{"gene":"DOCK1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1996,"finding":"DOCK180 was cloned as a 180 kDa CRK SH3-binding protein; when artificially membrane-targeted via a farnesylation signal, it localized to the cytoplasmic membrane and changed cell morphology from spindle to flat polygonal, indicating that membrane translocation of DOCK180 is required for its morphological effects.","method":"Molecular cloning, farnesylation membrane-targeting construct, morphological assay in 3T3 cells","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional experiment with membrane-targeting construct, single lab but two orthogonal approaches (localization + phenotype)","pmids":["8657152"],"is_preprint":false},{"year":1998,"finding":"DOCK180 directly binds Rac1 (but not RhoA or Cdc42Hs), overexpression increases GTP-bound Rac1 in cells, and coexpression of CrkII and p130Cas enhances DOCK180-dependent Rac1 activation; dominant-negative Rac1 suppresses DOCK180-induced membrane spreading, establishing DOCK180 as a novel activator of Rac1 in integrin signaling.","method":"GTP-Rac1 pulldown assay, overexpression, dominant-negative Rac1, JNK activation assay in 293T cells","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding and GTP-loading assays, dominant-negative epistasis, replicated by multiple subsequent labs","pmids":["9808620"],"is_preprint":false},{"year":1998,"finding":"CED-5, the C. elegans ortholog of DOCK180, is required for engulfment of cell corpses and cell migration of distal tip cells; human DOCK180 expression in C. elegans rescues the cell-migration defect of ced-5 mutants, establishing functional conservation of the CDM family in surface extension during engulfment.","method":"C. elegans genetics, transgenic rescue with human DOCK180, phenotypic analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with transgenic rescue, replicated across labs in subsequent work","pmids":["9548255"],"is_preprint":false},{"year":1998,"finding":"DOCK180 is phosphorylated and associates with CrkII specifically upon integrin stimulation or v-src/v-crk transformation; DOCK180 expression induces hyperphosphorylation of p130Cas and increased CrkII–p130Cas complex formation; coexpression of p130Cas and CrkII with DOCK180 induces focal-adhesion-localized membrane spreading, placing DOCK180 as an upregulator of the CrkII–p130Cas integrin signaling complex.","method":"Co-immunoprecipitation, reconstitution in NIH 3T3 and 3Y1 cells, phosphorylation assays, integrin stimulation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus reconstitution experiment showing p130Cas hyperphosphorylation, replicated in subsequent studies","pmids":["9733740"],"is_preprint":false},{"year":1998,"finding":"Drosophila Myoblast City (MBC), the DOCK180 homolog, is required for Rac-specific signaling in dorsal closure, myogenesis, and neural development; mammalian DOCK180 associates with Rac but not Cdc42 in a nucleotide-independent manner, establishing Mbc/DOCK180 as a specific upstream regulator of Rac.","method":"Drosophila mutant screen, genetic analysis, co-immunoprecipitation with Rac and Cdc42","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic screen plus biochemical binding specificity assay, replicated across organisms","pmids":["9808621"],"is_preprint":false},{"year":2000,"finding":"The αvβ5 integrin recruits the p130Cas–CrkII–DOCK180 molecular complex upon engagement with apoptotic cells, triggering Rac1 activation and phagosome formation; signaling through the β5 cytoplasmic tail is required for internalization, establishing DOCK180 as the effector linking αvβ5 integrin to Rac1 activation during phagocytosis.","method":"Co-immunoprecipitation, Rac1-GTP pulldown, dominant-negative constructs, β5 cytoplasmic tail mutants, phagocytosis assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, GTP pulldown, mutants, functional phagocytosis assay), replicated in later studies","pmids":["11146654"],"is_preprint":false},{"year":2001,"finding":"DOCK180 binds to PtdIns(3,4,5)P3 through a C-terminal basic region; PI3K activation translocates DOCK180 to the plasma membrane without necessarily increasing GTP-Rac in the absence of membrane targeting, indicating PtdIns(3,4,5)P3 controls DOCK180 membrane recruitment.","method":"PtdIns(3,4,5)P3-APB bead pulldown, PI3K co-expression, GTP-Rac assays, deletion mutant analysis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct lipid-binding assay plus PI3K co-expression localization experiment, single lab","pmids":["11171081"],"is_preprint":false},{"year":2001,"finding":"CED-12/ELMO directly binds to CED-5/DOCK180 and forms a ternary complex with CED-2/CrkII; this evolutionarily conserved CED-12–CED-5 complex acts as an upstream activator of Rac1, and ELMO1 functionally cooperates with CrkII and Dock180 to promote phagocytosis and cell shape changes.","method":"Yeast two-hybrid, co-immunoprecipitation, C. elegans genetic rescue, phagocytosis assay in mammalian cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — binding confirmed by multiple methods plus in vivo genetic rescue, independently replicated","pmids":["11595183"],"is_preprint":false},{"year":2001,"finding":"DOCK180 promotes Rac activation through the CED-2/CrkII–CED-5/DOCK180–CED-12/ELMO–CED-10/Rac pathway; CED-12 forms a ternary complex with CED-2 and CED-5 in vitro and its membrane localization is proposed to activate CED-10/Rac leading to cytoskeletal reorganization during cell migration and engulfment.","method":"In vitro protein binding assays, C. elegans genetics, epistasis analysis, cell migration and phagocytosis assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro complex formation plus genetic epistasis in C. elegans, replicated by concurrent work","pmids":["11703940"],"is_preprint":false},{"year":2001,"finding":"Laminin-10/11 preferentially activates Rac (not Rho) via the p130Cas–CrkII–DOCK180 pathway; phosphorylation of p130Cas and increased formation of the p130Cas–CrkII–DOCK180 complex is associated with Rac activation, and CrkII mutants defective in DOCK180 binding suppress cell migration on laminin-10/11.","method":"GTP-Rac/Rho pulldown, co-immunoprecipitation, dominant-negative CrkII mutants, Transwell migration assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, GTP-loading assay, and dominant-negative epistasis, single lab","pmids":["11369773"],"is_preprint":false},{"year":2002,"finding":"A conserved domain within Dock180 (the Docker/DHR-2/CZH2 domain) specifically recognizes nucleotide-free Rac and mediates GTP loading of Rac in vitro; ELMO1 is required for efficient GTP loading in cells, augments the Dock180–Rac interaction, and a trimeric ELMO1–Dock180–Rac1 complex can be detected, establishing the Dock180–ELMO complex as an unconventional bipartite GEF for Rac.","method":"In vitro nucleotide exchange assay, co-immunoprecipitation, domain mapping, cell-based Rac-GTP pulldown","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro GEF reconstitution with domain mapping, trimeric complex detection, independently replicated by Côté & Vuori (2002)","pmids":["12134158"],"is_preprint":false},{"year":2002,"finding":"The DHR-2 domain of DOCK180 specifically binds nucleotide-free Rac and activates Rac in vitro and in vivo; DHR-2 is both necessary and sufficient for Rac activation; several DOCK180-related proteins possess DHR-2 domains with GEF activity toward Rac or Cdc42, defining an evolutionarily conserved superfamily of atypical GEFs.","method":"In vitro nucleotide exchange assay, domain deletion/reconstitution, cell-based Rac-GTP assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution plus domain mutagenesis, independently replicated","pmids":["12432077"],"is_preprint":false},{"year":2003,"finding":"The Dock180–ELMO1 complex, which activates Rac, is required for mammalian cell migration; the Dock180–ELMO1 complex must form and localize to lamellipodia (via ELMO1 N-terminal 330 aa) for migration, not merely general Rac activation; CED-5/Dock180 function in migration in C. elegans also requires complex formation and Rac activation.","method":"Transwell migration assay, domain deletion mutants, C. elegans transgenic rescue, lamellipodia localization by immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple loss-of-function mutants with defined phenotypic readouts in both cell lines and in vivo C. elegans rescue","pmids":["14638695"],"is_preprint":false},{"year":2003,"finding":"RhoG directly interacts with ELMO in a GTP-dependent manner and forms a ternary complex with Dock180, leading to Rac1 activation; the RhoG–Elmo–Dock180 pathway is required for integrin-mediated Rac1 activation, cell spreading, and NGF-induced neurite outgrowth.","method":"Co-immunoprecipitation, GTP-dependent binding assay, dominant-negative and constitutively active RhoG, cell spreading and neurite outgrowth assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — GTP-dependent binding assay establishing direct interaction, plus multiple functional readouts, replicated in subsequent studies","pmids":["12879077"],"is_preprint":false},{"year":2003,"finding":"C. elegans PSR-1 (phosphatidylserine receptor) acts in the same engulfment pathway as CED-5/DOCK180 and CED-12/ELMO, possibly through direct interaction with CED-5 and CED-12, placing the phosphatidylserine receptor upstream of the CED-2–CED-5–CED-10–CED-12 signaling pathway.","method":"C. elegans genetics, in vitro binding assay (PSR-1 binding to PS), epistasis analysis","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in C. elegans plus in vitro PS-binding assay; direct interaction with CED-5 proposed but not fully reconstituted","pmids":["14645848"],"is_preprint":false},{"year":2004,"finding":"The PH domain of ELMO binds the Dock180–Rac complex in trans, stabilizing Rac in the nucleotide-free transition state; this PH-domain-dependent mechanism is essential for phagocytosis and cell migration both in mammalian cells and in C. elegans.","method":"In vitro GEF assay, mutagenesis of ELMO PH domain, phagocytosis and migration assays, C. elegans genetic rescue","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis, functional phagocytosis and migration assays, in vivo C. elegans validation","pmids":["15247908"],"is_preprint":false},{"year":2004,"finding":"MFG-E8 acts as a ligand for αvβ5 integrin, and coexpression of MFG-E8 with αvβ5 integrin potentiates integrin-mediated Rac1 activation; antisense DOCK180 abrogates MFG-E8–αvβ5-mediated Rac activation and impairs phagocytosis of apoptotic cells, establishing DOCK180 as the essential GEF downstream of the MFG-E8–αvβ5 signaling module.","method":"Rac1-GTP pulldown, antisense DOCK180 knockdown, mutagenesis of MFG-E8 RGD motif, phagocytosis assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GTP-loading assay plus functional phagocytosis readout with antisense knockdown, single lab","pmids":["14697347"],"is_preprint":false},{"year":2005,"finding":"The DHR-1 domain of DOCK180 binds PtdIns(3,4,5)P3 in vitro and in vivo and localizes the DOCK180 signaling complex to PtdIns(3,4,5)P3-rich regions at the leading edge; a form of DOCK180 lacking DHR-1 fails to promote cell migration despite inducing Rac GTP-loading, and replacement of DHR-1 with a canonical PH domain restores full function, demonstrating that DHR-1 couples PI3K signaling to Rac activation for directional cell movement.","method":"Lipid-binding assay (in vitro and in vivo), domain-swap experiments, cell migration assay, live-cell imaging of PtdIns(3,4,5)P3 localization","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro lipid-binding with mutagenesis, domain-swap rescue, and directional migration assay, single rigorous study with multiple orthogonal methods","pmids":["16025104"],"is_preprint":false},{"year":2005,"finding":"At basal state, the N-terminal SH3 domain of Dock180 intramolecularly binds its own Docker/DHR-2 domain, sterically blocking Rac access; ELMO binding to the SH3 domain disrupts this SH3–Docker interaction, relieving steric inhibition and contributing to Rac GEF activity (steric-inhibition model for Dock180 family regulation).","method":"Domain interaction mapping, in vitro binding competition, cell-based Rac-GTP assay, C. elegans genetic rescue","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — intramolecular binding competition assay plus functional GEF assay and in vivo C. elegans rescue, single lab with multiple orthogonal methods","pmids":["15723800"],"is_preprint":false},{"year":2005,"finding":"ARNO-dependent ARF6 activation promotes Rac1 activation through the Dock180/Elmo bipartite GEF complex; catalytically inactive Dock180 and an Elmo mutant unable to couple to Dock180 both block ARNO-induced Rac activation and cell motility, while a similar β-PIX mutant does not, establishing Dock180/Elmo as the specific downstream effector linking ARF6 to Rac activation at the leading edge.","method":"Catalytic-dead Dock180 mutant, Elmo coupling mutant, Rac1-GTP pulldown, cell motility assay in MDCK cells, immunolocalization","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — catalytic mutant epistasis plus