{"gene":"RASA4","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2001,"finding":"CAPRI (RASA4) was identified as a Ca2+-dependent Ras GTPase-activating protein (RasGAP) that inactivates the Ras-MAPK pathway following stimuli that elevate intracellular Ca2+. Ca2+ drives a fast C2 domain-dependent translocation of CAPRI to the plasma membrane, constituting the mechanistic basis for Ca2+-promoted Ras inactivation.","method":"Live-cell imaging of CAPRI translocation, in vivo Ras activity assays, C2 domain mutant analysis","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, functional GAP assays, domain mutants) in a focused mechanistic study; foundational paper replicated by subsequent work","pmids":["11448776"],"is_preprint":false},{"year":2005,"finding":"CAPRI acts as a low-pass filter for Ca2+ signals: its sustained plasma membrane translocation after stimulation is Ca2+- and C2 domain-dependent but the prolonged recruitment is predominantly Ca2+-independent, requiring integration by the C2 domains with agonist-evoked plasma membrane interaction sites for the pleckstrin homology (PH) domain. This sustained translocation converts different intensities of Ca2+ stimulation into different durations of Ras activity. In contrast, the related protein RASAL tracks Ca2+ oscillations repetitively, preserving frequency information.","method":"Real-time Ras activity assay (FRET-based), live-cell fluorescence imaging of translocation dynamics, domain mutant analysis, Ca2+ oscillation experiments","journal":"The Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (real-time Ras activity monitoring, live imaging, domain mutants) in a single rigorous study with direct functional correlation","pmids":["16009725"],"is_preprint":false},{"year":2011,"finding":"CAPRI (RASA4) forms homodimers in vitro and in vivo in a Ca2+-dependent manner. Dimerization requires a C-terminal helix motif forming a hydrophobic face. Monomeric CAPRI exhibits stronger RasGAP activity, while dimeric CAPRI exhibits stronger RapGAP activity. Ca2+ at physiologically relevant concentrations is both necessary and sufficient for dimer formation. Cell stimulation with histamine increases the ratio of dimer to monomer. Thus, Ca2+-dependent dimerization switches CAPRI between its dual RasGAP and RapGAP roles.","method":"Co-immunoprecipitation, deletion and point mutagenesis, in vivo GAP activity assays for Ras and Rap1, cell stimulation with histamine","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, structure-function mutagenesis, and in vivo functional assays for both GAP activities in the same study","pmids":["21460216"],"is_preprint":false},{"year":2006,"finding":"In mast cells (RBL cells), CAPRI overexpression suppresses antigen-induced degranulation and cytokine production. Antigen stimulation triggers Ca2+-dependent translocation of CAPRI to the plasma membrane, followed by re-localization to the cytoplasm that is concomitant with nuclear import of ERK2, indicating that CAPRI eliminates the early phase of ERK2 activation. A GAP-domain mutant (R472S) showed impaired plasma membrane translocation and did not suppress degranulation, ERK2 activation, or cytokine production, linking membrane translocation to functional suppression.","method":"Overexpression and GAP-domain point mutant (R472S) in RBL mast cells, degranulation assay, cytokine measurement, ERK2 localization imaging, intracellular Ca2+ measurement","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mutant with multiple cellular readouts (degranulation, ERK2 localization, cytokine production) in a single lab study","pmids":["16815298"],"is_preprint":false},{"year":2019,"finding":"In triple-negative breast cancer MDA-MB-231 cells, RASA4 localizes to the plasma membrane where it suppresses the Ras-MAPK pathway. Ca2+ influx through the TRPC3 channel sustains RASA4 at the plasma membrane. Blocking TRPC3 decreases plasma membrane-localized RASA4 and concomitantly activates MAPK pathways, promoting proliferation and apoptosis resistance. This defines a TRPC3–RASA4–MAPK signaling cascade.","method":"Subcellular fractionation and Western blot, immunocytochemistry, TRPC3 blocker (Pyr3) and dominant-negative TRPC3 overexpression, proliferation assays, apoptosis assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — subcellular fractionation with functional readouts, pharmacological and dominant-negative inhibition, single lab with two orthogonal inhibition approaches","pmids":["31003514"],"is_preprint":false},{"year":2014,"finding":"RASA4 isoform 2, which maps to chromosome 7 and encodes a GAP1-family GTPase-activating protein, undergoes recurrent isoform-specific DNA hypermethylation in juvenile myelomonocytic leukemia (JMML), occurring in 51% of 125 patients analyzed. Methylation of the RASA4 isoform 2 promoter correlated with PTPN11 mutation and monosomy 7 (where the remaining allele was hypermethylated), suggesting epigenetic