{"gene":"CAP1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2002,"finding":"The N-terminal domain of human CAP1 interacts with the actin-cofilin complex and accelerates F-actin depolymerization at the pointed end; the C-terminal domain facilitates filament elongation at the barbed end and stimulates ADP-ATP exchange on G-actin; the N-terminal domain relieves cofilin-mediated inhibition of nucleotide exchange, enabling recycling of both cofilin and actin for rapid filament turnover.","method":"Co-immunoprecipitation from HEK293 extracts; in vitro domain-deletion actin depolymerization and nucleotide exchange assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution with domain deletions, multiple orthogonal assays (depolymerization, nucleotide exchange, pulldown), single rigorous study","pmids":["11950878"],"is_preprint":false},{"year":2004,"finding":"CAP1 colocalizes with cofilin-1 at dynamic cortical actin regions in mammalian cells; CAP1 knockdown causes accumulation of cofilin-1 into abnormal cytoplasmic aggregates, excessive F-actin, impaired cell morphology, migration, and endocytosis, establishing that CAP1 is required for proper cofilin-1 localization and function in actin dynamics.","method":"siRNA knockdown in NIH3T3 and B16F1 cells; immunofluorescence colocalization; cell migration and endocytosis assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KD with multiple defined cellular phenotypes and colocalization, replicated across two cell lines","pmids":["15004221"],"is_preprint":false},{"year":2013,"finding":"CAP1 depletion in HeLa cells leads to increased F-actin accumulation, larger cell size, enhanced lamellipodia, altered cofilin phosphorylation and localization, activation of focal adhesion kinase (FAK), enhanced cell spreading, and elevated motility/invasion; CAP1 forms complexes with FAK and Talin, suggesting inside-out integrin signaling underlies the adhesion phenotypes.","method":"Stable shRNA knockdown; in vitro actin polymerization assays; Co-IP of CAP1 with FAK and Talin; Western blotting for cofilin phosphorylation; invasion assays through Matrigel","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus multiple orthogonal functional assays, single lab","pmids":["23737525"],"is_preprint":false},{"year":2014,"finding":"Mouse CAP1 N-terminal half forms hexameric structures and binds F-actin sides and ends, enhancing cofilin-mediated severing via conserved surface residues on the helical-folded domain; the C-terminal β-sheet domain is sufficient to catalyze ADP-actin nucleotide exchange, with the WH2 domain additionally required in the presence of cofilin; these activities are conserved between mouse and yeast Srv2/CAP.","method":"Electron microscopy of oligomeric structures; in vitro F-actin binding and severing assays with domain deletions and surface-residue mutagenesis; nucleotide exchange assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis, structural characterization, and multiple functional assays in a single rigorous study","pmids":["25228691"],"is_preprint":false},{"year":2014,"finding":"CAP1 is phosphorylated at S307 and S309 (human S308/S310); glycogen synthase kinase 3 (GSK3) phosphorylates S309. The phosphomimetic S307D/S309D mutant loses binding to cofilin and causes actin stress fiber accumulation, while the non-phosphorylatable S307A/S309A mutant shows increased cofilin binding and reduced actin binding, indicating phosphorylation facilitates cofilin release for subsequent actin severing cycles.","method":"Mass spectrometry phosphorylation mapping; kinase assays with GSK3; site-directed mutagenesis; Co-IP of CAP1 mutants with cofilin and actin; immunofluorescence in CAP1-knockdown rescue cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis plus binding assays and cell rescue, single lab with multiple orthogonal methods","pmids":["25315833"],"is_preprint":false},{"year":2008,"finding":"Upon apoptosis induction, CAP1 rapidly translocates to mitochondria independently of caspase activation; CAP1 knockdown confers resistance to apoptosis inducers; CAP1 overexpression stimulates cofilin-induced apoptosis; translocation requires the N-terminal mitochondrial-targeting domain and the C-terminal actin-binding domain.","method":"Subcellular fractionation and immunofluorescence during apoptosis; CAP1 knockdown with apoptosis assays; domain-deletion overexpression constructs; co-expression with cofilin","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, domain-deletion analysis, single lab","pmids":["18716285"],"is_preprint":false},{"year":2008,"finding":"CAP1 (adenylyl cyclase-associated protein 1) is identified as a substrate of MMP-9/gelatinase B; MMP-9 cleaves CAP1 with high efficiency comparable to gelatin; CAP1 is present in extracellular milieu in vivo in urine of patients with renal failure where activated MMP-9 is also detected.","method":"In vitro MMP-9 cleavage assay; mass spectrometry substrate identification from dying human myelomonocytic cells; urine analysis from autoimmune disease patients","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay with MS identification, single lab, no mutagenesis of cleavage site","pmids":["18671965"],"is_preprint":false},{"year":2017,"finding":"Cadmium (Cd2+) induces site-specific Cys29-dependent disulfide dimerization of CAP1 in rat renal mesangial cells; this dimer shows enriched association with cofilin and the cofilin-F-actin complex, promoting F-actin depolymerization; cells expressing a Cys29-mutant CAP1 incapable of dimerization are protected against Cd2+-induced cytoskeletal disruption.","method":"F-actin sedimentation assays; GST-cofilin pulldown; site-directed mutagenesis of Cys29; siRNA silencing; diamide cross-linking; reducing agent experiments","journal":"Archives of toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis, pulldown, sedimentation, and functional rescue, single lab","pmids":["29222746"],"is_preprint":false},{"year":2018,"finding":"CAP1 binds Rap1 GTPase in a GTP-independent, geranylgeranyl-specific manner via Rap1's C-terminal hypervariable region; the interaction is mediated by CAP1's C-terminal hydrophobic β-sheet domain; deltarasin (PDEδ disruptor) blocks the Rap1-CAP1 interaction; computational modeling shows lipid insertion into the β-solenoid interior stabilizes binding.","method":"Co-IP; GST pulldown; domain-deletion and mutagenesis; bio-layer interferometry; pharmacological competition with deltarasin; computational modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical binding assays with mutagenesis, biophysical affinity measurement, structural modeling, and pharmacological validation, single lab with multiple methods","pmids":["29618512"],"is_preprint":false},{"year":2021,"finding":"CAP1 binds and activates mammalian adenylyl cyclase in vitro via its N-terminal domain RLE motifs interacting with cyclase catalytic loops (C1a/C2a); CAP1 modulates cAMP levels in live cells in a Rap1-dependent manner; CAP1 overexpression/knockdown affects cAMP-dependent cell proliferation in an RLE motif-dependent manner, constituting