \"Generalizability beyond a single breast cancer cell line not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic knockout of RASA4 in neutrophils demonstrated it is required for Ras adaptation to chemoattractant, establishing that RASA4 sets the sensitivity threshold for gradient sensing and defines the chemotaxis operating range.\",\n      \"evidence\": \"CAPRI knockout in human neutrophil-like cells, Ras biosensors, phosphoprotein profiling (AKT, GSK-3, cofilin), chemotaxis across concentration gradients\",\n      \"pmids\": [\"34675073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo immune cell migration phenotype not assessed\",\n        \"Whether other RasGAPs partially compensate in specific tissues unknown\",\n        \"Direct measurement of Rap1 activity (via dimeric RASA4) in neutrophils not reported\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No high-resolution structure of RASA4 exists, the in vivo balance between monomeric RasGAP and dimeric RapGAP activities remains uncharacterized across tissues, and whether epigenetic silencing of RASA4 is functionally causative in myeloid malignancy has not been directly tested.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of full-length RASA4 or its dimer\",\n        \"Tissue-specific ratio of monomer/dimer and its physiological regulation uncharacterized\",\n        \"Functional rescue experiments in JMML models needed to establish causality of RASA4 silencing\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 4, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TRPC3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}