silencing of RASA4 as a mechanism contributing to dysregulated Ras signaling in JMML.","method":"Quantitative high-resolution mass spectrometry-based DNA methylation analysis, correlation with clinical/genetic parameters in 125 patients","journal":"Epigenetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — quantitative methylation profiling in a large patient cohort with genetic correlations; no direct functional rescue experiment but isoform-specific methylation established by rigorous method","pmids":["25147919"],"is_preprint":false},{"year":2021,"finding":"In human periodontal ligament (PDL) fibroblasts, infection with Treponema denticola (via its effector protein dentilisin) upregulates RASA4 mRNA expression, which leads to actin depolymerization, loss of cell adhesion, and increased matrix metalloproteinase-2 (MMP-2) activity. This defines a T. denticola–dentilisin→RASA4 upregulation→actin depolymerization/MMP-2 activation pathway in periodontal pathogenesis.","method":"Gene expression assays (mRNA quantification), functional cell assays (actin dynamics, cell adhesion, MMP-2 activity), T. denticola infection of primary human PDL cells, dentilisin-specific inhibition","journal":"Frontiers in Cellular and Infection Microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mRNA-level upregulation linked to functional cellular phenotypes with effector-specific experiments; single lab, no protein-level knockdown rescue","pmids":["34094999"],"is_preprint":false}],"current_model":"RASA4 (CAPRI) is a Ca2+-promoted RasGAP that translocates to the plasma membrane via its C2 domain in response to elevated intracellular Ca2+, where it inactivates Ras and suppresses MAPK signaling; Ca2+-dependent homodimerization via a C-terminal hydrophobic helix switches its catalytic preference from RasGAP (monomer) to RapGAP (dimer), enabling coordinated regulation of both Ras and Rap1, while its plasma membrane localization is additionally sustained by PH domain interactions and, in certain cell types, by Ca2+ influx through TRPC3."},"narrative":{"mechanistic_narrative":"RASA4 (CAPRI) is a Ca2+-dependent Ras GTPase-activating protein that couples elevated intracellular Ca2+ to inactivation of the Ras-MAPK pathway [PMID:11448776]. Following stimuli that raise cytosolic Ca2+, its C2 domain drives fast translocation to the plasma membrane, where it accelerates GTP hydrolysis on Ras [PMID:11448776]; sustained recruitment then becomes largely Ca2+-independent and depends on integration of the C2 domains with agonist-evoked PH-domain interaction sites, allowing different Ca2+ stimulus intensities to be converted into different durations of Ras activity [PMID:16009725]. Ca2+ at physiological concentrations also drives homodimerization through a C-terminal hydrophobic helix, and this switches catalytic preference: monomeric RASA4 acts more strongly as a RasGAP while the dimer acts more strongly as a RapGAP, coordinating regulation of both Ras and Rap1 [PMID:21460216]. In mast cells, this membrane translocation terminates the early phase of ERK2 activation and suppresses antigen-induced degranulation and cytokine production, with a GAP-domain mutant abolishing both translocation and suppression [PMID:16815298]. In triple-negative breast cancer cells, Ca2+ influx through TRPC3 sustains plasma-membrane RASA4 to restrain MAPK signaling, proliferation, and apoptosis resistance [PMID:31003514]. Isoform-specific promoter hypermethylation silences RASA4 in juvenile myelomonocytic leukemia, consistent with loss of its Ras-suppressive function in disease [PMID:25147919].","teleology":[{"year":2001,"claim":"Established RASA4/CAPRI as the molecular link between Ca2+ signals and Ras inactivation, defining how Ca2+ feeds back onto the Ras-MAPK pathway.","evidence":"Live-cell imaging of translocation, in vivo Ras activity assays, and C2 domain mutants","pmids":["11448776"],"confidence":"High","gaps":["Did not resolve how membrane retention is sustained beyond the initial Ca2+ spike","Catalytic preference between Ras and Rap not addressed"]},{"year":2005,"claim":"Showed RASA4 acts as a low-pass filter that translates Ca2+ stimulus intensity into Ras-activity duration, distinguishing it from oscillation-tracking relatives.","evidence":"FRET-based real-time Ras activity assay, live-cell imaging, and domain mutant analysis of Ca2+-dependent versus PH-dependent recruitment","pmids":["16009725"],"confidence":"High","gaps":["Identity of the agonist-evoked PH-domain membrane interaction sites not defined","Whether filtering behavior holds in physiological cell types untested"]},{"year":2006,"claim":"Demonstrated a cellular consequence of RASA4 action by showing it terminates early ERK2 activation and suppresses mast cell effector responses, tying membrane translocation to function.","evidence":"Overexpression and GAP-domain point mutant (R472S) in RBL mast cells with degranulation, cytokine, ERK2 