specificity control (β-PIX), multiple orthogonal approaches, single lab","pmids":["16213822"],"is_preprint":false},{"year":2005,"finding":"The C-terminal SH3 domain of CrkII regulates the stability and turnover of the DOCK180/ELMO Rac-GEF complex; a W276K CrkII mutation constitutively tethers the Crk/DOCK180/ELMO complex (with RhoG) and increases Rac-GTP loading, whereas the N-terminal SH3 promotes assembly between CrkII and DOCK180.","method":"Co-immunoprecipitation, Rac-GTP pulldown, phagocytosis assay, domain mutagenesis of CrkII","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and GTP-loading with specific domain mutants, single lab with multiple methods","pmids":["15700267"],"is_preprint":false},{"year":2006,"finding":"Shigella effector IpgB1 mimics RhoG to bind ELMO and exploit the RhoG–ELMO–Dock180 pathway, stimulating Rac1 activity and membrane ruffles; ELMO and Dock180 knockdown cells show reduced Shigella invasiveness and IpgB1-induced ruffles, demonstrating that pathogens can hijack the ELMO–Dock180 Rac-GEF module for cell invasion.","method":"Pulldown identifying ELMO as IpgB1 binding partner, siRNA knockdown of ELMO and Dock180, Rac1 activity assay, bacterial invasion assay, immunolocalization","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assay plus siRNA knockdown with two independent functional readouts (ruffles and invasion), replicated in related papers","pmids":["17173036"],"is_preprint":false},{"year":2006,"finding":"Elmo1 inhibits ubiquitylation of Dock180 on the plasma membrane, thereby preventing proteasomal degradation of Dock180; the Dock180 protein is constitutively ubiquitylated and its levels are enhanced by proteasome inhibitor; EGF, Crk, and adhesion signals enhance Dock180 ubiquitylation, while Elmo1 counteracts this, providing a mechanism for local control of Rac activation.","method":"In vivo ubiquitylation assay, proteasome inhibitor treatment, co-expression experiments, immunofluorescence, membrane fractionation","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (ubiquitylation assay, proteasome inhibition, fractionation), single lab","pmids":["16495483"],"is_preprint":false},{"year":2007,"finding":"BAI1, a seven-transmembrane adhesion-GPCR, functions as an upstream engulfment receptor that directly binds phosphatidylserine on apoptotic cells via its thrombospondin type 1 repeats; BAI1 forms a trimeric complex with ELMO and Dock180, and cooperates with the ELMO/Dock180/Rac pathway to promote maximal engulfment of apoptotic cells.","method":"Co-immunoprecipitation of BAI1–ELMO–Dock180 complex, phosphatidylserine binding assay, knockdown/overexpression phagocytosis assay ex vivo and in vivo","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — trimeric complex IP, direct PS-binding assay, in vitro and in vivo phagocytosis readouts, single rigorous study","pmids":["17960134"],"is_preprint":false},{"year":2007,"finding":"DOCK180 interacts with the netrin receptor DCC; netrin stimulation promotes formation of a DOCK180–DCC complex, leading to Rac1 activation; knockdown of DOCK180 reduces netrin-induced Rac1 activation, axon outgrowth, and axon attraction in vertebrate neurons; in vivo, DOCK180 is required for commissural axon projection in the neural tube.","method":"Co-immunoprecipitation, Rac1-GTP pulldown, siRNA knockdown, axon guidance and outgrowth assays, in vivo chick spinal cord experiments","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP establishing complex, GTP-loading assay, and in vivo axon guidance phenotype with knockdown","pmids":["18066058"],"is_preprint":false},{"year":2007,"finding":"In zebrafish, Dock1 and the closely related Dock5 are both required for embryonic fast-twitch myoblast fusion; the adaptor proteins Crk and Crkl, which physically interact with Dock proteins, are also required for myoblast fusion, placing Dock1 downstream of Crk/Crkl in the vertebrate myoblast fusion pathway.","method":"Morpholino antisense knockdown in zebrafish, phenotypic analysis of myoblast fusion","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific cellular phenotype (myoblast fusion) in zebrafish, single lab","pmids":["17670792"],"is_preprint":false},{"year":2008,"finding":"The DHR-1 domain of DOCK180 binds to SNX5 (and SNX1/2/6) at endosomes; DOCK180 colocalizes with SNX5 at endosomes; knockdown of SNX5 or DOCK180 (but not Rac1) causes redistribution of the cation-independent mannose 6-phosphate receptor (CI-MPR) from TGN to endosomes; DHR-1 expression alone restores CI-MPR distribution in DOCK180 knockdown cells, revealing a Rac1-GEF-independent role for DOCK180 in retrograde endosome-to-TGN trafficking.","method":"Mass spectrometry (nanoLC-MS/MS) to identify binding partners, co-immunoprecipitation of SNX5, siRNA knockdown, immunofluorescence of CI-MPR localization, domain-rescue experiment","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-identified interaction confirmed by co-IP, knockdown with specific trafficking phenotype, domain-rescue experiment, single lab with multiple orthogonal methods","pmids":["18596235"],"is_preprint":false},{"year":2008,"finding":"ANKRD28 interacts with DOCK180 via its SH3 domain in an ELMO-competing manner; ANKRD28 knockdown reduces cell migration velocity and alters focal adhesion protein distribution; coexpression of ANKRD28 with p130Cas, Crk, and DOCK180 induces p130Cas hyperphosphorylation and multiple long cellular processes, while ELMO coexpression instead produces broad lamellipodia, demonstrating that competing SH3-domain partners specify distinct outputs of the DOCK180–Rac pathway.","method":"Co-immunoprecipitation, siRNA knockdown, migration velocity assay, immunofluorescence of focal adhesion proteins, morphological analysis","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP binding competition plus knockdown with specific phenotypic readouts, single lab","pmids":["19118547"],"is_preprint":false},{"year":2008,"finding":"The alpha-helical extension of the ELMO1 PH domain (N-terminal amphipathic helix) directly mediates interaction with DOCK180; the ELMO1 PH domain structurally resembles FERM domains and cannot bind phospholipids; disruption of both DOCK180-interaction sites on ELMO1 (N-terminal helix and proline-rich/SH3 interaction) is required to fully disrupt the complex; loss of ELMO–DOCK180 coupling impairs Rac signaling without affecting DOCK180 GEF activity per se, implying additional roles for ELMO in Rac signal output.","method":"X-ray crystal structure of ELMO1 PH domain, mutagenesis of hydrophobic helix residues, co-immunoprecipitation, Rac signaling assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with mutational validation of binding interface, co-IP, functional Rac-signaling assay, single lab","pmids":["18768751"],"is_preprint":false},{"year":2009,"finding":"uPAR cooperates with β3 integrin-containing complexes to drive formation of the p130Cas–CrkII signaling complex, leading to DOCK180-dependent Rac activation, elongated-mesenchymal morphology, and cell motility/invasion; DOCK180 is identified as the specific GEF acting downstream of uPAR.","method":"Co-immunoprecipitation, Rac1-GTP pulldown, siRNA knockdown of DOCK180, morphology and invasion assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus GTP-loading assay and siRNA loss-of-function with morphology phenotype, single lab","pmids":["18725541"],"is_preprint":false},{"year":2009,"finding":"GRASP/Tamalin and IPCEF scaffold proteins promote assembly of an ARNO–Dock180 multiprotein complex via the ARNO coiled-coil domain; knockdown of either GRASP or IPCEF prevents the ARNO–Dock180 association and ARNO-induced Rac1 activation and motility, showing that these scaffolds are required for ARF-to-Rac GTPase crosstalk.","method":"Co-immunoprecipitation, Rac1-GTP pulldown, siRNA knockdown, cell motility assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with knockdown and functional Rac-activation assay, single lab","pmids":["20016009"],"is_preprint":false},{"year":2010,"finding":"The DHR-1 domain of Dock1 adopts a C2 domain scaffold with surface loops that form a basic pocket recognizing the PtdIns(3,4,5)P3 head group; point mutations that abolish phospholipid binding in vitro also abolish Dock1-induced cell polarization, establishing the structural basis for membrane targeting of Dock1's GEF activity.","method":"X-ray crystal structure of DHR-1, phospholipid binding assay, point mutagenesis, cell polarization assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with mutagenesis validating functional relevance, single lab","pmids":["20167601"],"is_preprint":false},{"year":2010,"finding":"Targeted deletion of the SH3 domain of DOCK180 in mice leads to embryonic lethality with markedly reduced DOCK180 protein expression; DOCK180-deficient mice exhibit cardiovascular abnormalities resembling CXCR4-deficient mice; in DOCK180-knockdown endothelial cells, CXCL12-induced Rac activation and cell motility are impaired, establishing DOCK180 as a link between CXCR4 signaling and Rac activation controlling cardiovascular development.","method":"Targeted gene deletion in mice, Rac-GTP pulldown in knockdown cells, cell motility assay, cardiovascular phenotyping","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse knockout phenotype with biochemical Rac-activation assay in cells, single lab with two orthogonal approaches","pmids":["20829512"],"is_preprint":false},{"year":2011,"finding":"PDGFRα signaling leads to Src-dependent phosphorylation of Dock180 at tyrosine 1811 (Dock180(Y1811)), enhancing association with CrkII and p130Cas and activating Rac1 to promote glioma cell growth, survival, and invasion; Dock180(Y1811F) mutant abrogates PDGFRα-stimulated activities, establishing Y1811 phosphorylation as the mechanistic link between PDGFRα and Rac1 activation.","method":"Phospho-specific antibody, siRNA knockdown with RNAi-resistant rescue (WT vs Y1811F), co-immunoprecipitation, Rac1-GTP pulldown, in vivo glioma tumor assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi-resistant rescue with site-specific mutant plus co-IP and in vivo glioma assay, single rigorous study","pmids":["22080864"],"is_preprint":false},{"year":2011,"finding":"The RhoG–ELMO1–Dock180 signaling module is required for dendritic spine morphogenesis in hippocampal neurons; depletion of Dock180 inhibits spine formation while overexpression promotes it; ELMO1 functions in complex with Dock180 to activate Rac GTPase for spine morphogenesis; RhoG acts upstream of the ELMO1–Dock180 complex in this context.","method":"RNAi screen of 70 Rho-GEFs, shRNA knockdown of Dock180, overexpression, Rac-GTP pulldown, confocal imaging of spine morphology","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with specific morphological phenotype and Rac-GTP assay, epistasis placing RhoG upstream, single lab","pmids":["21900250"],"is_preprint":false},{"year":2012,"finding":"EGFRvIII promotes glioblastoma tumorigenesis through Src family kinase (SFK)-dependent phosphorylation of Dock180 at tyrosine 722 (Dock180(Y722)), stimulating Rac1 signaling, cell survival, and migration; pharmacological or shRNA inhibition of SFKs attenuates EGFRvIII-induced Dock180(Y722) phosphorylation and Rac1 activity; Dock180(Y722F) mutant inhibits EGFRvIII-stimulated activities.","method":"Phospho-specific antibody, SFK pharmacological inhibitors, shRNA depletion, Y722F mutant, Rac1-GTP pulldown, migration and survival assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific mutant (Y722F) plus pharmacological and genetic inhibition of the kinase, multiple functional readouts, single rigorous study","pmids":["22323579"],"is_preprint":false},{"year":2013,"finding":"EGFRvIII induces PKA-dependent serine phosphorylation of Dock180 at S1250 within its DHR-2 domain; PKA inhibitors block this phosphorylation; expression of Dock180(S1250L) but not wild-type Dock180 in EGFRvIII-expressing glioma cells inhibits proliferation, survival, migration in vitro and tumor growth/invasion in vivo.","method":"In vitro PKA kinase assay, PKA inhibitors (H-89, KT5720), PKA inhibitor peptide overexpression, S1250L mutant rescue assays, Rac1-GTP pulldown, in vivo intracranial tumor model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus site-specific mutant rescue and in vivo tumor model, single rigorous study with multiple orthogonal methods","pmids":["23728337"],"is_preprint":false},{"year":2013,"finding":"DOCK1 interacts with HER2 and promotes HER2-induced Rac1 activation and cell migration; mammary-gland-specific inactivation of DOCK1 in a HER2 breast cancer mouse model significantly decreases tumor growth and lung metastasis; DOCK1 is required for maximal activation of HER2 effectors c-JUN and STAT3.","method":"Co-immunoprecipitation (DOCK1–HER2), Rac1-GTP pulldown, conditional DOCK1 knockout mouse model (HER2 background), tumor growth and metastasis quantification, gene expression profiling","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP plus in vivo conditional knockout model with two independent phenotypic readouts (tumor growth and metastasis), single rigorous