a CAP1-cyclase-Rap1 positive feedback regulatory unit.","method":"In vitro adenylyl cyclase activity assays; FRET-based cAMP sensor in live cells; CAP1 overexpression/knockdown; N-terminal domain deletions and RLE motif mutagenesis; constitutively active/negative Rap1 regulators","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution, live-cell FRET, mutagenesis, multiple orthogonal methods, single lab","pmids":["34099549"],"is_preprint":false},{"year":2021,"finding":"CAP1 is essential for cofilin1 function in growth cone actin dynamics; CAP1 knockout neurons show growth cone morphology defects and impaired neuron connectivity; genetic rescue experiments in CAP1/cofilin1 double-KO neurons demonstrated mutual functional interdependence—CAP1 was required for cofilin1 function and vice versa.","method":"Gene-targeted mouse KO; super-resolution microscopy; live cell imaging; pharmacological actin manipulation; double-KO rescue experiments in hippocampal neurons","journal":"Progress in neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via double-KO rescue, super-resolution imaging, multiple orthogonal methods, single lab","pmids":["33845164"],"is_preprint":false},{"year":2021,"finding":"CAP1 is enriched in dendritic spines; CAP1 deficiency impairs synaptic F-actin organization and dynamics and alters spine morphology; CAP1 cooperates with cofilin1 in spines through its helical folded domain; CAP1 and cofilin1 are functionally interdependent in control of spine morphology.","method":"Super-resolution microscopy; live cell imaging; CAP1-KO hippocampal neurons; domain-deletion rescue experiments; cofilin1 epistasis analysis","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — gene-targeted KO, super-resolution, domain-deletion rescue, functional epistasis, single lab","pmids":["36264429"],"is_preprint":false},{"year":2016,"finding":"CAP1 forms a complex with adenylyl cyclase 3 (AC3) and G-actin in pancreatic cancer cells; upon cAMP elevation by forskolin via AC3 activation, a rapid AC3/CAP1/G-actin complex forms that inhibits filopodia formation and cell motility.","method":"Western blotting; Co-IP of AC3, CAP1, and G-actin; AC1/AC3 knockdown; cell migration and filopodia assays","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP complex formation confirmed, functional cell assays, single lab, single study","pmids":["27891679"],"is_preprint":false},{"year":2018,"finding":"CAP1 functions as a receptor for resistin on human monocytes/macrophages; CAP1 siRNA silencing abolishes resistin-induced EMT marker induction (SNAIL, ZEB1, vimentin), SNAIL/ZEB1 nuclear translocation, and MCF-7 cell migration, demonstrating CAP1-dependent signaling downstream of resistin.","method":"siRNA-mediated CAP1 knockdown; Western blotting for EMT markers; qPCR array; wound-healing migration assay","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — knockdown with defined molecular readouts, single lab, single study","pmids":["31085453"],"is_preprint":false},{"year":2019,"finding":"CAP1 knockdown in pancreatic cancer cells enhances actin stress fibers, reduces cell motility and invasion; phosphorylation at the S308/S310 tandem site (elevated by hyper-active GSK3 in pancreatic cancer) is required for CAP1 function in invasiveness; GSK3 inhibition reduces motility; CAP1 depletion reduces FAK activity and cell adhesion; PDGF induces CAP1 dephosphorylation.","method":"CAP1 shRNA knockdown; phosphomimetic/non-phosphorylatable mutant rescue; GSK3 inhibitor treatment; Matrigel invasion assay; FAK activity measurement; PDGF stimulation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphor-mutant rescue experiments, kinase inhibitor, multiple cellular phenotypes, single lab","pmids":["30894654"],"is_preprint":false},{"year":2016,"finding":"CAP1 exerts cell-type-dependent functions in breast cancer invasiveness mediated by ERK; depletion of CAP1 in metastatic MDA-MB-231 and BT-549 cells stimulated metastatic potential while inhibiting it in non-metastatic MCF-7 cells; phosphomimetic S307D/S309D mutants had compromised rescue of both invasiveness and proliferation; alterations in FAK and ERK activities were consistent with opposite adhesion phenotypes.","method":"siRNA knockdown in multiple cell lines; phosphomimetic and non-phosphorylatable CAP1 mutant rescue; invasion/proliferation assays; Western blotting for FAK and ERK","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell lines, phospho-mutant rescue, kinase readouts, single lab","pmids":["27173014"],"is_preprint":false},{"year":2018,"finding":"CAP1 knockdown in mouse oocytes impairs meiotic spindle migration and asymmetric division with excessive actin filament accumulation near spindles; cofilin overexpression-mediated actin reduction is rescued by simultaneous CAP1 knockdown; co-expression of human CAP1 and cofilin synergistically decreases cytoplasmic actin; CAP1 overexpression reduces phosphorylated cofilin, indicating CAP1 facilitates actin depolymerization via ADF/cofilin interaction.","method":"Morpholino-mediated knockdown in mouse oocytes; confocal imaging; cofilin co-expression experiments; Western blotting for phospho-cofilin","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with multiple orthogonal readouts, single lab","pmids":["30404832"],"is_preprint":false},{"year":2022,"finding":"CAP1 binds the M1 and M3 subdomains of PCSK9's C-terminal Cys/His-rich domain (CHRD); this interaction stabilizes the closed conformation of PCSK9, exposing the M2 subdomain required for PCSK9-mediated LDLR degradation; CAP1 is secreted by hepatic cells; CAP1 siRNA only partially inhibited PCSK9 activity on LDLR; CAP1 prevents binding of inhibitory nanobody P1.40.","method":"X-ray crystallography of CHRD-P1.40 complex at 2.2 Å; site-directed mutagenesis; bio-layer interferometry; deep mutational scanning; SAXS; CAP1 siRNA knockdown; immunocytochemistry for LDLR","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 1 / Moderate — X-ray structure, mutagenesis, biophysical affinity measurement, SAXS, and functional cell assays, single lab with multiple orthogonal methods","pmids":["36566984"],"is_preprint":false},{"year":2023,"finding":"CAP1 mediates cAMP signals through Epac and PKA effectors to activate Rap1, stimulating matrix adhesion in colon cancer cells; CAP1 knockdown abolishes the stimulatory effects of forskolin, isoproterenol, Epac, and PKA on matrix adhesion and reduces FAK and Rap1 activities in SW480 cells.","method":"CAP1 siRNA knockdown; cAMP activator (forskolin, isoproterenol) treatments; Epac and PKA pathway modulation; matrix adhesion assays; FAK and Rap1 activity measurements","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis using pharmacological cAMP pathway tools, multiple pathway readouts, single lab","pmids":["36621727"],"is_preprint":false},{"year":2021,"finding":"CAP1 promotes RNA polymerase II-Ser2 phosphorylation by facilitating CDK9 activity, thereby enhancing transcription elongation; this function depends on CAP1's actin-depolymerization activity in the nucleoplasm.","method":"CAP1 