localization, and Ca2+ readouts","pmids":["16815298"],"confidence":"Medium","gaps":["Based on overexpression rather than endogenous loss-of-function","Single cell line and lab"]},{"year":2011,"claim":"Resolved how a single GAP regulates two GTPases by showing Ca2+-driven dimerization switches catalytic preference between RasGAP and RapGAP activity.","evidence":"Reciprocal Co-IP, deletion/point mutagenesis of a C-terminal hydrophobic helix, and in vivo GAP assays for Ras and Rap1 with histamine stimulation","pmids":["21460216"],"confidence":"High","gaps":["No structural model of the dimer interface","Downstream consequences of Rap1 regulation not characterized"]},{"year":2014,"claim":"Connected RASA4 to malignant Ras dysregulation by identifying isoform-specific promoter hypermethylation as a silencing mechanism in JMML.","evidence":"Quantitative mass spectrometry-based DNA methylation profiling in 125 patients with genetic correlations","pmids":["25147919"],"confidence":"Medium","gaps":["No functional rescue confirming silencing drives Ras activation","Causality versus correlation with PTPN11 mutation and monosomy 7 not established"]},{"year":2019,"claim":"Defined an upstream channel input by showing TRPC3-mediated Ca2+ influx sustains plasma-membrane RASA4 to restrain MAPK-driven proliferation in breast cancer.","evidence":"Subcellular fractionation, immunocytochemistry, TRPC3 pharmacological and dominant-negative inhibition, with proliferation and apoptosis assays","pmids":["31003514"],"confidence":"Medium","gaps":["Direct molecular link between TRPC3 and RASA4 retention not shown","Single cell line"]},{"year":2021,"claim":"Implicated RASA4 in host-pathogen signaling by linking its upregulation to cytoskeletal and matrix remodeling in periodontal fibroblasts.","evidence":"mRNA quantification and functional assays (actin dynamics, adhesion, MMP-2 activity) on T. denticola/dentilisin-infected primary PDL cells","pmids":["34094999"],"confidence":"Medium","gaps":["mRNA-level only without protein knockdown rescue","GAP activity not directly linked to actin/MMP-2 phenotype"]},{"year":null,"claim":"A structural basis for the dimerization-driven RasGAP-to-RapGAP switch and how it is coordinated with Ca2+- and PH-dependent membrane retention across cell types remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of monomeric versus dimeric RASA4","Physiological balance of Ras versus Rap1 regulation in vivo unknown","Endogenous loss-of-function phenotypes largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,4]}],"complexes":["RASA4 homodimer"],"partners":["HRAS","RAP1","TRPC3"],"other_free_text":[]}},"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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CAPRI.","date":"2005","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/15981271","citation_count":33,"is_preprint":false},{"pmid":"370343","id":"PMC_370343","title":"Relationships between strains of Mycoplasma mycoides subspp. mycoides and capri studied by two-dimensional gel electrophoresis of cell proteins.","date":"1978","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/370343","citation_count":33,"is_preprint":false},{"pmid":"39237205","id":"PMC_39237205","title":"CAPRI-Q: The CAPRI resource evaluating the quality of predicted structures of protein complexes.","date":"2024","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/39237205","citation_count":32,"is_preprint":false},{"pmid":"15981265","id":"PMC_15981265","title":"Performance of the first protein docking server ClusPro in CAPRI rounds 3-5.","date":"2005","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/15981265","citation_count":31,"is_preprint":false},{"pmid":"17671979","id":"PMC_17671979","title":"RosettaDock in CAPRI rounds 6-12.","date":"2007","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/17671979","citation_count":28,"is_preprint":false},{"pmid":"15981253","id":"PMC_15981253","title":"Modeling side-chains using molecular dynamics improve recognition of binding region in CAPRI targets.","date":"2005","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/15981253","citation_count":28,"is_preprint":false},{"pmid":"20602351","id":"PMC_20602351","title":"Optimization of pyDock for the new CAPRI challenges: Docking of homology-based models, domain-domain assembly and protein-RNA binding.","date":"2010","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/20602351","citation_count":27,"is_preprint":false},{"pmid":"15981250","id":"PMC_15981250","title":"Modeling oligomers with Cn or Dn symmetry: application to CAPRI target 10.","date":"2005","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/15981250","citation_count":27,"is_preprint":false},{"pmid":"27701780","id":"PMC_27701780","title":"Lessons from (co-)evolution in the docking of proteins and peptides for CAPRI Rounds 