study","pmids":["23592719"],"is_preprint":false},{"year":2013,"finding":"CXCL12 stimulation promotes interaction between Gαi2 and ELMO1; Gαi2-dependent membrane translocation of ELMO1 associates with Dock180 to activate Rac1 and Rac2; both Gi signaling and ELMO1 are required for CXCL12-mediated actin polymerization and migration of breast cancer cells; knockdown of ELMO1 impairs lung metastasis in vivo.","method":"Co-immunoprecipitation (Gαi2–ELMO1), Rac1/2-GTP pulldown, siRNA knockdown, actin polymerization assay, migration/invasion assay, in vivo metastasis model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP plus GTP-loading assay, siRNA knockdown, and in vivo metastasis readout, single lab with multiple methods","pmids":["23591873"],"is_preprint":false},{"year":2013,"finding":"DOCK1 is recruited to dorsal ruffles via binding of its C-terminal polybasic amino acid cluster to phosphatidic acid (PA); DOCK5 does not bind PA and is dispensable for dorsal ruffle formation; blocking PA–DOCK1 interaction impairs PDGF-induced dorsal ruffle formation; phospholipase D, which synthesizes PA, is specifically required for dorsal (not peripheral) ruffle formation, establishing a phospholipase D–PA–DOCK1 axis for dorsal ruffle biogenesis.","method":"PA lipid-binding assay, DOCK1/DOCK5 deficient MEFs, PDGF stimulation, membrane ruffle imaging, PLD inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct lipid-binding assay, genetic knockout cells, PLD inhibitor, with specific phenotypic readout; single lab with multiple orthogonal methods","pmids":["23362269"],"is_preprint":false},{"year":2013,"finding":"GRASP/Tamalin directly binds both cytohesin-2/ARNO (via its coiled-coil domain) and Dock180 (via the Ala/Pro-rich region of GRASP interacting with the SH3 domain of Dock180); GRASP knockdown impairs HGF-stimulated Rac1 activation and epithelial migration, showing GRASP bridges the ARF-GEF and Rac-GEF to coordinate GTPase crosstalk.","method":"Direct binding assay (pull-down), siRNA knockdown, Rac1-GTP pulldown, migration assay","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay for the GRASP–Dock180 interface plus siRNA knockdown with functional Rac-activation and migration readouts, single lab","pmids":["23441967"],"is_preprint":false},{"year":2014,"finding":"Dock1 and Rac1 are required for efficient engulfment of apoptotic cells by mammary epithelial phagocytes; conditional inactivation of Dock1 or Rac1 in the mammary gland delays initiation and progression of involution and impairs Stat3 activation, revealing an unexpected role for Dock1/Rac1 signaling in initiating mammary gland involution via Stat3.","method":"Conditional knockout mouse models (mammary-gland-specific Dock1 and Rac1 deletion), in vitro phagocytosis assay, immunohistochemistry, Stat3 activation western blot","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent conditional KO mouse models, in vitro phagocytosis assay, and biochemical Stat3 activation readout, single lab with multiple orthogonal approaches","pmids":["25118935"],"is_preprint":false},{"year":2015,"finding":"ELMO1/Dock180 protects endothelial cells from apoptosis via activation of the Rac1–PAK–AKT signaling cascade; overexpression of Elmo1 and Dock180 in zebrafish reduces apoptotic EC number and promotes blood vessel formation during embryogenesis.","method":"Overexpression and knockdown in human ECs, caspase-3/7 and annexin V apoptosis assays, Rac1/PAK/AKT activation western blots, in vivo zebrafish vascular development","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in cells plus in vivo zebrafish model, multiple signaling pathway readouts, single lab","pmids":["25586182"],"is_preprint":false},{"year":2017,"finding":"Genetic inactivation of DOCK1 ablates macropinocytosis-dependent nutrient uptake and cellular invasion in Ras-transformed cells; TBOPP, a selective DOCK1 inhibitor that blocks GEF function, suppresses DOCK1-mediated invasion and macropinocytosis without impairing the closely related DOCK2 and DOCK5; TBOPP suppresses cancer metastasis and growth in vivo.","method":"Genetic DOCK1 inactivation (MEFs), chemical library screen identifying TBOPP, selectivity assays against DOCK2/DOCK5, macropinocytosis and invasion assays, in vivo mouse metastasis and tumor growth models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus selective chemical inhibitor with in vitro and in vivo functional readouts and DOCK family specificity controls","pmids":["28467910"],"is_preprint":false},{"year":2017,"finding":"DOCK180 activates the MLK3–JNK signaling axis in a RAC1-dependent manner downstream of EGFR; MLK3 silencing or MLK inhibition blocks EGF-induced JNK activation and GBM cell migration/invasion; DOCK180 overexpression in invasive GBM cells drives invasion through the EGFR–DOCK180–RAC1–MLK3–JNK pathway.","method":"siRNA knockdown of MLK3 and DOCK180, MLK pharmacological inhibitor, JNK activation assay, migration and invasion assays","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown plus pharmacological inhibition with specific signaling readout (JNK), single lab","pmids":["28487380"],"is_preprint":false},{"year":2018,"finding":"HGF induces formation of a MET–AXL–ELMO2–DOCK180 complex on the plasma membrane, stimulating RAC1-dependent cytoskeleton reorganization, cell migration, and invasion; both MET and AXL kinase activities are required for RAC1 activation through this complex.","method":"Co-immunoprecipitation (MET–AXL–ELMO2–DOCK180), RAC1-GTP pulldown, kinase inhibition, siRNA knockdown, migration/invasion assay, live-cell imaging","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishing complex plus GTP-loading assay and functional migration readout, single lab","pmids":["30108175"],"is_preprint":false},{"year":2018,"finding":"The catalytic DHR-2 domain of DOCK1 greatly accelerates GDP/GTP exchange of Rac1P29S (a self-activating melanoma mutation); in DOCK1-deficient MEFs, Rac1P29S fails to induce matrix invasion and macropinocytosis that are seen in wild-type MEFs; selective DOCK1 inhibitor suppresses invasion and macropinocytosis in melanoma and breast cancer cells harboring Rac1P29S.","method":"In vitro nucleotide exchange assay (DOCK1 DHR-2 + Rac1P29S), DOCK1-deficient MEFs, selective DOCK1 inhibitor (TBOPP), invasion and macropinocytosis assays in cancer cells","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro GEF assay with Rac1P29S plus genetic KO MEFs and pharmacological inhibition with functional readouts, single lab with multiple orthogonal methods","pmids":["29432733"],"is_preprint":false},{"year":2018,"finding":"Mutations in zebrafish dock1 result in delayed radial sorting and decreased myelination of peripheral axons by Schwann cells, without affecting Schwann cell number or migration, demonstrating that Dock1 GEF activity is required for Schwann cell cytoskeletal rearrangements during myelination.","method":"Forward genetic screen in zebrafish, morpholino rescue/complementation, in situ hybridization, transmission electron microscopy, live imaging","journal":"Neural development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen with multiple phenotypic validation methods (TEM, live imaging), single lab","pmids":["30089513"],"is_preprint":false},{"year":2022,"finding":"Metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, contributing to metformin resistance; the selective DOCK1 inhibitor TBOPP potentiates metformin's anti-tumor activity in liver cancer cell lines, patient-derived organoids, and in vivo xenograft and immunocompetent mouse models, establishing DOCK1-mediated RAC1 activation as a resistance mechanism to metformin.","method":"Genome-wide CRISPR-Cas9 knockout screen, phosphorylation assays, Rac1-GTP pulldown, TBOPP pharmacological inhibition, in vitro and in vivo tumor models, patient-derived organoids","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen plus biochemical validation and multiple in vitro and in vivo models, single lab with multiple orthogonal methods","pmids":["35217990"],"is_preprint":false},{"year":2004,"finding":"Endogenous DOCK180 exists as a large (~700 kDa) nuclear complex with ELMO proteins; this nuclear DOCK180/ELMO complex retains functional Rac-GEF activity; DOCK180 associates with different ELMO isoforms (ELMO1, 2, or 3) in different cell lines, suggesting cell-type-specific nuclear complexes.","method":"Biochemical fractionation, gel filtration chromatography, co-immunoprecipitation, in vitro Rac-GEF assay of nuclear fractions","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation plus in vitro GEF assay of isolated nuclear complex, single lab","pmids":["15288806"],"is_preprint":false},{"year":2001,"finding":"Nck-2 adaptor protein interacts with DOCK180 via its second and third SH3 domains binding to the C-terminal region of DOCK180 (residues 1819–1836 as primary site); tandem SH3 domains enhance weak individual interactions, with KD values of ~415 nM and ~3 nM for the two binding events as measured by surface plasmon resonance.","method":"Yeast two-hybrid screen, surface plasmon resonance kinetic analysis, SH3 domain point mutagenesis, deletion mapping","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative SPR binding assay with mutagenesis defining the interaction sites, single lab","pmids":["11240126"],"is_preprint":false}],"current_model":"DOCK1 (DOCK180) is an atypical, bipartite Rac1-specific guanine nucleotide exchange factor (GEF) whose catalytic DHR-2 domain directly binds nucleotide-free Rac1 and drives GTP loading; its DHR-1 domain couples PI3K signaling to GEF localization by binding PtdIns(3,4,5)P3 and, independently, phosphatidic acid, while its N-terminal SH3 domain provides autoinhibition that is relieved by ELMO binding; ELMO further stabilizes the Rac–DOCK1 transition state, inhibits DOCK1 ubiquitylation/degradation, and targets the complex to the plasma membrane; upstream, DOCK1 is activated by diverse receptors (integrins/p130Cas/CrkII, αvβ5, BAI1, DCC/netrin, HER2, PDGFRα, CXCR4, uPAR) and by RhoG-to-ELMO signaling, and is regulated by Src- and PKA-dependent phosphorylation at Y722, Y1811, and S1250; the DOCK1–ELMO–Rac axis controls apoptotic cell engulfment, directional cell migration, myoblast fusion, axon guidance, Schwann cell myelination, and cardiovascular development, and is hijacked by pathogens and oncogenes to drive invasion and metastasis."},"narrative":{"mechanistic_narrative":"DOCK1 (DOCK180) is an atypical, Rac1-specific guanine nucleotide exchange factor that converts upstream receptor and lipid signals into localized Rac1 activation to drive cytoskeletal remodeling during apoptotic-cell engulfment, directional migration, myoblast fusion, axon guidance, and cardiovascular development [PMID:9808620, PMID:9548255, PMID:12134158]. Its catalytic DHR-2 (Docker/CZH2) domain directly recognizes nucleotide-free Rac1 and is both necessary and sufficient to catalyze GTP loading, defining DOCK1 and its relatives as a conserved superfamily of unconventional GEFs distinct from Dbl-family proteins [PMID:12134158, PMID:12432077]. DOCK1 functions as a bipartite GEF with ELMO: ELMO binding relieves an autoinhibitory intramolecular contact between the N-terminal SH3 domain and DHR-2, stabilizes the nucleotide-free Rac transition state through its PH domain in trans, and protects DOCK1 from ubiquitin-dependent degradation at the membrane [PMID:12134158, PMID:15247908, PMID:15723800, PMID:16495483]. Membrane targeting of the GEF is governed by the DHR-1 domain, which adopts a C2 fold that binds PtdIns(3,4,5)P3 to couple PI3K signaling to Rac activation at the leading edge, and by a C-terminal polybasic cluster that binds phosphatidic acid to drive dorsal ruffle formation [PMID:16025104, PMID:20167601, PMID:23362269]. Upstream, DOCK1 is engaged by integrin/p130Cas/CrkII complexes and engulfment receptors including αvβ5 and BAI1 during clearance of apoptotic cells, and by RhoG-loaded ELMO, the netrin receptor DCC, and chemokine and growth-factor receptors (CXCR4, HER2, PDGFRα, MET/AXL) to direct migration and development [PMID:9733740, PMID:11146654, PMID:12879077, PMID:17960134, PMID:18066058, PMID:20829512, PMID:23592719]. Src- and PKA-dependent phosphorylation at Y722, Y1811, and S1250 tunes DOCK1 activity downstream of oncogenic receptors, and DOCK1-driven Rac1 activation supports macropinocytic nutrient uptake, invasion, and metastasis, making it a tractable target via the selective inhibitor TBOPP [PMID:22080864, PMID:22323579, PMID:23728337, PMID:28467910, PMID:29432733]. Beyond canonical GEF signaling, DOCK1 also has a Rac1-independent role in retrograde endosome-to-TGN trafficking through DHR-1-mediated binding to sorting nexins [PMID:18596235].","teleology":[{"year":1996,"claim":"Established that DOCK180 is a membrane-translocating CRK-binding protein whose relocation to the plasma membrane is required to alter cell morphology, the first hint of a signaling effector role.","evidence":"Molecular cloning and farnesylation membrane-targeting construct with morphological readout in 3T3 cells","pmids":["8657152"],"confidence":"Medium","gaps":["No molecular activity