knockdown and overexpression in A549 cells; ChIP assays for Pol II-Ser2 phosphorylation; CDK9 activity assays; nuclear fractionation; in vivo xenograft confirmation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional assays with molecular readout, single lab, nuclear localization tied to function but mechanism partially inferred","pmids":["33911205"],"is_preprint":false},{"year":2021,"finding":"miR-144/451 directly targets CAP1 mRNA in erythroid cells; enforced CAP1 overexpression inhibits contractile actin ring formation in erythroblasts and blocks terminal differentiation and enucleation, demonstrating a negative regulatory role for CAP1 in erythropoiesis through actin dynamics.","method":"miRNA target validation; CAP1 overexpression in erythroblasts; immunofluorescence of actin rings; differentiation and enucleation assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — gain-of-function with defined actin and differentiation readouts, single lab, single study","pmids":["33496386"],"is_preprint":false},{"year":2021,"finding":"CAP2 overexpression rescues growth cone size, morphology, and differentiation defects in CAP1-deficient neurons, demonstrating functional redundancy of CAP1 and CAP2 in differentiating neurons.","method":"CAP1-KO mouse neurons; CAP2-KO mouse; CAP2 overexpression rescue in CAP1-KO neurons; growth cone morphology and motility imaging; brain anatomy analysis","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue across two KO lines, direct functional readout, single lab","pmids":["34204261"],"is_preprint":false}],"current_model":"CAP1 (cyclase-associated protein 1) is a multidomain actin regulator whose N-terminal hexameric domain binds F-actin and enhances cofilin-mediated severing, while the C-terminal β-sheet domain catalyzes ADP-to-ATP nucleotide exchange on actin monomers and serves as a geranylgeranyl-binding interface for Rap1; phosphorylation at the tandem S307/S309 site by GSK3 controls cofilin binding and release, cycling CAP1 through its actin-turnover function; CAP1 also translocates to mitochondria to promote cofilin-dependent apoptosis, acts as a cell-surface receptor for resistin linking adipokine signaling to EMT and inflammatory cascades, binds and activates adenylyl cyclase via RLE motifs in a Rap1-dependent positive feedback loop that modulates cAMP microdomains, and enhances PCSK9 activity by stabilizing its closed conformation to promote LDLR degradation."},"narrative":{"mechanistic_narrative":"CAP1 (cyclase-associated protein 1) is a multidomain regulator of actin filament turnover that couples cofilin-mediated severing to monomer recharging [PMID:11950878, PMID:25228691]. Its N-terminal helical domain forms hexameric assemblies that bind F-actin sides and ends and enhance cofilin-mediated severing/pointed-end depolymerization, while the C-terminal β-sheet domain catalyzes ADP-to-ATP nucleotide exchange on G-actin to recycle monomers for renewed elongation; the N-terminal domain relieves cofilin's inhibition of nucleotide exchange, enabling rapid filament turnover [PMID:11950878, PMID:25228691]. CAP1 colocalizes with and is functionally interdependent with cofilin-1, and its loss causes excess F-actin, cofilin mislocalization, and defects in cell morphology, migration, endocytosis, growth-cone dynamics, dendritic-spine morphology, and meiotic spindle positioning [PMID:15004221, PMID:33845164, PMID:36264429, PMID:30404832]. This actin-turnover cycle is gated by tandem phosphorylation at S307/S309 (human S308/S310) by GSK3: phosphomimetic mutants lose cofilin binding and accumulate stress fibers whereas non-phosphorylatable mutants bind cofilin more tightly, so phosphorylation drives cofilin release between severing cycles [PMID:25315833]. Through this cytoskeletal activity and complexes with FAK and Talin, CAP1 modulates integrin-based adhesion, FAK/ERK signaling, and cancer cell invasiveness in a cell-type-dependent manner [PMID:23737525, PMID:27173014]. Beyond actin, CAP1 binds prenylated Rap1 via its C-terminal β-sheet domain and binds and activates adenylyl cyclase through N-terminal RLE motifs, forming a Rap1-dependent cyclase feedback unit that tunes cAMP and downstream Epac/PKA-driven Rap1 activation and adhesion [PMID:29618512, PMID:34099549, PMID:36621727]. Additional reported activities include translocation to mitochondria to promote cofilin-dependent apoptosis [PMID:18716285], receptor function for resistin upstream of EMT signaling [PMID:31085453], stabilization of the closed PCSK9 conformation to promote LDLR degradation [PMID:36566984], and promotion of CDK9-dependent RNA Pol II Ser2 phosphorylation and transcription elongation [PMID:33911205].","teleology":[{"year":2002,"claim":"Established the bipartite biochemical logic of CAP1: how a single protein could both promote filament disassembly and recharge monomers for regrowth.","evidence":"Co-IP from HEK293 and in vitro domain-deletion depolymerization and nucleotide-exchange assays","pmids":["11950878"],"confidence":"High","gaps":["Did not resolve the structural basis of the N-terminal cofilin/actin interaction","Stoichiometry and oligomeric state untested"]},{"year":2004,"claim":"Showed CAP1 is required in cells, not just in vitro, for correct cofilin-1 localization and actin-dependent processes.","evidence":"siRNA knockdown in NIH3T3 and B16F1 with colocalization, migration, and endocytosis assays","pmids":["15004221"],"confidence":"High","gaps":["Mechanism linking CAP1 loss to cofilin aggregation not defined","No domain mapping of the cellular requirement"]},{"year":2008,"claim":"Identified two non-canonical contexts for CAP1: apoptotic mitochondrial translocation and extracellular presence as an MMP-9 substrate.","evidence":"Subcellular fractionation during apoptosis with domain-deletion constructs; in vitro MMP-9 cleavage with MS substrate identification and patient urine analysis","pmids":["18716285","18671965"],"confidence":"Medium","gaps":["Mitochondrial targeting signal mapped only by deletion, not a defined motif","MMP-9 cleavage site not mutagenized; physiological role of extracellular CAP1 unclear"]},{"year":2013,"claim":"Connected CAP1's actin function to adhesion signaling by demonstrating physical association with FAK and Talin and effects on integrin-based motility/invasion.","evidence":"Stable shRNA knockdown in HeLa with reciprocal Co-IP, actin polymerization, and Matrigel invasion assays","pmids":["23737525"],"confidence":"High","gaps":["Direct vs indirect nature of FAK/Talin binding not resolved","Did not establish whether adhesion effects are separable from actin turnover"]},{"year":2014,"claim":"Resolved the structural and regulatory mechanism: hexameric N-terminal domain severs while a GSK3-phosphorylated tandem serine site cycles cofilin binding/release.","evidence":"EM of oligomers plus in vitro severing/nucleotide-exchange with mutagenesis; MS phospho-mapping, GSK3 kinase assays, and phospho-mutant Co-IP and rescue","pmids":["25228691","25315833"],"confidence":"High","gaps":["High-resolution structure of the actin-bound hexamer