28-35.","date":"2016","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/27701780","citation_count":26,"is_preprint":false},{"pmid":"17198089","id":"PMC_17198089","title":"Impact of interferon-alpha in combined chemoradioimmunotherapy for pancreatic adenocarcinoma (CapRI): first data from the immunomonitoring.","date":"2007","source":"Journal of immunotherapy (Hagerstown, Md. : 1997)","url":"https://pubmed.ncbi.nlm.nih.gov/17198089","citation_count":26,"is_preprint":false},{"pmid":"20589643","id":"PMC_20589643","title":"The targets of CAPRI Rounds 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trial.","date":"2024","source":"Annals of oncology : official journal of the European Society for Medical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39214459","citation_count":23,"is_preprint":false},{"pmid":"1097587","id":"PMC_1097587","title":"Modification of the membrane composition of Mycoplasma mycoides subsp. capri by the growth medium.","date":"1975","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/1097587","citation_count":23,"is_preprint":false},{"pmid":"6757862","id":"PMC_6757862","title":"The nucleotide sequence of the 5S rRNA from Spiroplasma species BC3 and Mycoplasma mycoides sp. capri PG3.","date":"1982","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/6757862","citation_count":23,"is_preprint":false},{"pmid":"24115176","id":"PMC_24115176","title":"Using a consensus approach based on the conservation of inter-residue contacts to rank CAPRI models.","date":"2013","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/24115176","citation_count":22,"is_preprint":false},{"pmid":"12784370","id":"PMC_12784370","title":"Evaluation of the 3D-Dock protein docking suite in rounds 1 and 2 of the CAPRI blind trial.","date":"2003","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/12784370","citation_count":22,"is_preprint":false},{"pmid":"1953789","id":"PMC_1953789","title":"The peptides APLHK, EHIPA and GAPL are hydropathically equivalent peptide mimics of a fibrinogen binding domain of glycoprotein IIb/IIIa.","date":"1991","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1953789","citation_count":21,"is_preprint":false},{"pmid":"28002624","id":"PMC_28002624","title":"FlexPepDock lessons from CAPRI peptide-protein rounds and suggested new criteria for assessment of model quality and utility.","date":"2017","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/28002624","citation_count":21,"is_preprint":false},{"pmid":"16485127","id":"PMC_16485127","title":"Immunomodulatory impact of interferon-alpha in combination with chemoradiation of pancreatic adenocarcinoma (CapRI).","date":"2006","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/16485127","citation_count":21,"is_preprint":false},{"pmid":"15981267","id":"PMC_15981267","title":"The targets of CAPRI rounds 3-5.","date":"2005","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/15981267","citation_count":21,"is_preprint":false},{"pmid":"28845596","id":"PMC_28845596","title":"Improved performance in CAPRI round 37 using LZerD docking and template-based modeling with combined scoring functions.","date":"2017","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/28845596","citation_count":20,"is_preprint":false},{"pmid":"24227686","id":"PMC_24227686","title":"Inclusion of the orientational entropic effect and low-resolution experimental information for protein-protein docking in Critical Assessment of PRedicted Interactions (CAPRI).","date":"2013","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/24227686","citation_count":20,"is_preprint":false},{"pmid":"21460216","id":"PMC_21460216","title":"Ca2+-dependent monomer and dimer formation switches CAPRI Protein between Ras GTPase-activating protein (GAP) and RapGAP activities.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21460216","citation_count":19,"is_preprint":false},{"pmid":"25951987","id":"PMC_25951987","title":"Mechanisms involved in quinolone resistance in Mycoplasma mycoides subsp. capri.","date":"2015","source":"Veterinary journal (London, England : 1997)","url":"https://pubmed.ncbi.nlm.nih.gov/25951987","citation_count":19,"is_preprint":false},{"pmid":"28905425","id":"PMC_28905425","title":"Modeling CAPRI targets 110-120 by template-based and free docking using contact potential and combined scoring function.","date":"2017","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/28905425","citation_count":19,"is_preprint":false},{"pmid":"363150","id":"PMC_363150","title":"Effect of membrane cholesterol on potassium transport in Mycoplasma mycoides var. Capri (PG3).","date":"1978","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/363150","citation_count":19,"is_preprint":false},{"pmid":"16973118","id":"PMC_16973118","title":"Mycoplasma mycoides subsp. capri and Mycoplasma mycoides subsp. mycoides LC can be grouped into a single subspecies.","date":"2006","source":"Veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/16973118","citation_count":18,"is_preprint":false},{"pmid":"24123494","id":"PMC_24123494","title":"Extending