assigned","Rac connection not yet made","Endogenous regulation of membrane targeting unknown"]},{"year":1998,"claim":"Defined DOCK180 as a specific activator of Rac1 acting within integrin/p130Cas/CrkII signaling, answering what GTPase the protein controls and in what receptor context.","evidence":"GTP-Rac pulldowns, dominant-negative Rac1 epistasis, and reciprocal co-IP in 293T/NIH 3T3 cells, plus genetic conservation in C. elegans (CED-5) and Drosophila (MBC)","pmids":["9808620","9733740","9548255","9808621"],"confidence":"High","gaps":["Catalytic mechanism of Rac activation not yet defined","Whether binding alone vs enzymatic activity drives GTP loading unresolved"]},{"year":2000,"claim":"Showed that an engulfment receptor (αvβ5 integrin) recruits the p130Cas–CrkII–DOCK180 complex to trigger Rac1-dependent phagosome formation, linking the GEF to apoptotic-cell clearance.","evidence":"Co-IP, Rac1-GTP pulldown, β5 cytoplasmic-tail mutants, and phagocytosis assays","pmids":["11146654"],"confidence":"High","gaps":["Direct PS-recognition receptor not yet identified","Mechanism coupling integrin engagement to GEF activation unclear"]},{"year":2001,"claim":"Identified ELMO/CED-12 as an obligate partner forming a conserved CrkII–DOCK180–ELMO–Rac module, and localized DOCK180 membrane recruitment to PtdIns(3,4,5)P3 binding, defining the core signaling complex and its lipid input.","evidence":"Yeast two-hybrid, co-IP, C. elegans genetic rescue/epistasis, PtdIns(3,4,5)P3 bead pulldown with PI3K co-expression","pmids":["11595183","11703940","11171081","11240126","11369773"],"confidence":"High","gaps":["Biochemical role of ELMO in catalysis not defined","Lipid-binding domain not yet mapped at residue level"]},{"year":2002,"claim":"Demonstrated that the DHR-2/Docker domain directly binds nucleotide-free Rac and catalyzes GTP loading, with ELMO augmenting exchange, establishing DOCK180–ELMO as an unconventional bipartite Rac-GEF and founding a new GEF superfamily.","evidence":"In vitro nucleotide exchange assays, domain mapping, trimeric ELMO1–Dock180–Rac1 complex detection, cell-based Rac-GTP pulldown","pmids":["12134158","12432077"],"confidence":"High","gaps":["Structural basis of Rac recognition not yet solved","How upstream signals gate catalysis unresolved"]},{"year":2003,"claim":"Placed RhoG upstream of ELMO–DOCK180 as a GTP-dependent activator and showed that complex localization to lamellipodia, not bulk Rac activation, drives migration, refining how and where the GEF acts.","evidence":"GTP-dependent co-IP, constitutively active/dominant-negative RhoG, domain-deletion migration assays, C. elegans rescue, neurite-outgrowth and spreading assays","pmids":["12879077","14638695"],"confidence":"High","gaps":["How RhoG–ELMO engagement is triggered by receptors unclear","Spatial coupling of localization to catalysis not mechanistically resolved"]},{"year":2004,"claim":"Resolved ELMO's catalytic contribution by showing its PH domain stabilizes Rac in the nucleotide-free transition state in trans, and reported a large nuclear DOCK180/ELMO complex with retained GEF activity.","evidence":"In vitro GEF assays with ELMO PH-domain mutagenesis, phagocytosis/migration assays, C. elegans rescue, biochemical fractionation and gel filtration","pmids":["15247908","15288806"],"confidence":"High","gaps":["Functional significance of nuclear complex not established","MFG-E8/PSR upstream coupling not fully reconstituted"]},{"year":2005,"claim":"Defined the autoinhibition mechanism—intramolecular SH3–DHR-2 contact blocks Rac access, relieved by ELMO—and showed the DHR-1 domain couples PI3K/PtdIns(3,4,5)P3 to directional Rac activation, separating GEF activity from spatial control.","evidence":"Intramolecular binding competition, in vitro/in vivo lipid binding, DHR-1 domain-swap rescue, directional migration assays, ARF6/ARNO epistasis with catalytic-dead and ELMO-coupling mutants","pmids":["15723800","16025104","16213822","15700267"],"confidence":"High","gaps":["Structural detail of DHR-1–lipid recognition not yet solved","Quantitative contribution of autoinhibition release vs ELMO stabilization unresolved"]},{"year":2007,"claim":"Expanded the upstream receptor repertoire by identifying BAI1 as a PS-binding engulfment GPCR forming a BAI1–ELMO–DOCK180 complex, and DCC as a netrin receptor linking DOCK180 to axon guidance in vivo.","evidence":"Trimeric complex co-IP, PS-binding assays, in vitro/in vivo phagocytosis, Rac1-GTP pulldown, in vivo chick commissural axon guidance with knockdown","pmids":["17960134","18066058"],"confidence":"High","gaps":["How distinct receptors converge on the same GEF in different cell types unresolved","Receptor-to-GEF activation step not biochemically reconstituted"]},{"year":2008,"claim":"Resolved the ELMO1–DOCK180 binding interface structurally and uncovered a Rac1-independent role for DHR-1 in retrograde endosome-to-TGN trafficking via sorting nexins, broadening DOCK180's functional scope.","evidence":"X-ray structure of ELMO1 PH domain with mutagenesis and co-IP; mass spectrometry-identified SNX5 interaction with knockdown and CI-MPR trafficking/domain-rescue readouts; ANKRD28 competition experiments","pmids":["18768751","18596235","19118547"],"confidence":"High","gaps":["Physiological importance of the trafficking role relative to GEF function unclear","How competing SH3 partners are selected in vivo unresolved"]},{"year":2010,"claim":"Provided the structural basis for membrane targeting by showing DHR-1 is a C2-fold domain with a basic pocket for the PtdIns(3,4,5)P3 head group, and established DOCK180 as essential for cardiovascular development downstream of CXCR4 in vivo.","evidence":"X-ray crystal structure of DHR-1 with point mutagenesis and cell polarization assays; targeted SH3-domain deletion in mice with cardiovascular phenotyping and CXCL12-induced Rac assays","pmids":["20167601","20829512","20016009","21900250"],"confidence":"High","gaps":["How lipid binding and GEF catalysis are allosterically coupled unresolved","Cell-type-specific receptor inputs in vivo not dissected"]},{"year":2013,"claim":"Established phosphorylation-based and lipid-based control of DOCK1 in oncogenic signaling—Src-dependent Y1811, PKA-dependent S1250, and PA binding—and demonstrated DOCK1 requirement for HER2-driven and CXCR4-driven tumor growth and metastasis in vivo.","evidence":"Phospho-specific antibodies, site-specific mutant rescue (Y1811F, S1250L), in vitro PKA kinase assay, PA lipid-binding assay with DOCK1/DOCK5 knockout MEFs, conditional DOCK1 knockout HER2 mouse model, Gαi2–ELMO1 co-IP with in vivo metastasis","pmids":["22080864","23728337","23362269","23592719","23591873","23441967"],"confidence":"High","gaps":["Integration of multiple phosphosites into a unified activation logic unresolved","Whether phosphorylation alters catalysis vs localization vs partner binding not fully separated"]},{"year":2012,"claim":"Identified Src-family-dependent Y722 phosphorylation downstream of EGFRvIII and an EGFR–DOCK180–RAC1–MLK3–JNK axis as drivers of glioblastoma invasion, linking receptor tyrosine kinase oncogenes to a defined DOCK1 signaling output.","evidence":"Phospho-specific antibody, SFK inhibitors, shRNA depletion, Y722F mutant, JNK activation, migration/invasion assays","pmids":["22323579","28487380"],"confidence":"High","gaps":["Relative contribution of Y722 vs Y1811 vs S1250 in tumors unresolved","Downstream effector selectivity of Rac1 not defined"]},{"year":2017,"claim":"Demonstrated that DOCK1 GEF activity is required for macropinocytosis-dependent nutrient uptake and invasion in Ras- and Rac1P29S-transformed cells, and validated the selective inhibitor TBOPP as suppressing metastasis without affecting DOCK2/DOCK5.","evidence":"Genetic DOCK1 inactivation in MEFs, chemical screen for TBOPP with DOCK family selectivity controls, in vitro nucleotide exchange on Rac1P29S, macropinocytosis/invasion assays, in vivo mouse metastasis models","pmids":["28467910","29432733","25118935"],"confidence":"High","gaps":["Mechanism coupling Rac1 activation to macropinosome formation not detailed","TBOPP mode of GEF inhibition not structurally defined"]},{"year":2022,"claim":"Identified DOCK1-mediated RAC1 activation as a metformin-resistance mechanism, showing phosphorylation-driven DOCK1 activity promotes survival and that TBOPP potentiates anti-tumor activity across organoid and mouse models.","evidence":"Genome-wide CRISPR-Cas9 knockout screen, phosphorylation and Rac1-GTP assays, TBOPP treatment in cell lines, patient-derived organoids, and xenograft/immunocompetent mouse models","pmids":["35217990"],"confidence":"High","gaps":["Kinase responsible for metformin-induced DOCK1 phosphorylation not identified","Downstream survival effectors of Rac1 not defined"]},{"year":null,"claim":"How the multiple inputs—ELMO autoinhibition release, DHR-1/PA lipid binding, RhoG/G-protein/receptor engagement, and Src/PKA phosphorylation—are integrated into a single quantitative activation logic at defined membrane microdomains remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified structural model of the activated receptor–DOCK1–ELMO–Rac assembly","Physiological role of the nuclear DOCK180/ELMO complex unknown","How phosphosite combinations tune catalysis vs localization not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,10,11,46]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[6,17,31,39]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,5,23,24]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6,17,22,45]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[26]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[49]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[13,17,47]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,13,24,32]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,23,41]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[33,35,37,43,48]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[25,32,47]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[26]}],"complexes":["DOCK1-ELMO bipartite Rac-GEF complex","p130Cas-CrkII-DOCK180 complex","BAI1-ELMO-DOCK180 engulfment complex","MET-AXL-ELMO2-DOCK180 complex"],"partners":["ELMO1","RAC1","CRK","BCAR1","RHOG","DCC","ERBB2","SNX5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14185","full_name":"Dedicator of cytokinesis protein 1","aliases":["180 kDa protein downstream of CRK","DOCK180"],"length_aa":1865,"mass_kda":215.3,"function":"Involved in cytoskeletal rearrangements required for phagocytosis of apoptotic cells and cell motility. Along with DOCK1, mediates CRK/CRKL regulation of epithelial and endothelial cell spreading and migration on type IV collagen (PubMed:19004829). Functions as a guanine nucleotide exchange factor (GEF), which activates Rac Rho small GTPases by exchanging bound GDP for free GTP. 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survival.","date":"2011","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/22175896","citation_count":17,"is_preprint":false},{"pmid":"27660415","id":"PMC_27660415","title":"Downregulation of DOCK1 sensitizes bladder cancer cells to cisplatin through preventing epithelial-mesenchymal transition.","date":"2016","source":"Drug design, development and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/27660415","citation_count":16,"is_preprint":false},{"pmid":"36179995","id":"PMC_36179995","title":"TLR4 activation induces inflammatory vascular permeability via Dock1 targeting and NOX4 upregulation.","date":"2022","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/36179995","citation_count":15,"is_preprint":false},{"pmid":"27662902","id":"PMC_27662902","title":"RHOG-DOCK1-RAC1 Signaling Axis Is Perturbed in DHEA-Induced Polycystic Ovary in Rat Model.","date":"2016","source":"Reproductive sciences (Thousand Oaks, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/27662902","citation_count":13,"is_preprint":false},{"pmid":"30089513","id":"PMC_30089513","title":"Mutations in dock1 disrupt early Schwann cell development.","date":"2018","source":"Neural development","url":"https://pubmed.ncbi.nlm.nih.gov/30089513","citation_count":11,"is_preprint":false},{"pmid":"35778533","id":"PMC_35778533","title":"Combinatorial genetics reveals the Dock1-Rac2 axis as a potential target for the treatment of NPM1;Cohesin mutated 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medicines","url":"https://pubmed.ncbi.nlm.nih.gov/39014275","citation_count":8,"is_preprint":false},{"pmid":"24365888","id":"PMC_24365888","title":"The Rac-specific exchange factors Dock1 and Dock5 are dispensable for the establishment of the glomerular filtration barrier in vivo.","date":"2013","source":"Small GTPases","url":"https://pubmed.ncbi.nlm.nih.gov/24365888","citation_count":7,"is_preprint":false},{"pmid":"35655066","id":"PMC_35655066","title":"Semen Ziziphi Spinosae attenuates blood-brain barrier dysfunction induced by lipopolysaccharide by targeting the FAK-DOCK180-Rac1-WAVE2-Arp3 signaling pathway.","date":"2022","source":"NPJ science of food","url":"https://pubmed.ncbi.nlm.nih.gov/35655066","citation_count":7,"is_preprint":false},{"pmid":"25957600","id":"PMC_25957600","title":"Regulatory role of guanine nucleotide exchange factor (GEF) Dock180 phosphorylation on Tyr/Ser in mediation of gastric mucosal Rac1 activation in response to Helicobacter pylori and ghrelin.","date":"2015","source":"Inflammopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25957600","citation_count":7,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50225,"output_tokens":13381,"usd":0.175695,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":25265,"output_tokens":6253,"usd":0.141325,"stage2_stop_reason":"end_turn"},"total_usd":0.31702,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"DOCK180 was cloned as a 180 kDa CRK SH3-binding protein; when artificially membrane-targeted via a farnesylation signal, it localized to the cytoplasmic membrane and changed cell morphology from spindle to flat polygonal, indicating that membrane translocation of DOCK180 is required for its morphological effects.