absent","Upstream signals controlling GSK3 toward CAP1 not defined"]},{"year":2016,"claim":"Revealed CAP1's intersection with cAMP machinery through complexes with adenylyl cyclase 3 and G-actin and cell-type-dependent control of invasiveness.","evidence":"Co-IP of AC3/CAP1/G-actin and migration/filopodia assays in pancreatic cancer cells; siRNA and phospho-mutant rescue with FAK/ERK readouts in breast cancer lines","pmids":["27891679","27173014"],"confidence":"Medium","gaps":["Directness of the AC3/CAP1/G-actin complex assembly not biochemically reconstituted","Determinants of opposite cell-type-dependent outcomes unexplained"]},{"year":2018,"claim":"Defined CAP1 as a prenyl-specific Rap1 partner and a resistin receptor, expanding it into lipid-dependent signaling and adipokine-driven EMT.","evidence":"Co-IP/GST pulldown, BLI, deltarasin competition and modeling for Rap1; siRNA with EMT marker and migration readouts for resistin","pmids":["29618512","31085453"],"confidence":"Medium","gaps":["Functional consequence of geranylgeranyl-dependent Rap1 binding in vivo unresolved","Resistin receptor role rests on knockdown without direct binding kinetics"]},{"year":2021,"claim":"Demonstrated CAP1 directly activates adenylyl cyclase via RLE motifs in a Rap1-dependent feedback loop, and established its essential, cofilin-interdependent role in neuronal growth cones and spines plus a nuclear transcription-elongation function.","evidence":"In vitro cyclase assays, live-cell cAMP FRET, RLE mutagenesis; CAP1-KO/double-KO mouse neuron rescue with super-resolution imaging; ChIP and CDK9 assays in A549; miRNA and overexpression in erythroblasts","pmids":["34099549","33845164","36264429","33911205","33496386"],"confidence":"High","gaps":["Structural basis of the RLE–cyclase catalytic-loop interaction not solved","How nuclear actin depolymerization couples to CDK9 activity is inferred","In vivo relevance of erythroid negative regulation untested"]},{"year":2022,"claim":"Showed CAP1 functions extracellularly to enhance PCSK9-mediated LDLR degradation by stabilizing PCSK9's active closed conformation.","evidence":"X-ray crystallography of CHRD-P1.40, BLI, deep mutational scanning, SAXS, and CAP1 siRNA with LDLR readout","pmids":["36566984"],"confidence":"High","gaps":["siRNA only partially inhibited PCSK9 activity, leaving CAP1-independent contribution undefined","Physiological/clinical impact on cholesterol metabolism not established"]},{"year":2023,"claim":"Placed CAP1 downstream of cAMP effectors Epac and PKA as the node relaying these signals to Rap1 and FAK for matrix adhesion.","evidence":"CAP1 siRNA with forskolin/isoproterenol/Epac/PKA modulation and FAK/Rap1 activity readouts in colon cancer cells","pmids":["36621727"],"confidence":"Medium","gaps":["Direct molecular link between Epac/PKA and CAP1 not shown","Epistasis from pharmacology alone, no reconstitution"]},{"year":null,"claim":"How CAP1's distinct activities — actin turnover, cyclase/Rap1 signaling, mitochondrial apoptosis, surface resistin receptor, and extracellular PCSK9 enhancement — are coordinated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model partitioning CAP1 pools across cytosol, nucleus, mitochondria, plasma membrane, and secretion","Whether phosphorylation or prenyl/lipid binding switches between functions is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,3,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,9,4]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[8]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,0]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,3,11]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[19]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[13]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[6,17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,18,8]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[2,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[17]}],"complexes":[],"partners":["CFL1","ACTB","RAP1A","ADCY3","PTK2","TLN1","PCSK9","GSK3B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q01518","full_name":"Adenylyl cyclase-associated protein 1","aliases":[],"length_aa":475,"mass_kda":51.9,"function":"Directly regulates filament dynamics and has been implicated in a number of complex developmental and morphological processes, including mRNA localization and the establishment of cell polarity","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q01518/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CAP1","classification":"Common Essential","n_dependent_lines":809,"n_total_lines":1208,"dependency_fraction":0.6697019867549668},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTG1","stoichiometry":10.0},{"gene":"ACTB","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CAP1","total_profiled":1310},"omim":[{"mim_id":"618385","title":"CYCLASE-ASSOCIATED ACTIN CYTOSKELETON REGULATORY PROTEIN 2; CAP2","url":"https://www.omim.org/entry/618385"},{"mim_id":"617801","title":"CYCLASE-ASSOCIATED ACTIN CYTOSKELETON REGULATORY PROTEIN 1; CAP1","url":"https://www.omim.org/entry/617801"},{"mim_id":"616190","title":"CAP METHYLTRANSFERASE 2; CMTR2","url":"https://www.omim.org/entry/616190"},{"mim_id":"616189","title":"CAP METHYLTRANSFERASE 1; CMTR1","url":"https://www.omim.org/entry/616189"},{"mim_id":"616135","title":"INTERFERON-INDUCED PROTEIN WITH TETRATRICOPEPTIDE REPEATS 5; IFIT5","url":"https://www.omim.org/entry/616135"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CAP1"},"hgnc":{"alias_symbol":["CAP"],"prev_symbol":[]},"alphafold":{"accession":"Q01518","domains":[{"cath_id":"1.25.40.330","chopping":"41-202","consensus_level":"high","plddt":94.6188,"start":41,"end":202},{"cath_id":"2.160.20.70","chopping":"322-471","consensus_level":"high","plddt":95.2165,"start":322,"end":471}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01518","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01518-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01518-F1-predicted_aligned_error_v6.png","plddt_mean":81.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CAP1","jax_strain_url":"https://www.jax.org/strain/search?query=CAP1"},"sequence":{"accession":"Q01518","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01518.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01518/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01518"}},"corpus_meta":[{"pmid":"16061697","id":"PMC_16061697","title":"The 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research","url":"https://pubmed.ncbi.nlm.nih.gov/26542710","citation_count":6,"is_preprint":false},{"pmid":"15112332","id":"PMC_15112332","title":"Hamster contraception associated protein 1 (CAP1).","date":"2004","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/15112332","citation_count":6,"is_preprint":false},{"pmid":"34148878","id":"PMC_34148878","title":"Relationship of intracellular proteolysis with CAP1 and cofilin1 in non-small-cell lung cancer.","date":"2021","source":"Journal of biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/34148878","citation_count":5,"is_preprint":false},{"pmid":"32504809","id":"PMC_32504809","title":"Roles for Drosophila cap1 2'-O-ribose methyltransferase in the small RNA silencing pathway associated with Argonaute 2.","date":"2020","source":"Insect biochemistry and molecular 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Activity.