RosettaDock with water, sugar, and pH for prediction of complex structures and affinities for CAPRI rounds 20-27.","date":"2013","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/24123494","citation_count":18,"is_preprint":false},{"pmid":"20802067","id":"PMC_20802067","title":"Enhancement of targeted homologous recombination in Mycoplasma mycoides subsp. capri by inclusion of heterologous recA.","date":"2010","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20802067","citation_count":18,"is_preprint":false},{"pmid":"378256","id":"PMC_378256","title":"Active K+ transport in Mycoplasma mycoides var. Capri. Net and unidirectional K+ movements.","date":"1979","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/378256","citation_count":18,"is_preprint":false},{"pmid":"34094999","id":"PMC_34094999","title":"Treponema denticola-Induced RASA4 Upregulation Mediates Cytoskeletal Dysfunction and MMP-2 Activity in Periodontal Fibroblasts.","date":"2021","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34094999","citation_count":17,"is_preprint":false},{"pmid":"27667482","id":"PMC_27667482","title":"Modeling oblong proteins and water-mediated interfaces with RosettaDock in CAPRI rounds 28-35.","date":"2016","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/27667482","citation_count":17,"is_preprint":false},{"pmid":"21122584","id":"PMC_21122584","title":"News from the \"5th International Meeting on Inflammatory Bowel Diseases\" CAPRI 2010.","date":"2010","source":"Journal of Crohn's & colitis","url":"https://pubmed.ncbi.nlm.nih.gov/21122584","citation_count":17,"is_preprint":false},{"pmid":"20597089","id":"PMC_20597089","title":"Rosetta in CAPRI rounds 13-19.","date":"2010","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/20597089","citation_count":17,"is_preprint":false},{"pmid":"36912","id":"PMC_36912","title":"Active K+ transport in Mycoplasms mycoides var. Capri. Relationships between K+ distribution, electrical potential and ATPase activity.","date":"1979","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/36912","citation_count":17,"is_preprint":false},{"pmid":"27785830","id":"PMC_27785830","title":"Protein-protein and peptide-protein docking and refinement using ATTRACT in CAPRI.","date":"2016","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/27785830","citation_count":16,"is_preprint":false},{"pmid":"31697428","id":"PMC_31697428","title":"Performance and enhancement of the LZerD protein assembly pipeline in CAPRI 38-46.","date":"2019","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/31697428","citation_count":16,"is_preprint":false},{"pmid":"27654025","id":"PMC_27654025","title":"Human and server docking prediction for CAPRI round 30-35 using LZerD with combined scoring functions.","date":"2016","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/27654025","citation_count":16,"is_preprint":false},{"pmid":"36860319","id":"PMC_36860319","title":"Efficacy and safety of a biomarker-driven cetuximab-based treatment regimen over 3 treatment lines in mCRC patients with RAS/BRAF wild type tumors at start of first line: The CAPRI 2 GOIM trial.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36860319","citation_count":16,"is_preprint":false},{"pmid":"12784360","id":"PMC_12784360","title":"GAPDOCK: a Genetic Algorithm Approach to Protein Docking in CAPRI round 1.","date":"2003","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/12784360","citation_count":16,"is_preprint":false},{"pmid":"31742764","id":"PMC_31742764","title":"Novel sampling strategies and a coarse-grained score function for docking homomers, flexible heteromers, and oligosaccharides using Rosetta in CAPRI rounds 37-45.","date":"2019","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/31742764","citation_count":15,"is_preprint":false},{"pmid":"17803233","id":"PMC_17803233","title":"Assessing the energy landscape of CAPRI targets by FunHunt.","date":"2007","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/17803233","citation_count":15,"is_preprint":false},{"pmid":"17671980","id":"PMC_17671980","title":"The targets of CAPRI rounds 6-12.","date":"2007","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/17671980","citation_count":15,"is_preprint":false},{"pmid":"27718275","id":"PMC_27718275","title":"Performance of ZDOCK and IRAD in CAPRI rounds 28-34.","date":"2016","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/27718275","citation_count":14,"is_preprint":false},{"pmid":"27802576","id":"PMC_27802576","title":"Performance of MDockPP in CAPRI rounds 28-29 and 31-35 including the prediction of water-mediated interactions.","date":"2016","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/27802576","citation_count":14,"is_preprint":false},{"pmid":"23996302","id":"PMC_23996302","title":"Improved flexible refinement of protein docking in CAPRI rounds 22-27.","date":"2013","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/23996302","citation_count":14,"is_preprint":false},{"pmid":"16815298","id":"PMC_16815298","title":"The plasma membrane shuttling of CAPRI is related to regulation of mast cell activation.