\",\n      \"method\": \"Molecular cloning, farnesylation membrane-targeting construct, morphological assay in 3T3 cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional experiment with membrane-targeting construct, single lab but two orthogonal approaches (localization + phenotype)\",\n      \"pmids\": [\"8657152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"DOCK180 directly binds Rac1 (but not RhoA or Cdc42Hs), overexpression increases GTP-bound Rac1 in cells, and coexpression of CrkII and p130Cas enhances DOCK180-dependent Rac1 activation; dominant-negative Rac1 suppresses DOCK180-induced membrane spreading, establishing DOCK180 as a novel activator of Rac1 in integrin signaling.\",\n      \"method\": \"GTP-Rac1 pulldown assay, overexpression, dominant-negative Rac1, JNK activation assay in 293T cells\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding and GTP-loading assays, dominant-negative epistasis, replicated by multiple subsequent labs\",\n      \"pmids\": [\"9808620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CED-5, the C. elegans ortholog of DOCK180, is required for engulfment of cell corpses and cell migration of distal tip cells; human DOCK180 expression in C. elegans rescues the cell-migration defect of ced-5 mutants, establishing functional conservation of the CDM family in surface extension during engulfment.\",\n      \"method\": \"C. elegans genetics, transgenic rescue with human DOCK180, phenotypic analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with transgenic rescue, replicated across labs in subsequent work\",\n      \"pmids\": [\"9548255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"DOCK180 is phosphorylated and associates with CrkII specifically upon integrin stimulation or v-src/v-crk transformation; DOCK180 expression induces hyperphosphorylation of p130Cas and increased CrkII–p130Cas complex formation; coexpression of p130Cas and CrkII with DOCK180 induces focal-adhesion-localized membrane spreading, placing DOCK180 as an upregulator of the CrkII–p130Cas integrin signaling complex.\",\n      \"method\": \"Co-immunoprecipitation, reconstitution in NIH 3T3 and 3Y1 cells, phosphorylation assays, integrin stimulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus reconstitution experiment showing p130Cas hyperphosphorylation, replicated in subsequent studies\",\n      \"pmids\": [\"9733740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Drosophila Myoblast City (MBC), the DOCK180 homolog, is required for Rac-specific signaling in dorsal closure, myogenesis, and neural development; mammalian DOCK180 associates with Rac but not Cdc42 in a nucleotide-independent manner, establishing Mbc/DOCK180 as a specific upstream regulator of Rac.\",\n      \"method\": \"Drosophila mutant screen, genetic analysis, co-immunoprecipitation with Rac and Cdc42\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic screen plus biochemical binding specificity assay, replicated across organisms\",\n      \"pmids\": [\"9808621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The αvβ5 integrin recruits the p130Cas–CrkII–DOCK180 molecular complex upon engagement with apoptotic cells, triggering Rac1 activation and phagosome formation; signaling through the β5 cytoplasmic tail is required for internalization, establishing DOCK180 as the effector linking αvβ5 integrin to Rac1 activation during phagocytosis.\",\n      \"method\": \"Co-immunoprecipitation, Rac1-GTP pulldown, dominant-negative constructs, β5 cytoplasmic tail mutants, phagocytosis assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, GTP pulldown, mutants, functional phagocytosis assay), replicated in later studies\",\n      \"pmids\": [\"11146654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"DOCK180 binds to PtdIns(3,4,5)P3 through a C-terminal basic region; PI3K activation translocates DOCK180 to the plasma membrane without necessarily increasing GTP-Rac in the absence of membrane targeting, indicating PtdIns(3,4,5)P3 controls DOCK180 membrane recruitment.\",\n      \"method\": \"PtdIns(3,4,5)P3-APB bead pulldown, PI3K co-expression, GTP-Rac assays, deletion mutant analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct lipid-binding assay plus PI3K co-expression localization experiment, single lab\",\n      \"pmids\": [\"11171081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CED-12/ELMO directly binds to CED-5/DOCK180 and forms a ternary complex with CED-2/CrkII; this evolutionarily conserved CED-12–CED-5 complex acts as an upstream activator of Rac1, and ELMO1 functionally cooperates with CrkII and Dock180 to promote phagocytosis and cell shape changes.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, C. elegans genetic rescue, phagocytosis assay in mammalian cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — binding confirmed by multiple methods plus in vivo genetic rescue, independently replicated\",\n      \"pmids\": [\"11595183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"DOCK180 promotes Rac activation through the CED-2/CrkII–CED-5/DOCK180–CED-12/ELMO–CED-10/Rac pathway; CED-12 forms a ternary complex with CED-2 and CED-5 in vitro and its membrane localization is proposed to activate CED-10/Rac leading to cytoskeletal reorganization during cell migration and engulfment.\",\n      \"method\": \"In vitro protein binding assays, C. elegans genetics, epistasis analysis, cell migration and phagocytosis assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro complex formation plus genetic epistasis in C. elegans, replicated by concurrent work\",\n      \"pmids\": [\"11703940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Laminin-10/11 preferentially activates Rac (not Rho) via the p130Cas–CrkII–DOCK180 pathway; phosphorylation of p130Cas and increased formation of the p130Cas–CrkII–DOCK180 complex is associated with Rac activation, and CrkII mutants defective in DOCK180 binding suppress cell migration on laminin-10/11.\",\n      \"method\": \"GTP-Rac/Rho pulldown, co-immunoprecipitation, dominant-negative CrkII mutants, Transwell migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, GTP-loading assay, and dominant-negative epistasis, single lab\",\n      \"pmids\": [\"11369773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A conserved domain within Dock180 (the Docker/DHR-2/CZH2 domain) specifically recognizes nucleotide-free Rac and mediates GTP loading of Rac in vitro; ELMO1 is required for efficient GTP loading in cells, augments the Dock180–Rac interaction, and a trimeric ELMO1–Dock180–Rac1 complex can be detected, establishing the Dock180–ELMO complex as an unconventional bipartite GEF for Rac.\",\n      \"method\": \"In vitro nucleotide exchange assay, co-immunoprecipitation, domain mapping, cell-based Rac-GTP pulldown\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro GEF reconstitution with domain mapping, trimeric complex detection, independently replicated by Côté & Vuori (2002)\",\n      \"pmids\": [\"12134158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The DHR-2 domain of DOCK180 specifically binds nucleotide-free Rac and activates Rac in vitro and in vivo; DHR-2 is both necessary and sufficient for Rac activation; several DOCK180-related proteins possess DHR-2 domains with GEF activity toward Rac or Cdc42, defining an evolutionarily conserved superfamily of atypical GEFs.\",\n      \"method\": \"In vitro nucleotide exchange assay, domain deletion/reconstitution, cell-based Rac-GTP assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution plus domain mutagenesis, independently replicated\",\n      \"pmids\": [\"12432077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The Dock180–ELMO1 complex, which activates Rac, is required for mammalian cell migration; the Dock180–ELMO1 complex must form and localize to lamellipodia (via ELMO1 N-terminal 330 aa) for migration, not merely general Rac activation; CED-5/Dock180 function in migration in C. elegans also requires complex formation and Rac activation.\",\n      \"method\": \"Transwell migration assay, domain deletion mutants, C. elegans transgenic rescue, lamellipodia localization by immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple loss-of-function mutants with defined phenotypic readouts in both cell lines and in vivo C. elegans rescue\",\n      \"pmids\": [\"14638695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RhoG directly interacts with ELMO in a GTP-dependent manner and forms a ternary complex with Dock180, leading to Rac1 activation; the RhoG–Elmo–Dock180 pathway is required for integrin-mediated Rac1 activation, cell spreading, and NGF-induced neurite outgrowth.\",\n      \"method\": \"Co-immunoprecipitation, GTP-dependent binding assay, dominant-negative and constitutively active RhoG, cell spreading and neurite outgrowth assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — GTP-dependent binding assay establishing direct interaction, plus multiple functional readouts, replicated in subsequent studies\",\n      \"pmids\": [\"12879077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"C. elegans PSR-1 (phosphatidylserine receptor) acts in the same engulfment pathway as CED-5/DOCK180 and CED-12/ELMO, possibly through direct interaction with CED-5 and CED-12, placing the phosphatidylserine receptor upstream of the CED-2–CED-5–CED-10–CED-12 signaling pathway.\",\n      \"method\": \"C. elegans genetics, in vitro binding assay (PSR-1 binding to PS), epistasis analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in C. elegans plus in vitro PS-binding assay; direct interaction with CED-5 proposed but not fully reconstituted\",\n      \"pmids\": [\"14645848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The PH domain of ELMO binds the Dock180–Rac complex in trans, stabilizing Rac in the nucleotide-free transition state; this PH-domain-dependent mechanism is essential for phagocytosis and cell migration both in mammalian cells and in C. elegans.\",\n      \"method\": \"In vitro GEF assay, mutagenesis of ELMO PH domain, phagocytosis and migration assays, C. elegans genetic rescue\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis, functional phagocytosis and migration assays, in vivo C. elegans validation\",\n      \"pmids\": [\"15247908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MFG-E8 acts as a ligand for αvβ5 integrin, and coexpression of MFG-E8 with αvβ5 integrin potentiates integrin-mediated Rac1 activation; antisense DOCK180 abrogates MFG-E8–αvβ5-mediated Rac activation and impairs phagocytosis of apoptotic cells, establishing DOCK180 as the essential GEF downstream of the MFG-E8–αvβ5 signaling module.\",\n      \"method\": \"Rac1-GTP pulldown, antisense DOCK180 knockdown, mutagenesis of MFG-E8 RGD motif, phagocytosis assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GTP-loading assay plus functional phagocytosis readout with antisense knockdown, single lab\",\n      \"pmids\": [\"14697347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The DHR-1 domain of DOCK180 binds PtdIns(3,4,5)P3 in vitro and in vivo and localizes the DOCK180 signaling complex to PtdIns(3,4,5)P3-rich regions at the leading edge; a form of DOCK180 lacking DHR-1 fails to promote cell migration despite inducing Rac GTP-loading, and replacement of DHR-1 with a canonical PH domain restores full function, demonstrating that DHR-1 couples PI3K signaling to Rac activation for directional cell movement.\",\n      \"method\": \"Lipid-binding assay (in vitro and in vivo), domain-swap experiments, cell migration assay, live-cell imaging of PtdIns(3,4,5)P3 localization\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro lipid-binding with mutagenesis, domain-swap rescue, and directional migration assay, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"16025104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"At basal state, the N-terminal SH3 domain of Dock180 intramolecularly binds its own Docker/DHR-2 domain, sterically blocking Rac access; ELMO binding to the SH3 domain disrupts this SH3–Docker interaction, relieving steric inhibition and contributing to Rac GEF activity (steric-inhibition model for Dock180 family regulation).