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/37830556","citation_count":4,"is_preprint":false},{"pmid":"33911205","id":"PMC_33911205","title":"Novel role of CAP1 in regulation RNA polymerase II-mediated transcription elongation depends on its actin-depolymerization activity in nucleoplasm.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/33911205","citation_count":4,"is_preprint":false},{"pmid":"11960715","id":"PMC_11960715","title":"CAP1 expression is developmentally regulated in Xenopus.","date":"2002","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/11960715","citation_count":4,"is_preprint":false},{"pmid":"36162133","id":"PMC_36162133","title":"Correlation between SAP2 and CAP1 in clinical strains of Candida albicans at planktonic and biofilm states.","date":"2022","source":"Canadian journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36162133","citation_count":3,"is_preprint":false},{"pmid":"37773847","id":"PMC_37773847","title":"Role of serum CAP1 protein in the diagnosis of patients with first-time acute myocardial infarction.","date":"2023","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37773847","citation_count":3,"is_preprint":false},{"pmid":"39719238","id":"PMC_39719238","title":"Molecular and cellular mechanisms of PDAC progression based on RETN-CAP1-mediated macrophage-fibroblast crosstalk: Action of ITGB5 and ITGB1 recombinant proteins.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39719238","citation_count":3,"is_preprint":false},{"pmid":"41022574","id":"PMC_41022574","title":"ISOPENTENYL TRANSFERASE3 activation triggers root ammonium hypersensitivity via the cytokinin-ARR10/ARR12-CAP1 signaling pathway.","date":"2025","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/41022574","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51835,"output_tokens":5795,"usd":0.121215,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14458,"output_tokens":4156,"usd":0.088095,"stage2_stop_reason":"end_turn"},"total_usd":0.20931,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"The N-terminal domain of human CAP1 interacts with the actin-cofilin complex and accelerates F-actin depolymerization at the pointed end; the C-terminal domain facilitates filament elongation at the barbed end and stimulates ADP-ATP exchange on G-actin; the N-terminal domain relieves cofilin-mediated inhibition of nucleotide exchange, enabling recycling of both cofilin and actin for rapid filament turnover.\",\n      \"method\": \"Co-immunoprecipitation from HEK293 extracts; in vitro domain-deletion actin depolymerization and nucleotide exchange assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution with domain deletions, multiple orthogonal assays (depolymerization, nucleotide exchange, pulldown), single rigorous study\",\n      \"pmids\": [\"11950878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CAP1 colocalizes with cofilin-1 at dynamic cortical actin regions in mammalian cells; CAP1 knockdown causes accumulation of cofilin-1 into abnormal cytoplasmic aggregates, excessive F-actin, impaired cell morphology, migration, and endocytosis, establishing that CAP1 is required for proper cofilin-1 localization and function in actin dynamics.\",\n      \"method\": \"siRNA knockdown in NIH3T3 and B16F1 cells; immunofluorescence colocalization; cell migration and endocytosis assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KD with multiple defined cellular phenotypes and colocalization, replicated across two cell lines\",\n      \"pmids\": [\"15004221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CAP1 depletion in HeLa cells leads to increased F-actin accumulation, larger cell size, enhanced lamellipodia, altered cofilin phosphorylation and localization, activation of focal adhesion kinase (FAK), enhanced cell spreading, and elevated motility/invasion; CAP1 forms complexes with FAK and Talin, suggesting inside-out integrin signaling underlies the adhesion phenotypes.\",\n      \"method\": \"Stable shRNA knockdown; in vitro actin polymerization assays; Co-IP of CAP1 with FAK and Talin; Western blotting for cofilin phosphorylation; invasion assays through Matrigel\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus multiple orthogonal functional assays, single lab\",\n      \"pmids\": [\"23737525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mouse CAP1 N-terminal half forms hexameric structures and binds F-actin sides and ends, enhancing cofilin-mediated severing via conserved surface residues on the helical-folded domain; the C-terminal β-sheet domain is sufficient to catalyze ADP-actin nucleotide exchange, with the WH2 domain additionally required in the presence of cofilin; these activities are conserved between mouse and yeast Srv2/CAP.\",\n      \"method\": \"Electron microscopy of oligomeric structures; in vitro F-actin binding and severing assays with domain deletions and surface-residue mutagenesis; nucleotide exchange assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis, structural characterization, and multiple functional assays in a single rigorous study\",\n      \"pmids\": [\"25228691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CAP1 is phosphorylated at S307 and S309 (human S308/S310); glycogen synthase kinase 3 (GSK3) phosphorylates S309. The phosphomimetic S307D/S309D mutant loses binding to cofilin and causes actin stress fiber accumulation, while the non-phosphorylatable S307A/S309A mutant shows increased cofilin binding and reduced actin binding, indicating phosphorylation facilitates cofilin release for subsequent actin severing cycles.\",\n      \"method\": \"Mass spectrometry phosphorylation mapping; kinase assays with GSK3; site-directed mutagenesis; Co-IP of CAP1 mutants with cofilin and actin; immunofluorescence in CAP1-knockdown rescue cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis plus binding assays and cell rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25315833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Upon apoptosis induction, CAP1 rapidly translocates to mitochondria independently of caspase activation; CAP1 knockdown confers resistance to apoptosis inducers; CAP1 overexpression stimulates cofilin-induced apoptosis; translocation requires the N-terminal mitochondrial-targeting domain and the C-terminal actin-binding domain.\",\n      \"method\": \"Subcellular fractionation and immunofluorescence during apoptosis; CAP1 knockdown with apoptosis assays; domain-deletion overexpression constructs; co-expression with cofilin\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, domain-deletion analysis, single lab\",\n      \"pmids\": [\"18716285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CAP1 (adenylyl cyclase-associated protein 1) is identified as a substrate of MMP-9/gelatinase B; MMP-9 cleaves CAP1 with high efficiency comparable to gelatin; CAP1 is present in extracellular milieu in vivo in urine of patients with renal failure where activated MMP-9 is also detected.