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16815298","citation_count":13,"is_preprint":false},{"pmid":"23900782","id":"PMC_23900782","title":"The targets of CAPRI rounds 20-27.","date":"2013","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/23900782","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43677,"output_tokens":2579,"usd":0.084858,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18684,"output_tokens":5500,"usd":0.171767,"resynth_parse_fail":true,"stage2_stop_reason":"end_turn"},"total_usd":0.256625,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the 100 papers, I need to identify which ones are actually about the RASA4/CAPRI/GAPL protein (a Ca2+-promoted Ras GTPase-activating protein). The vast majority of papers are about the \"CAPRI\" protein-protein docking experiment, clinical trials named \"CAPRI,\" Mycoplasma mycoides subsp. capri, or other unrelated uses of the acronym. I'll focus only on papers about the RASA4/CAPRI protein.\n\nRelevant papers:\n- PMID 11448776: Identifies CAPRI as Ca2+-dependent RasGAP, C2 domain translocation\n- PMID 16009725: CAPRI vs RASAL temporal filtering of Ca2+, PH domain involvement\n- PMID 21460216: Ca2+-dependent dimerization switches between RasGAP/RapGAP activities\n- PMID 31003514: TRPC3/RASA4/MAPK pathway in TNBC\n- PMID 25147919: RASA4 isoform 2 DNA hypermethylation in JMML\n- PMID 16815298: CAPRI translocation in mast cells, ERK2 regulation\n- PMID 34094999: RASA4 upregulation by T. denticola mediates actin depolymerization\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"CAPRI (RASA4) was identified as a Ca2+-dependent Ras GTPase-activating protein (RasGAP) that inactivates the Ras-MAPK pathway following stimuli that elevate intracellular Ca2+. Ca2+ drives a fast C2 domain-dependent translocation of CAPRI to the plasma membrane, constituting the mechanistic basis for Ca2+-promoted Ras inactivation.\",\n      \"method\": \"Live-cell imaging of CAPRI translocation, in vivo Ras activity assays, C2 domain mutant analysis\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, functional GAP assays, domain mutants) in a focused mechanistic study; foundational paper replicated by subsequent work\",\n      \"pmids\": [\"11448776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CAPRI acts as a low-pass filter for Ca2+ signals: its sustained plasma membrane translocation after stimulation is Ca2+- and C2 domain-dependent but the prolonged recruitment is predominantly Ca2+-independent, requiring integration by the C2 domains with agonist-evoked plasma membrane interaction sites for the pleckstrin homology (PH) domain. This sustained translocation converts different intensities of Ca2+ stimulation into different durations of Ras activity. In contrast, the related protein RASAL tracks Ca2+ oscillations repetitively, preserving frequency information.\",\n      \"method\": \"Real-time Ras activity assay (FRET-based), live-cell fluorescence imaging of translocation dynamics, domain mutant analysis, Ca2+ oscillation experiments\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (real-time Ras activity monitoring, live imaging, domain mutants) in a single rigorous study with direct functional correlation\",\n      \"pmids\": [\"16009725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CAPRI (RASA4) forms homodimers in vitro and in vivo in a Ca2+-dependent manner. Dimerization requires a C-terminal helix motif forming a hydrophobic face. Monomeric CAPRI exhibits stronger RasGAP activity, while dimeric CAPRI exhibits stronger RapGAP activity. Ca2+ at physiologically relevant concentrations is both necessary and sufficient for dimer formation. Cell stimulation with histamine increases the ratio of dimer to monomer. Thus, Ca2+-dependent dimerization switches CAPRI between its dual RasGAP and RapGAP roles.\",\n      \"method\": \"Co-immunoprecipitation, deletion and point mutagenesis, in vivo GAP activity assays for Ras and Rap1, cell stimulation with histamine\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, structure-function mutagenesis, and in vivo functional assays for both GAP activities in the same study\",\n      \"pmids\": [\"21460216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In mast cells (RBL cells), CAPRI overexpression suppresses antigen-induced degranulation and cytokine production. Antigen stimulation triggers Ca2+-dependent translocation of CAPRI to the plasma membrane, followed by re-localization to the cytoplasm that is concomitant with nuclear import of ERK2, indicating that CAPRI eliminates the early phase of ERK2 activation. A GAP-domain mutant (R472S) showed impaired plasma membrane translocation and did not suppress degranulation, ERK2 activation, or cytokine production, linking membrane translocation to functional suppression.