\",\n      \"method\": \"Domain interaction mapping, in vitro binding competition, cell-based Rac-GTP assay, C. elegans genetic rescue\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — intramolecular binding competition assay plus functional GEF assay and in vivo C. elegans rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15723800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ARNO-dependent ARF6 activation promotes Rac1 activation through the Dock180/Elmo bipartite GEF complex; catalytically inactive Dock180 and an Elmo mutant unable to couple to Dock180 both block ARNO-induced Rac activation and cell motility, while a similar β-PIX mutant does not, establishing Dock180/Elmo as the specific downstream effector linking ARF6 to Rac activation at the leading edge.\",\n      \"method\": \"Catalytic-dead Dock180 mutant, Elmo coupling mutant, Rac1-GTP pulldown, cell motility assay in MDCK cells, immunolocalization\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant epistasis plus specificity control (β-PIX), multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"16213822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The C-terminal SH3 domain of CrkII regulates the stability and turnover of the DOCK180/ELMO Rac-GEF complex; a W276K CrkII mutation constitutively tethers the Crk/DOCK180/ELMO complex (with RhoG) and increases Rac-GTP loading, whereas the N-terminal SH3 promotes assembly between CrkII and DOCK180.\",\n      \"method\": \"Co-immunoprecipitation, Rac-GTP pulldown, phagocytosis assay, domain mutagenesis of CrkII\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and GTP-loading with specific domain mutants, single lab with multiple methods\",\n      \"pmids\": [\"15700267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Shigella effector IpgB1 mimics RhoG to bind ELMO and exploit the RhoG–ELMO–Dock180 pathway, stimulating Rac1 activity and membrane ruffles; ELMO and Dock180 knockdown cells show reduced Shigella invasiveness and IpgB1-induced ruffles, demonstrating that pathogens can hijack the ELMO–Dock180 Rac-GEF module for cell invasion.\",\n      \"method\": \"Pulldown identifying ELMO as IpgB1 binding partner, siRNA knockdown of ELMO and Dock180, Rac1 activity assay, bacterial invasion assay, immunolocalization\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assay plus siRNA knockdown with two independent functional readouts (ruffles and invasion), replicated in related papers\",\n      \"pmids\": [\"17173036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Elmo1 inhibits ubiquitylation of Dock180 on the plasma membrane, thereby preventing proteasomal degradation of Dock180; the Dock180 protein is constitutively ubiquitylated and its levels are enhanced by proteasome inhibitor; EGF, Crk, and adhesion signals enhance Dock180 ubiquitylation, while Elmo1 counteracts this, providing a mechanism for local control of Rac activation.\",\n      \"method\": \"In vivo ubiquitylation assay, proteasome inhibitor treatment, co-expression experiments, immunofluorescence, membrane fractionation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (ubiquitylation assay, proteasome inhibition, fractionation), single lab\",\n      \"pmids\": [\"16495483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"BAI1, a seven-transmembrane adhesion-GPCR, functions as an upstream engulfment receptor that directly binds phosphatidylserine on apoptotic cells via its thrombospondin type 1 repeats; BAI1 forms a trimeric complex with ELMO and Dock180, and cooperates with the ELMO/Dock180/Rac pathway to promote maximal engulfment of apoptotic cells.\",\n      \"method\": \"Co-immunoprecipitation of BAI1–ELMO–Dock180 complex, phosphatidylserine binding assay, knockdown/overexpression phagocytosis assay ex vivo and in vivo\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — trimeric complex IP, direct PS-binding assay, in vitro and in vivo phagocytosis readouts, single rigorous study\",\n      \"pmids\": [\"17960134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DOCK180 interacts with the netrin receptor DCC; netrin stimulation promotes formation of a DOCK180–DCC complex, leading to Rac1 activation; knockdown of DOCK180 reduces netrin-induced Rac1 activation, axon outgrowth, and axon attraction in vertebrate neurons; in vivo, DOCK180 is required for commissural axon projection in the neural tube.\",\n      \"method\": \"Co-immunoprecipitation, Rac1-GTP pulldown, siRNA knockdown, axon guidance and outgrowth assays, in vivo chick spinal cord experiments\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP establishing complex, GTP-loading assay, and in vivo axon guidance phenotype with knockdown\",\n      \"pmids\": [\"18066058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In zebrafish, Dock1 and the closely related Dock5 are both required for embryonic fast-twitch myoblast fusion; the adaptor proteins Crk and Crkl, which physically interact with Dock proteins, are also required for myoblast fusion, placing Dock1 downstream of Crk/Crkl in the vertebrate myoblast fusion pathway.\",\n      \"method\": \"Morpholino antisense knockdown in zebrafish, phenotypic analysis of myoblast fusion\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific cellular phenotype (myoblast fusion) in zebrafish, single lab\",\n      \"pmids\": [\"17670792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The DHR-1 domain of DOCK180 binds to SNX5 (and SNX1/2/6) at endosomes; DOCK180 colocalizes with SNX5 at endosomes; knockdown of SNX5 or DOCK180 (but not Rac1) causes redistribution of the cation-independent mannose 6-phosphate receptor (CI-MPR) from TGN to endosomes; DHR-1 expression alone restores CI-MPR distribution in DOCK180 knockdown cells, revealing a Rac1-GEF-independent role for DOCK180 in retrograde endosome-to-TGN trafficking.\",\n      \"method\": \"Mass spectrometry (nanoLC-MS/MS) to identify binding partners, co-immunoprecipitation of SNX5, siRNA knockdown, immunofluorescence of CI-MPR localization, domain-rescue experiment\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-identified interaction confirmed by co-IP, knockdown with specific trafficking phenotype, domain-rescue experiment, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18596235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ANKRD28 interacts with DOCK180 via its SH3 domain in an ELMO-competing manner; ANKRD28 knockdown reduces cell migration velocity and alters focal adhesion protein distribution; coexpression of ANKRD28 with p130Cas, Crk, and DOCK180 induces p130Cas hyperphosphorylation and multiple long cellular processes, while ELMO coexpression instead produces broad lamellipodia, demonstrating that competing SH3-domain partners specify distinct outputs of the DOCK180–Rac pathway.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, migration velocity assay, immunofluorescence of focal adhesion proteins, morphological analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP binding competition plus knockdown with specific phenotypic readouts, single lab\",\n      \"pmids\": [\"19118547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The alpha-helical extension of the ELMO1 PH domain (N-terminal amphipathic helix) directly mediates interaction with DOCK180; the ELMO1 PH domain structurally resembles FERM domains and cannot bind phospholipids; disruption of both DOCK180-interaction sites on ELMO1 (N-terminal helix and proline-rich/SH3 interaction) is required to fully disrupt the complex; loss of ELMO–DOCK180 coupling impairs Rac signaling without affecting DOCK180 GEF activity per se, implying additional roles for ELMO in Rac signal output.\",\n      \"method\": \"X-ray crystal structure of ELMO1 PH domain, mutagenesis of hydrophobic helix residues, co-immunoprecipitation, Rac signaling assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with mutational validation of binding interface, co-IP, functional Rac-signaling assay, single lab\",\n      \"pmids\": [\"18768751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"uPAR cooperates with β3 integrin-containing complexes to drive formation of the p130Cas–CrkII signaling complex, leading to DOCK180-dependent Rac activation, elongated-mesenchymal morphology, and cell motility/invasion; DOCK180 is identified as the specific GEF acting downstream of uPAR.\",\n      \"method\": \"Co-immunoprecipitation, Rac1-GTP pulldown, siRNA knockdown of DOCK180, morphology and invasion assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus GTP-loading assay and siRNA loss-of-function with morphology phenotype, single lab\",\n      \"pmids\": [\"18725541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GRASP/Tamalin and IPCEF scaffold proteins promote assembly of an ARNO–Dock180 multiprotein complex via the ARNO coiled-coil domain; knockdown of either GRASP or IPCEF prevents the ARNO–Dock180 association and ARNO-induced Rac1 activation and motility, showing that these scaffolds are required for ARF-to-Rac GTPase crosstalk.\",\n      \"method\": \"Co-immunoprecipitation, Rac1-GTP pulldown, siRNA knockdown, cell motility assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with knockdown and functional Rac-activation assay, single lab\",\n      \"pmids\": [\"20016009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The DHR-1 domain of Dock1 adopts a C2 domain scaffold with surface loops that form a basic pocket recognizing the PtdIns(3,4,5)P3 head group; point mutations that abolish phospholipid binding in vitro also abolish Dock1-induced cell polarization, establishing the structural basis for membrane targeting of Dock1's GEF activity.\",\n      \"method\": \"X-ray crystal structure of DHR-1, phospholipid binding assay, point mutagenesis, cell polarization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with mutagenesis validating functional relevance, single lab\",\n      \"pmids\": [\"20167601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Targeted deletion of the SH3 domain of DOCK180 in mice leads to embryonic lethality with markedly reduced DOCK180 protein expression; DOCK180-deficient mice exhibit cardiovascular abnormalities resembling CXCR4-deficient mice; in DOCK180-knockdown endothelial cells, CXCL12-induced Rac activation and cell motility are impaired, establishing DOCK180 as a link between CXCR4 signaling and Rac activation controlling cardiovascular development.\",\n      \"method\": \"Targeted gene deletion in mice, Rac-GTP pulldown in knockdown cells, cell motility assay, cardiovascular phenotyping\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse knockout phenotype with biochemical Rac-activation assay in cells, single lab with two orthogonal approaches\",\n      \"pmids\": [\"20829512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PDGFRα signaling leads to Src-dependent phosphorylation of Dock180 at tyrosine 1811 (Dock180(Y1811)), enhancing association with CrkII and p130Cas and activating Rac1 to promote glioma cell growth, survival, and invasion; Dock180(Y1811F) mutant abrogates PDGFRα-stimulated activities, establishing Y1811 phosphorylation as the mechanistic link between PDGFRα and Rac1 activation.\",\n      \"method\": \"Phospho-specific antibody, siRNA knockdown with RNAi-resistant rescue (WT vs Y1811F), co-immunoprecipitation, Rac1-GTP pulldown, in vivo glioma tumor assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi-resistant rescue with site-specific mutant plus co-IP and in vivo glioma assay, single rigorous study\",\n      \"pmids\": [\"22080864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The RhoG–ELMO1–Dock180 signaling module is required for dendritic spine morphogenesis in hippocampal neurons; depletion of Dock180 inhibits spine formation while overexpression promotes it; ELMO1 functions in complex with Dock180 to activate Rac GTPase for spine morphogenesis; RhoG acts upstream of the ELMO1–Dock180 complex in this context.\",\n      \"method\": \"RNAi screen of 70 Rho-GEFs, shRNA knockdown of Dock180, overexpression, Rac-GTP pulldown, confocal imaging of spine morphology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with specific morphological phenotype and Rac-GTP assay, epistasis placing RhoG upstream, single lab\",\n      \"pmids\": [\"21900250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"EGFRvIII promotes glioblastoma tumorigenesis through Src family kinase (SFK)-dependent phosphorylation of Dock180 at tyrosine 722 (Dock180(Y722)), stimulating Rac1 signaling, cell survival, and migration; pharmacological or shRNA inhibition of SFKs attenuates EGFRvIII-induced Dock180(Y722) phosphorylation and Rac1 activity; Dock180(Y722F) mutant inhibits EGFRvIII-stimulated activities.