\",\n      \"method\": \"In vitro MMP-9 cleavage assay; mass spectrometry substrate identification from dying human myelomonocytic cells; urine analysis from autoimmune disease patients\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay with MS identification, single lab, no mutagenesis of cleavage site\",\n      \"pmids\": [\"18671965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cadmium (Cd2+) induces site-specific Cys29-dependent disulfide dimerization of CAP1 in rat renal mesangial cells; this dimer shows enriched association with cofilin and the cofilin-F-actin complex, promoting F-actin depolymerization; cells expressing a Cys29-mutant CAP1 incapable of dimerization are protected against Cd2+-induced cytoskeletal disruption.\",\n      \"method\": \"F-actin sedimentation assays; GST-cofilin pulldown; site-directed mutagenesis of Cys29; siRNA silencing; diamide cross-linking; reducing agent experiments\",\n      \"journal\": \"Archives of toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis, pulldown, sedimentation, and functional rescue, single lab\",\n      \"pmids\": [\"29222746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CAP1 binds Rap1 GTPase in a GTP-independent, geranylgeranyl-specific manner via Rap1's C-terminal hypervariable region; the interaction is mediated by CAP1's C-terminal hydrophobic β-sheet domain; deltarasin (PDEδ disruptor) blocks the Rap1-CAP1 interaction; computational modeling shows lipid insertion into the β-solenoid interior stabilizes binding.\",\n      \"method\": \"Co-IP; GST pulldown; domain-deletion and mutagenesis; bio-layer interferometry; pharmacological competition with deltarasin; computational modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical binding assays with mutagenesis, biophysical affinity measurement, structural modeling, and pharmacological validation, single lab with multiple methods\",\n      \"pmids\": [\"29618512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CAP1 binds and activates mammalian adenylyl cyclase in vitro via its N-terminal domain RLE motifs interacting with cyclase catalytic loops (C1a/C2a); CAP1 modulates cAMP levels in live cells in a Rap1-dependent manner; CAP1 overexpression/knockdown affects cAMP-dependent cell proliferation in an RLE motif-dependent manner, constituting a CAP1-cyclase-Rap1 positive feedback regulatory unit.\",\n      \"method\": \"In vitro adenylyl cyclase activity assays; FRET-based cAMP sensor in live cells; CAP1 overexpression/knockdown; N-terminal domain deletions and RLE motif mutagenesis; constitutively active/negative Rap1 regulators\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution, live-cell FRET, mutagenesis, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34099549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CAP1 is essential for cofilin1 function in growth cone actin dynamics; CAP1 knockout neurons show growth cone morphology defects and impaired neuron connectivity; genetic rescue experiments in CAP1/cofilin1 double-KO neurons demonstrated mutual functional interdependence—CAP1 was required for cofilin1 function and vice versa.\",\n      \"method\": \"Gene-targeted mouse KO; super-resolution microscopy; live cell imaging; pharmacological actin manipulation; double-KO rescue experiments in hippocampal neurons\",\n      \"journal\": \"Progress in neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via double-KO rescue, super-resolution imaging, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33845164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CAP1 is enriched in dendritic spines; CAP1 deficiency impairs synaptic F-actin organization and dynamics and alters spine morphology; CAP1 cooperates with cofilin1 in spines through its helical folded domain; CAP1 and cofilin1 are functionally interdependent in control of spine morphology.\",\n      \"method\": \"Super-resolution microscopy; live cell imaging; CAP1-KO hippocampal neurons; domain-deletion rescue experiments; cofilin1 epistasis analysis\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene-targeted KO, super-resolution, domain-deletion rescue, functional epistasis, single lab\",\n      \"pmids\": [\"36264429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CAP1 forms a complex with adenylyl cyclase 3 (AC3) and G-actin in pancreatic cancer cells; upon cAMP elevation by forskolin via AC3 activation, a rapid AC3/CAP1/G-actin complex forms that inhibits filopodia formation and cell motility.\",\n      \"method\": \"Western blotting; Co-IP of AC3, CAP1, and G-actin; AC1/AC3 knockdown; cell migration and filopodia assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP complex formation confirmed, functional cell assays, single lab, single study\",\n      \"pmids\": [\"27891679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CAP1 functions as a receptor for resistin on human monocytes/macrophages; CAP1 siRNA silencing abolishes resistin-induced EMT marker induction (SNAIL, ZEB1, vimentin), SNAIL/ZEB1 nuclear translocation, and MCF-7 cell migration, demonstrating CAP1-dependent signaling downstream of resistin.\",\n      \"method\": \"siRNA-mediated CAP1 knockdown; Western blotting for EMT markers; qPCR array; wound-healing migration assay\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — knockdown with defined molecular readouts, single lab, single study\",\n      \"pmids\": [\"31085453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CAP1 knockdown in pancreatic cancer cells enhances actin stress fibers, reduces cell motility and invasion; phosphorylation at the S308/S310 tandem site (elevated by hyper-active GSK3 in pancreatic cancer) is required for CAP1 function in invasiveness; GSK3 inhibition reduces motility; CAP1 depletion reduces FAK activity and cell adhesion; PDGF induces CAP1 dephosphorylation.\",\n      \"method\": \"CAP1 shRNA knockdown; phosphomimetic/non-phosphorylatable mutant rescue; GSK3 inhibitor treatment; Matrigel invasion assay; FAK activity measurement; PDGF stimulation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphor-mutant rescue experiments, kinase inhibitor, multiple cellular phenotypes, single lab\",\n      \"pmids\": [\"30894654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CAP1 exerts cell-type-dependent functions in breast cancer invasiveness mediated by ERK; depletion of CAP1 in metastatic MDA-MB-231 and BT-549 cells stimulated metastatic potential while inhibiting it in non-metastatic MCF-7 cells; phosphomimetic S307D/S309D mutants had compromised rescue of both invasiveness and proliferation; alterations in FAK and ERK activities were consistent with opposite adhesion phenotypes.