\",\n      \"method\": \"Overexpression and GAP-domain point mutant (R472S) in RBL mast cells, degranulation assay, cytokine measurement, ERK2 localization imaging, intracellular Ca2+ measurement\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mutant with multiple cellular readouts (degranulation, ERK2 localization, cytokine production) in a single lab study\",\n      \"pmids\": [\"16815298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In triple-negative breast cancer MDA-MB-231 cells, RASA4 localizes to the plasma membrane where it suppresses the Ras-MAPK pathway. Ca2+ influx through the TRPC3 channel sustains RASA4 at the plasma membrane. Blocking TRPC3 decreases plasma membrane-localized RASA4 and concomitantly activates MAPK pathways, promoting proliferation and apoptosis resistance. This defines a TRPC3–RASA4–MAPK signaling cascade.\",\n      \"method\": \"Subcellular fractionation and Western blot, immunocytochemistry, TRPC3 blocker (Pyr3) and dominant-negative TRPC3 overexpression, proliferation assays, apoptosis assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — subcellular fractionation with functional readouts, pharmacological and dominant-negative inhibition, single lab with two orthogonal inhibition approaches\",\n      \"pmids\": [\"31003514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RASA4 isoform 2, which maps to chromosome 7 and encodes a GAP1-family GTPase-activating protein, undergoes recurrent isoform-specific DNA hypermethylation in juvenile myelomonocytic leukemia (JMML), occurring in 51% of 125 patients analyzed. Methylation of the RASA4 isoform 2 promoter correlated with PTPN11 mutation and monosomy 7 (where the remaining allele was hypermethylated), suggesting epigenetic silencing of RASA4 as a mechanism contributing to dysregulated Ras signaling in JMML.\",\n      \"method\": \"Quantitative high-resolution mass spectrometry-based DNA methylation analysis, correlation with clinical/genetic parameters in 125 patients\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — quantitative methylation profiling in a large patient cohort with genetic correlations; no direct functional rescue experiment but isoform-specific methylation established by rigorous method\",\n      \"pmids\": [\"25147919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In human periodontal ligament (PDL) fibroblasts, infection with Treponema denticola (via its effector protein dentilisin) upregulates RASA4 mRNA expression, which leads to actin depolymerization, loss of cell adhesion, and increased matrix metalloproteinase-2 (MMP-2) activity. This defines a T. denticola–dentilisin→RASA4 upregulation→actin depolymerization/MMP-2 activation pathway in periodontal pathogenesis.\",\n      \"method\": \"Gene expression assays (mRNA quantification), functional cell assays (actin dynamics, cell adhesion, MMP-2 activity), T. denticola infection of primary human PDL cells, dentilisin-specific inhibition\",\n      \"journal\": \"Frontiers in Cellular and Infection Microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mRNA-level upregulation linked to functional cellular phenotypes with effector-specific experiments; single lab, no protein-level knockdown rescue\",\n      \"pmids\": [\"34094999\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RASA4 (CAPRI) is a Ca2+-promoted RasGAP that translocates to the plasma membrane via its C2 domain in response to elevated intracellular Ca2+, where it inactivates Ras and suppresses MAPK signaling; Ca2+-dependent homodimerization via a C-terminal hydrophobic helix switches its catalytic preference from RasGAP (monomer) to RapGAP (dimer), enabling coordinated regulation of both Ras and Rap1, while its plasma membrane localization is additionally sustained by PH domain interactions and, in certain cell types, by Ca2+ influx through TRPC3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RASA4 (CAPRI) is a Ca2+-dependent Ras GTPase-activating protein that couples elevated intracellular Ca2+ to inactivation of the Ras-MAPK pathway [#0]. Following stimuli that raise cytosolic Ca2+, its C2 domain drives fast translocation to the plasma membrane, where it accelerates GTP hydrolysis on Ras [#0]; sustained recruitment then becomes largely Ca2+-independent and depends on integration of the C2 domains with agonist-evoked PH-domain interaction sites, allowing different Ca2+ stimulus intensities to be converted into different durations of Ras activity [#1]. Ca2+ at physiological concentrations also drives homodimerization through a C-terminal hydrophobic helix, and this switches catalytic preference: monomeric RASA4 acts more strongly as a RasGAP while the dimer acts more strongly as a RapGAP, coordinating regulation of both Ras and Rap1 [#2]. In mast cells, this membrane translocation terminates the early phase of ERK2 activation and suppresses antigen-induced degranulation and cytokine production, with a GAP-domain mutant abolishing both translocation and suppression [#3]. In triple-negative breast cancer cells, Ca2+ influx through TRPC3 sustains plasma-membrane RASA4 to restrain MAPK signaling, proliferation, and apoptosis resistance [#4]. Isoform-specific promoter hypermethylation silences RASA4 in juvenile myelomonocytic leukemia, consistent with loss of its Ras-suppressive function in disease [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established RASA4/CAPRI as the molecular link between Ca2+ signals and Ras inactivation, defining how Ca2+ feeds back onto the Ras-MAPK pathway.