\",\n      \"method\": \"Phospho-specific antibody, SFK pharmacological inhibitors, shRNA depletion, Y722F mutant, Rac1-GTP pulldown, migration and survival assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific mutant (Y722F) plus pharmacological and genetic inhibition of the kinase, multiple functional readouts, single rigorous study\",\n      \"pmids\": [\"22323579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EGFRvIII induces PKA-dependent serine phosphorylation of Dock180 at S1250 within its DHR-2 domain; PKA inhibitors block this phosphorylation; expression of Dock180(S1250L) but not wild-type Dock180 in EGFRvIII-expressing glioma cells inhibits proliferation, survival, migration in vitro and tumor growth/invasion in vivo.\",\n      \"method\": \"In vitro PKA kinase assay, PKA inhibitors (H-89, KT5720), PKA inhibitor peptide overexpression, S1250L mutant rescue assays, Rac1-GTP pulldown, in vivo intracranial tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus site-specific mutant rescue and in vivo tumor model, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"23728337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DOCK1 interacts with HER2 and promotes HER2-induced Rac1 activation and cell migration; mammary-gland-specific inactivation of DOCK1 in a HER2 breast cancer mouse model significantly decreases tumor growth and lung metastasis; DOCK1 is required for maximal activation of HER2 effectors c-JUN and STAT3.\",\n      \"method\": \"Co-immunoprecipitation (DOCK1–HER2), Rac1-GTP pulldown, conditional DOCK1 knockout mouse model (HER2 background), tumor growth and metastasis quantification, gene expression profiling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP plus in vivo conditional knockout model with two independent phenotypic readouts (tumor growth and metastasis), single rigorous study\",\n      \"pmids\": [\"23592719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CXCL12 stimulation promotes interaction between Gαi2 and ELMO1; Gαi2-dependent membrane translocation of ELMO1 associates with Dock180 to activate Rac1 and Rac2; both Gi signaling and ELMO1 are required for CXCL12-mediated actin polymerization and migration of breast cancer cells; knockdown of ELMO1 impairs lung metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation (Gαi2–ELMO1), Rac1/2-GTP pulldown, siRNA knockdown, actin polymerization assay, migration/invasion assay, in vivo metastasis model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP plus GTP-loading assay, siRNA knockdown, and in vivo metastasis readout, single lab with multiple methods\",\n      \"pmids\": [\"23591873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DOCK1 is recruited to dorsal ruffles via binding of its C-terminal polybasic amino acid cluster to phosphatidic acid (PA); DOCK5 does not bind PA and is dispensable for dorsal ruffle formation; blocking PA–DOCK1 interaction impairs PDGF-induced dorsal ruffle formation; phospholipase D, which synthesizes PA, is specifically required for dorsal (not peripheral) ruffle formation, establishing a phospholipase D–PA–DOCK1 axis for dorsal ruffle biogenesis.\",\n      \"method\": \"PA lipid-binding assay, DOCK1/DOCK5 deficient MEFs, PDGF stimulation, membrane ruffle imaging, PLD inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct lipid-binding assay, genetic knockout cells, PLD inhibitor, with specific phenotypic readout; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23362269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GRASP/Tamalin directly binds both cytohesin-2/ARNO (via its coiled-coil domain) and Dock180 (via the Ala/Pro-rich region of GRASP interacting with the SH3 domain of Dock180); GRASP knockdown impairs HGF-stimulated Rac1 activation and epithelial migration, showing GRASP bridges the ARF-GEF and Rac-GEF to coordinate GTPase crosstalk.\",\n      \"method\": \"Direct binding assay (pull-down), siRNA knockdown, Rac1-GTP pulldown, migration assay\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay for the GRASP–Dock180 interface plus siRNA knockdown with functional Rac-activation and migration readouts, single lab\",\n      \"pmids\": [\"23441967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Dock1 and Rac1 are required for efficient engulfment of apoptotic cells by mammary epithelial phagocytes; conditional inactivation of Dock1 or Rac1 in the mammary gland delays initiation and progression of involution and impairs Stat3 activation, revealing an unexpected role for Dock1/Rac1 signaling in initiating mammary gland involution via Stat3.\",\n      \"method\": \"Conditional knockout mouse models (mammary-gland-specific Dock1 and Rac1 deletion), in vitro phagocytosis assay, immunohistochemistry, Stat3 activation western blot\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent conditional KO mouse models, in vitro phagocytosis assay, and biochemical Stat3 activation readout, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"25118935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ELMO1/Dock180 protects endothelial cells from apoptosis via activation of the Rac1–PAK–AKT signaling cascade; overexpression of Elmo1 and Dock180 in zebrafish reduces apoptotic EC number and promotes blood vessel formation during embryogenesis.\",\n      \"method\": \"Overexpression and knockdown in human ECs, caspase-3/7 and annexin V apoptosis assays, Rac1/PAK/AKT activation western blots, in vivo zebrafish vascular development\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in cells plus in vivo zebrafish model, multiple signaling pathway readouts, single lab\",\n      \"pmids\": [\"25586182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Genetic inactivation of DOCK1 ablates macropinocytosis-dependent nutrient uptake and cellular invasion in Ras-transformed cells; TBOPP, a selective DOCK1 inhibitor that blocks GEF function, suppresses DOCK1-mediated invasion and macropinocytosis without impairing the closely related DOCK2 and DOCK5; TBOPP suppresses cancer metastasis and growth in vivo.\",\n      \"method\": \"Genetic DOCK1 inactivation (MEFs), chemical library screen identifying TBOPP, selectivity assays against DOCK2/DOCK5, macropinocytosis and invasion assays, in vivo mouse metastasis and tumor growth models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus selective chemical inhibitor with in vitro and in vivo functional readouts and DOCK family specificity controls\",\n      \"pmids\": [\"28467910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DOCK180 activates the MLK3–JNK signaling axis in a RAC1-dependent manner downstream of EGFR; MLK3 silencing or MLK inhibition blocks EGF-induced JNK activation and GBM cell migration/invasion; DOCK180 overexpression in invasive GBM cells drives invasion through the EGFR–DOCK180–RAC1–MLK3–JNK pathway.\",\n      \"method\": \"siRNA knockdown of MLK3 and DOCK180, MLK pharmacological inhibitor, JNK activation assay, migration and invasion assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown plus pharmacological inhibition with specific signaling readout (JNK), single lab\",\n      \"pmids\": [\"28487380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HGF induces formation of a MET–AXL–ELMO2–DOCK180 complex on the plasma membrane, stimulating RAC1-dependent cytoskeleton reorganization, cell migration, and invasion; both MET and AXL kinase activities are required for RAC1 activation through this complex.\",\n      \"method\": \"Co-immunoprecipitation (MET–AXL–ELMO2–DOCK180), RAC1-GTP pulldown, kinase inhibition, siRNA knockdown, migration/invasion assay, live-cell imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishing complex plus GTP-loading assay and functional migration readout, single lab\",\n      \"pmids\": [\"30108175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The catalytic DHR-2 domain of DOCK1 greatly accelerates GDP/GTP exchange of Rac1P29S (a self-activating melanoma mutation); in DOCK1-deficient MEFs, Rac1P29S fails to induce matrix invasion and macropinocytosis that are seen in wild-type MEFs; selective DOCK1 inhibitor suppresses invasion and macropinocytosis in melanoma and breast cancer cells harboring Rac1P29S.\",\n      \"method\": \"In vitro nucleotide exchange assay (DOCK1 DHR-2 + Rac1P29S), DOCK1-deficient MEFs, selective DOCK1 inhibitor (TBOPP), invasion and macropinocytosis assays in cancer cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro GEF assay with Rac1P29S plus genetic KO MEFs and pharmacological inhibition with functional readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29432733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mutations in zebrafish dock1 result in delayed radial sorting and decreased myelination of peripheral axons by Schwann cells, without affecting Schwann cell number or migration, demonstrating that Dock1 GEF activity is required for Schwann cell cytoskeletal rearrangements during myelination.\",\n      \"method\": \"Forward genetic screen in zebrafish, morpholino rescue/complementation, in situ hybridization, transmission electron microscopy, live imaging\",\n      \"journal\": \"Neural development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen with multiple phenotypic validation methods (TEM, live imaging), single lab\",\n      \"pmids\": [\"30089513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, contributing to metformin resistance; the selective DOCK1 inhibitor TBOPP potentiates metformin's anti-tumor activity in liver cancer cell lines, patient-derived organoids, and in vivo xenograft and immunocompetent mouse models, establishing DOCK1-mediated RAC1 activation as a resistance mechanism to metformin.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 knockout screen, phosphorylation assays, Rac1-GTP pulldown, TBOPP pharmacological inhibition, in vitro and in vivo tumor models, patient-derived organoids\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen plus biochemical validation and multiple in vitro and in vivo models, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35217990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Endogenous DOCK180 exists as a large (~700 kDa) nuclear complex with ELMO proteins; this nuclear DOCK180/ELMO complex retains functional Rac-GEF activity; DOCK180 associates with different ELMO isoforms (ELMO1, 2, or 3) in different cell lines, suggesting cell-type-specific nuclear complexes.\",\n      \"method\": \"Biochemical fractionation, gel filtration chromatography, co-immunoprecipitation, in vitro Rac-GEF assay of nuclear fractions\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation plus in vitro GEF assay of isolated nuclear complex, single lab\",\n      \"pmids\": [\"15288806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Nck-2 adaptor protein interacts with DOCK180 via its second and third SH3 domains binding to the C-terminal region of DOCK180 (residues 1819–1836 as primary site); tandem SH3 domains enhance weak individual interactions, with KD values of ~415 nM and ~3 nM for the two binding events as measured by surface plasmon resonance.\",\n      \"method\": \"Yeast two-hybrid screen, surface plasmon resonance kinetic analysis, SH3 domain point mutagenesis, deletion mapping\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative SPR binding assay with mutagenesis defining the interaction sites, single lab\",\n      \"pmids\": [\"11240126\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DOCK1 (DOCK180) is an atypical, bipartite Rac1-specific guanine nucleotide exchange factor (GEF) whose catalytic DHR-2 domain directly binds nucleotide-free Rac1 and drives GTP loading; its DHR-1 domain couples PI3K signaling to GEF localization by binding PtdIns(3,4,5)P3 and, independently, phosphatidic acid, while its N-terminal SH3 domain provides autoinhibition that is relieved by ELMO binding; ELMO further stabilizes the Rac–DOCK1 transition state, inhibits DOCK1 ubiquitylation/degradation, and targets the complex to the plasma membrane; upstream, DOCK1 is activated by diverse receptors (integrins/p130Cas/CrkII, αvβ5, BAI1, DCC/netrin, HER2, PDGFRα, CXCR4, uPAR) and by RhoG-to-ELMO signaling, and is regulated by Src- and PKA-dependent phosphorylation at Y722, Y1811, and S1250; the DOCK1–ELMO–Rac axis controls apoptotic cell engulfment, directional cell migration, myoblast fusion, axon guidance, Schwann cell myelination, and cardiovascular development, and is hijacked by pathogens and oncogenes to drive invasion and metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DOCK1 (DOCK180) is an atypical, Rac1-specific guanine nucleotide exchange factor that converts upstream receptor and lipid signals into localized Rac1 activation to drive cytoskeletal remodeling during apoptotic-cell engulfment, directional migration, myoblast fusion, axon guidance, and cardiovascular development [#1, #2, #10]. Its catalytic DHR-2 (Docker/CZH2) domain directly recognizes nucleotide-free Rac1 and is both necessary and sufficient to catalyze GTP loading, defining DOCK1 and its relatives as a conserved superfamily of unconventional GEFs distinct from Dbl-family proteins [#10, #11]. DOCK1 functions as a bipartite GEF with ELMO: ELMO binding relieves an autoinhibitory intramolecular contact between the N-terminal SH3 domain and DHR-2, stabilizes the nucleotide-free Rac transition state through its PH domain in trans, and protects DOCK1 from ubiquitin-dependent degradation at the membrane [#10, #15, #18, #22]. Membrane targeting of the GEF is governed by the DHR-1 domain, which adopts a C2 fold that binds PtdIns(3,4,5)P3 to couple PI3K signaling to Rac activation at the leading edge, and by a C-terminal polybasic cluster that binds phosphatidic acid to drive dorsal ruffle formation [#17, #31, #39]. Upstream, DOCK1 is engaged by integrin/p130Cas/CrkII complexes and engulfment receptors including \\u03b1v\\u03b25 and BAI1 during clearance of apoptotic cells, and by RhoG-loaded ELMO, the netrin receptor DCC, and chemokine and growth-factor receptors (CXCR4, HER2, PDGFR\\u03b1, MET/AXL) to direct migration and development [#3, #5, #13, #23, #24, #32, #37]. Src- and PKA-dependent phosphorylation at Y722, Y1811, and S1250 tunes DOCK1 activity downstream of oncogenic receptors, and DOCK1-driven Rac1 activation supports macropinocytic nutrient uptake, invasion, and metastasis, making it a tractable target via the selective inhibitor TBOPP [#33, #35, #36, #43, #46]. Beyond canonical GEF signaling, DOCK1 also has a Rac1-independent role in retrograde endosome-to-TGN trafficking through DHR-1-mediated binding to sorting nexins [#26].