\",\n      \"method\": \"siRNA knockdown in multiple cell lines; phosphomimetic and non-phosphorylatable CAP1 mutant rescue; invasion/proliferation assays; Western blotting for FAK and ERK\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell lines, phospho-mutant rescue, kinase readouts, single lab\",\n      \"pmids\": [\"27173014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CAP1 knockdown in mouse oocytes impairs meiotic spindle migration and asymmetric division with excessive actin filament accumulation near spindles; cofilin overexpression-mediated actin reduction is rescued by simultaneous CAP1 knockdown; co-expression of human CAP1 and cofilin synergistically decreases cytoplasmic actin; CAP1 overexpression reduces phosphorylated cofilin, indicating CAP1 facilitates actin depolymerization via ADF/cofilin interaction.\",\n      \"method\": \"Morpholino-mediated knockdown in mouse oocytes; confocal imaging; cofilin co-expression experiments; Western blotting for phospho-cofilin\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"30404832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CAP1 binds the M1 and M3 subdomains of PCSK9's C-terminal Cys/His-rich domain (CHRD); this interaction stabilizes the closed conformation of PCSK9, exposing the M2 subdomain required for PCSK9-mediated LDLR degradation; CAP1 is secreted by hepatic cells; CAP1 siRNA only partially inhibited PCSK9 activity on LDLR; CAP1 prevents binding of inhibitory nanobody P1.40.\",\n      \"method\": \"X-ray crystallography of CHRD-P1.40 complex at 2.2 Å; site-directed mutagenesis; bio-layer interferometry; deep mutational scanning; SAXS; CAP1 siRNA knockdown; immunocytochemistry for LDLR\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — X-ray structure, mutagenesis, biophysical affinity measurement, SAXS, and functional cell assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36566984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CAP1 mediates cAMP signals through Epac and PKA effectors to activate Rap1, stimulating matrix adhesion in colon cancer cells; CAP1 knockdown abolishes the stimulatory effects of forskolin, isoproterenol, Epac, and PKA on matrix adhesion and reduces FAK and Rap1 activities in SW480 cells.\",\n      \"method\": \"CAP1 siRNA knockdown; cAMP activator (forskolin, isoproterenol) treatments; Epac and PKA pathway modulation; matrix adhesion assays; FAK and Rap1 activity measurements\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis using pharmacological cAMP pathway tools, multiple pathway readouts, single lab\",\n      \"pmids\": [\"36621727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CAP1 promotes RNA polymerase II-Ser2 phosphorylation by facilitating CDK9 activity, thereby enhancing transcription elongation; this function depends on CAP1's actin-depolymerization activity in the nucleoplasm.\",\n      \"method\": \"CAP1 knockdown and overexpression in A549 cells; ChIP assays for Pol II-Ser2 phosphorylation; CDK9 activity assays; nuclear fractionation; in vivo xenograft confirmation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional assays with molecular readout, single lab, nuclear localization tied to function but mechanism partially inferred\",\n      \"pmids\": [\"33911205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-144/451 directly targets CAP1 mRNA in erythroid cells; enforced CAP1 overexpression inhibits contractile actin ring formation in erythroblasts and blocks terminal differentiation and enucleation, demonstrating a negative regulatory role for CAP1 in erythropoiesis through actin dynamics.\",\n      \"method\": \"miRNA target validation; CAP1 overexpression in erythroblasts; immunofluorescence of actin rings; differentiation and enucleation assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — gain-of-function with defined actin and differentiation readouts, single lab, single study\",\n      \"pmids\": [\"33496386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CAP2 overexpression rescues growth cone size, morphology, and differentiation defects in CAP1-deficient neurons, demonstrating functional redundancy of CAP1 and CAP2 in differentiating neurons.\",\n      \"method\": \"CAP1-KO mouse neurons; CAP2-KO mouse; CAP2 overexpression rescue in CAP1-KO neurons; growth cone morphology and motility imaging; brain anatomy analysis\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue across two KO lines, direct functional readout, single lab\",\n      \"pmids\": [\"34204261\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CAP1 (cyclase-associated protein 1) is a multidomain actin regulator whose N-terminal hexameric domain binds F-actin and enhances cofilin-mediated severing, while the C-terminal β-sheet domain catalyzes ADP-to-ATP nucleotide exchange on actin monomers and serves as a geranylgeranyl-binding interface for Rap1; phosphorylation at the tandem S307/S309 site by GSK3 controls cofilin binding and release, cycling CAP1 through its actin-turnover function; CAP1 also translocates to mitochondria to promote cofilin-dependent apoptosis, acts as a cell-surface receptor for resistin linking adipokine signaling to EMT and inflammatory cascades, binds and activates adenylyl cyclase via RLE motifs in a Rap1-dependent positive feedback loop that modulates cAMP microdomains, and enhances PCSK9 activity by stabilizing its closed conformation to promote LDLR degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CAP1 (cyclase-associated protein 1) is a multidomain regulator of actin filament turnover that couples cofilin-mediated severing to monomer recharging [#0, #3]. Its N-terminal helical domain forms hexameric assemblies that bind F-actin sides and ends and enhance cofilin-mediated severing/pointed-end depolymerization, while the C-terminal β-sheet domain catalyzes ADP-to-ATP nucleotide exchange on G-actin to recycle monomers for renewed elongation; the N-terminal domain relieves cofilin's inhibition of nucleotide exchange, enabling rapid filament turnover [#0, #3]. CAP1 colocalizes with and is functionally interdependent with cofilin-1, and its loss causes excess F-actin, cofilin mislocalization, and defects in cell morphology, migration, endocytosis, growth-cone dynamics, dendritic-spine morphology, and meiotic spindle positioning [#1, #10, #11, #16]. This actin-turnover cycle is gated by tandem phosphorylation at S307/S309 (human S308/S310) by GSK3: phosphomimetic mutants lose cofilin binding and accumulate stress fibers whereas non-phosphorylatable mutants bind cofilin more tightly, so phosphorylation drives cofilin release between severing cycles [#4]. Through this cytoskeletal activity and complexes with FAK and Talin, CAP1 modulates integrin-based adhesion, FAK/ERK signaling, and cancer cell invasiveness in a cell-type-dependent manner [#2, #15]. Beyond actin, CAP1 binds prenylated Rap1 via its C-terminal β-sheet domain and binds and activates adenylyl cyclase through N-terminal RLE motifs, forming a Rap1-dependent cyclase feedback unit that tunes cAMP and downstream Epac/PKA-driven Rap1 activation and adhesion [#8, #9, #18]. Additional reported activities include translocation to mitochondria to promote cofilin-dependent apoptosis [#5], receptor function for resistin upstream of EMT signaling [#13], stabilization of the closed PCSK9 conformation to promote LDLR degradation [#17], and promotion of CDK9-dependent RNA Pol II Ser2 phosphorylation and transcription elongation [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the bipartite biochemical logic of CAP1: how a single protein could both promote filament disassembly and recharge monomers for regrowth.