\",\n      \"evidence\": \"Live-cell imaging of translocation, in vivo Ras activity assays, and C2 domain mutants\",\n      \"pmids\": [\"11448776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how membrane retention is sustained beyond the initial Ca2+ spike\", \"Catalytic preference between Ras and Rap not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed RASA4 acts as a low-pass filter that translates Ca2+ stimulus intensity into Ras-activity duration, distinguishing it from oscillation-tracking relatives.\",\n      \"evidence\": \"FRET-based real-time Ras activity assay, live-cell imaging, and domain mutant analysis of Ca2+-dependent versus PH-dependent recruitment\",\n      \"pmids\": [\"16009725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the agonist-evoked PH-domain membrane interaction sites not defined\", \"Whether filtering behavior holds in physiological cell types untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated a cellular consequence of RASA4 action by showing it terminates early ERK2 activation and suppresses mast cell effector responses, tying membrane translocation to function.\",\n      \"evidence\": \"Overexpression and GAP-domain point mutant (R472S) in RBL mast cells with degranulation, cytokine, ERK2 localization, and Ca2+ readouts\",\n      \"pmids\": [\"16815298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Based on overexpression rather than endogenous loss-of-function\", \"Single cell line and lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved how a single GAP regulates two GTPases by showing Ca2+-driven dimerization switches catalytic preference between RasGAP and RapGAP activity.\",\n      \"evidence\": \"Reciprocal Co-IP, deletion/point mutagenesis of a C-terminal hydrophobic helix, and in vivo GAP assays for Ras and Rap1 with histamine stimulation\",\n      \"pmids\": [\"21460216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the dimer interface\", \"Downstream consequences of Rap1 regulation not characterized\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected RASA4 to malignant Ras dysregulation by identifying isoform-specific promoter hypermethylation as a silencing mechanism in JMML.\",\n      \"evidence\": \"Quantitative mass spectrometry-based DNA methylation profiling in 125 patients with genetic correlations\",\n      \"pmids\": [\"25147919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional rescue confirming silencing drives Ras activation\", \"Causality versus correlation with PTPN11 mutation and monosomy 7 not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined an upstream channel input by showing TRPC3-mediated Ca2+ influx sustains plasma-membrane RASA4 to restrain MAPK-driven proliferation in breast cancer.\",\n      \"evidence\": \"Subcellular fractionation, immunocytochemistry, TRPC3 pharmacological and dominant-negative inhibition, with proliferation and apoptosis assays\",\n      \"pmids\": [\"31003514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between TRPC3 and RASA4 retention not shown\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated RASA4 in host-pathogen signaling by linking its upregulation to cytoskeletal and matrix remodeling in periodontal fibroblasts.\",\n      \"evidence\": \"mRNA quantification and functional assays (actin dynamics, adhesion, MMP-2 activity) on T. denticola/dentilisin-infected primary PDL cells\",\n      \"pmids\": [\"34094999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mRNA-level only without protein knockdown rescue\", \"GAP activity not directly linked to actin/MMP-2 phenotype\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A structural basis for the dimerization-driven RasGAP-to-RapGAP switch and how it is coordinated with Ca2+- and PH-dependent membrane retention across cell types remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of monomeric versus dimeric RASA4\", \"Physiological balance of Ras versus Rap1 regulation in vivo unknown\", \"Endogenous loss-of-function phenotypes largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"complexes\": [\"RASA4 homodimer\"],\n    \"partners\": [\"HRAS\", \"RAP1\", \"TRPC3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}