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that DOCK180 is a membrane-translocating CRK-binding protein whose relocation to the plasma membrane is required to alter cell morphology, the first hint of a signaling effector role.\",\n      \"evidence\": \"Molecular cloning and farnesylation membrane-targeting construct with morphological readout in 3T3 cells\",\n      \"pmids\": [\"8657152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular activity assigned\", \"Rac connection not yet made\", \"Endogenous regulation of membrane targeting unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined DOCK180 as a specific activator of Rac1 acting within integrin/p130Cas/CrkII signaling, answering what GTPase the protein controls and in what receptor context.\",\n      \"evidence\": \"GTP-Rac pulldowns, dominant-negative Rac1 epistasis, and reciprocal co-IP in 293T/NIH 3T3 cells, plus genetic conservation in C. elegans (CED-5) and Drosophila (MBC)\",\n      \"pmids\": [\"9808620\", \"9733740\", \"9548255\", \"9808621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism of Rac activation not yet defined\", \"Whether binding alone vs enzymatic activity drives GTP loading unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed that an engulfment receptor (\\u03b1v\\u03b25 integrin) recruits the p130Cas\\u2013CrkII\\u2013DOCK180 complex to trigger Rac1-dependent phagosome formation, linking the GEF to apoptotic-cell clearance.\",\n      \"evidence\": \"Co-IP, Rac1-GTP pulldown, \\u03b25 cytoplasmic-tail mutants, and phagocytosis assays\",\n      \"pmids\": [\"11146654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PS-recognition receptor not yet identified\", \"Mechanism coupling integrin engagement to GEF activation unclear\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified ELMO/CED-12 as an obligate partner forming a conserved CrkII\\u2013DOCK180\\u2013ELMO\\u2013Rac module, and localized DOCK180 membrane recruitment to PtdIns(3,4,5)P3 binding, defining the core signaling complex and its lipid input.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, C. elegans genetic rescue/epistasis, PtdIns(3,4,5)P3 bead pulldown with PI3K co-expression\",\n      \"pmids\": [\"11595183\", \"11703940\", \"11171081\", \"11240126\", \"11369773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical role of ELMO in catalysis not defined\", \"Lipid-binding domain not yet mapped at residue level\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that the DHR-2/Docker domain directly binds nucleotide-free Rac and catalyzes GTP loading, with ELMO augmenting exchange, establishing DOCK180\\u2013ELMO as an unconventional bipartite Rac-GEF and founding a new GEF superfamily.\",\n      \"evidence\": \"In vitro nucleotide exchange assays, domain mapping, trimeric ELMO1\\u2013Dock180\\u2013Rac1 complex detection, cell-based Rac-GTP pulldown\",\n      \"pmids\": [\"12134158\", \"12432077\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Rac recognition not yet solved\", \"How upstream signals gate catalysis unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed RhoG upstream of ELMO\\u2013DOCK180 as a GTP-dependent activator and showed that complex localization to lamellipodia, not bulk Rac activation, drives migration, refining how and where the GEF acts.\",\n      \"evidence\": \"GTP-dependent co-IP, constitutively active/dominant-negative RhoG, domain-deletion migration assays, C. elegans rescue, neurite-outgrowth and spreading assays\",\n      \"pmids\": [\"12879077\", \"14638695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RhoG\\u2013ELMO engagement is triggered by receptors unclear\", \"Spatial coupling of localization to catalysis not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved ELMO's catalytic contribution by showing its PH domain stabilizes Rac in the nucleotide-free transition state in trans, and reported a large nuclear DOCK180/ELMO complex with retained GEF activity.\",\n      \"evidence\": \"In vitro GEF assays with ELMO PH-domain mutagenesis, phagocytosis/migration assays, C. elegans rescue, biochemical fractionation and gel filtration\",\n      \"pmids\": [\"15247908\", \"15288806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of nuclear complex not established\", \"MFG-E8/PSR upstream coupling not fully reconstituted\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the autoinhibition mechanism\\u2014intramolecular SH3\\u2013DHR-2 contact blocks Rac access, relieved by ELMO\\u2014and showed the DHR-1 domain couples PI3K/PtdIns(3,4,5)P3 to directional Rac activation, separating GEF activity from spatial control.\",\n      \"evidence\": \"Intramolecular binding competition, in vitro/in vivo lipid binding, DHR-1 domain-swap rescue, directional migration assays, ARF6/ARNO epistasis with catalytic-dead and ELMO-coupling mutants\",\n      \"pmids\": [\"15723800\", \"16025104\", \"16213822\", \"15700267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of DHR-1\\u2013lipid recognition not yet solved\", \"Quantitative contribution of autoinhibition release vs ELMO stabilization unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Expanded the upstream receptor repertoire by identifying BAI1 as a PS-binding engulfment GPCR forming a BAI1\\u2013ELMO\\u2013DOCK180 complex, and DCC as a netrin receptor linking DOCK180 to axon guidance in vivo.\",\n      \"evidence\": \"Trimeric complex co-IP, PS-binding assays, in vitro/in vivo phagocytosis, Rac1-GTP pulldown, in vivo chick commissural axon guidance with knockdown\",\n      \"pmids\": [\"17960134\", \"18066058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How distinct receptors converge on the same GEF in different cell types unresolved\", \"Receptor-to-GEF activation step not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the ELMO1\\u2013DOCK180 binding interface structurally and uncovered a Rac1-independent role for DHR-1 in retrograde endosome-to-TGN trafficking via sorting nexins, broadening DOCK180's functional scope.\",\n      \"evidence\": \"X-ray structure of ELMO1 PH domain with mutagenesis and co-IP; mass spectrometry-identified SNX5 interaction with knockdown and CI-MPR trafficking/domain-rescue readouts; ANKRD28 competition experiments\",\n      \"pmids\": [\"18768751\", \"18596235\", \"19118547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological importance of the trafficking role relative to GEF function unclear\", \"How competing SH3 partners are selected in vivo unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided the structural basis for membrane targeting by showing DHR-1 is a C2-fold domain with a basic pocket for the PtdIns(3,4,5)P3 head group, and established DOCK180 as essential for cardiovascular development downstream of CXCR4 in vivo.\",\n      \"evidence\": \"X-ray crystal structure of DHR-1 with point mutagenesis and cell polarization assays; targeted SH3-domain deletion in mice with cardiovascular phenotyping and CXCL12-induced Rac assays\",\n      \"pmids\": [\"20167601\", \"20829512\", \"20016009\", \"21900250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How lipid binding and GEF catalysis are allosterically coupled unresolved\", \"Cell-type-specific receptor inputs in vivo not dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established phosphorylation-based and lipid-based control of DOCK1 in oncogenic signaling\\u2014Src-dependent Y1811, PKA-dependent S1250, and PA binding\\u2014and demonstrated DOCK1 requirement for HER2-driven and CXCR4-driven tumor growth and metastasis in vivo.\",\n      \"evidence\": \"Phospho-specific antibodies, site-specific mutant rescue (Y1811F, S1250L), in vitro PKA kinase assay, PA lipid-binding assay with DOCK1/DOCK5 knockout MEFs, conditional DOCK1 knockout HER2 mouse model, G\\u03b1i2\\u2013ELMO1 co-IP with in vivo metastasis\",\n      \"pmids\": [\"22080864\", \"23728337\", \"23362269\", \"23592719\", \"23591873\", \"23441967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of multiple phosphosites into a unified activation logic unresolved\", \"Whether phosphorylation alters catalysis vs localization vs partner binding not fully separated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified Src-family-dependent Y722 phosphorylation downstream of EGFRvIII and an EGFR\\u2013DOCK180\\u2013RAC1\\u2013MLK3\\u2013JNK axis as drivers of glioblastoma invasion, linking receptor tyrosine kinase oncogenes to a defined DOCK1 signaling output.\",\n      \"evidence\": \"Phospho-specific antibody, SFK inhibitors, shRNA depletion, Y722F mutant, JNK activation, migration/invasion assays\",\n      \"pmids\": [\"22323579\", \"28487380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of Y722 vs Y1811 vs S1250 in tumors unresolved\", \"Downstream effector selectivity of Rac1 not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that DOCK1 GEF activity is required for macropinocytosis-dependent nutrient uptake and invasion in Ras- and Rac1P29S-transformed cells, and validated the selective inhibitor TBOPP as suppressing metastasis without affecting DOCK2/DOCK5.\",\n      \"evidence\": \"Genetic DOCK1 inactivation in MEFs, chemical screen for TBOPP with DOCK family selectivity controls, in vitro nucleotide exchange on Rac1P29S, macropinocytosis/invasion assays, in vivo mouse metastasis models\",\n      \"pmids\": [\"28467910\", \"29432733\", \"25118935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling Rac1 activation to macropinosome formation not detailed\", \"TBOPP mode of GEF inhibition not structurally defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified DOCK1-mediated RAC1 activation as a metformin-resistance mechanism, showing phosphorylation-driven DOCK1 activity promotes survival and that TBOPP potentiates anti-tumor activity across organoid and mouse models.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 knockout screen, phosphorylation and Rac1-GTP assays, TBOPP treatment in cell lines, patient-derived organoids, and xenograft/immunocompetent mouse models\",\n      \"pmids\": [\"35217990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for metformin-induced DOCK1 phosphorylation not identified\", \"Downstream survival effectors of Rac1 not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple inputs\\u2014ELMO autoinhibition release, DHR-1/PA lipid binding, RhoG/G-protein/receptor engagement, and Src/PKA phosphorylation\\u2014are integrated into a single quantitative activation logic at defined membrane microdomains remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified structural model of the activated receptor\\u2013DOCK1\\u2013ELMO\\u2013Rac assembly\", \"Physiological role of the nuclear DOCK180/ELMO complex unknown\", \"How phosphosite combinations tune catalysis vs localization not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 10, 11, 46]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [6, 17, 31, 39]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 5, 23, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6, 17, 22, 45]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [26]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [49]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [13, 17, 47]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 13, 24, 32]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 23, 41]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [33, 35, 37, 43, 48]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [25, 32, 47]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"complexes\": [\n      \"DOCK1-ELMO bipartite Rac-GEF complex\",\n      \"p130Cas-CrkII-DOCK180 complex\",\n      \"BAI1-ELMO-DOCK180 engulfment complex\",\n      \"MET-AXL-ELMO2-DOCK180 complex\"\n    ],\n    \"partners\": [\n      \"ELMO1\",\n      \"RAC1\",\n      \"CRK\",\n      \"BCAR1\",\n      \"RHOG\",\n      \"DCC\",\n      \"ERBB2\",\n      \"SNX5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}