\",\n      \"evidence\": \"Co-IP from HEK293 and in vitro domain-deletion depolymerization and nucleotide-exchange assays\",\n      \"pmids\": [\"11950878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of the N-terminal cofilin/actin interaction\", \"Stoichiometry and oligomeric state untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed CAP1 is required in cells, not just in vitro, for correct cofilin-1 localization and actin-dependent processes.\",\n      \"evidence\": \"siRNA knockdown in NIH3T3 and B16F1 with colocalization, migration, and endocytosis assays\",\n      \"pmids\": [\"15004221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking CAP1 loss to cofilin aggregation not defined\", \"No domain mapping of the cellular requirement\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified two non-canonical contexts for CAP1: apoptotic mitochondrial translocation and extracellular presence as an MMP-9 substrate.\",\n      \"evidence\": \"Subcellular fractionation during apoptosis with domain-deletion constructs; in vitro MMP-9 cleavage with MS substrate identification and patient urine analysis\",\n      \"pmids\": [\"18716285\", \"18671965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial targeting signal mapped only by deletion, not a defined motif\", \"MMP-9 cleavage site not mutagenized; physiological role of extracellular CAP1 unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected CAP1's actin function to adhesion signaling by demonstrating physical association with FAK and Talin and effects on integrin-based motility/invasion.\",\n      \"evidence\": \"Stable shRNA knockdown in HeLa with reciprocal Co-IP, actin polymerization, and Matrigel invasion assays\",\n      \"pmids\": [\"23737525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect nature of FAK/Talin binding not resolved\", \"Did not establish whether adhesion effects are separable from actin turnover\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the structural and regulatory mechanism: hexameric N-terminal domain severs while a GSK3-phosphorylated tandem serine site cycles cofilin binding/release.\",\n      \"evidence\": \"EM of oligomers plus in vitro severing/nucleotide-exchange with mutagenesis; MS phospho-mapping, GSK3 kinase assays, and phospho-mutant Co-IP and rescue\",\n      \"pmids\": [\"25228691\", \"25315833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the actin-bound hexamer absent\", \"Upstream signals controlling GSK3 toward CAP1 not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed CAP1's intersection with cAMP machinery through complexes with adenylyl cyclase 3 and G-actin and cell-type-dependent control of invasiveness.\",\n      \"evidence\": \"Co-IP of AC3/CAP1/G-actin and migration/filopodia assays in pancreatic cancer cells; siRNA and phospho-mutant rescue with FAK/ERK readouts in breast cancer lines\",\n      \"pmids\": [\"27891679\", \"27173014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of the AC3/CAP1/G-actin complex assembly not biochemically reconstituted\", \"Determinants of opposite cell-type-dependent outcomes unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined CAP1 as a prenyl-specific Rap1 partner and a resistin receptor, expanding it into lipid-dependent signaling and adipokine-driven EMT.\",\n      \"evidence\": \"Co-IP/GST pulldown, BLI, deltarasin competition and modeling for Rap1; siRNA with EMT marker and migration readouts for resistin\",\n      \"pmids\": [\"29618512\", \"31085453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of geranylgeranyl-dependent Rap1 binding in vivo unresolved\", \"Resistin receptor role rests on knockdown without direct binding kinetics\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated CAP1 directly activates adenylyl cyclase via RLE motifs in a Rap1-dependent feedback loop, and established its essential, cofilin-interdependent role in neuronal growth cones and spines plus a nuclear transcription-elongation function.\",\n      \"evidence\": \"In vitro cyclase assays, live-cell cAMP FRET, RLE mutagenesis; CAP1-KO/double-KO mouse neuron rescue with super-resolution imaging; ChIP and CDK9 assays in A549; miRNA and overexpression in erythroblasts\",\n      \"pmids\": [\"34099549\", \"33845164\", \"36264429\", \"33911205\", \"33496386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the RLE–cyclase catalytic-loop interaction not solved\", \"How nuclear actin depolymerization couples to CDK9 activity is inferred\", \"In vivo relevance of erythroid negative regulation untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed CAP1 functions extracellularly to enhance PCSK9-mediated LDLR degradation by stabilizing PCSK9's active closed conformation.\",\n      \"evidence\": \"X-ray crystallography of CHRD-P1.40, BLI, deep mutational scanning, SAXS, and CAP1 siRNA with LDLR readout\",\n      \"pmids\": [\"36566984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"siRNA only partially inhibited PCSK9 activity, leaving CAP1-independent contribution undefined\", \"Physiological/clinical impact on cholesterol metabolism not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed CAP1 downstream of cAMP effectors Epac and PKA as the node relaying these signals to Rap1 and FAK for matrix adhesion.\",\n      \"evidence\": \"CAP1 siRNA with forskolin/isoproterenol/Epac/PKA modulation and FAK/Rap1 activity readouts in colon cancer cells\",\n      \"pmids\": [\"36621727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between Epac/PKA and CAP1 not shown\", \"Epistasis from pharmacology alone, no reconstitution\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CAP1's distinct activities — actin turnover, cyclase/Rap1 signaling, mitochondrial apoptosis, surface resistin receptor, and extracellular PCSK9 enhancement — are coordinated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model partitioning CAP1 pools across cytosol, nucleus, mitochondria, plasma membrane, and secretion\", \"Whether phosphorylation or prenyl/lipid binding switches between functions is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 3, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 9, 4]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 0]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 3, 11]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [6, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0030036\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 18, 8]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CFL1\", \"ACTB\", \"RAP1A\", \"ADCY3\", \"PTK2\", \"TLN1\", \"PCSK9\", \"GSK3B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}