{"gene":"NEDD9","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2007,"finding":"HEF1/NEDD9 interacts with Aurora A kinase at the basal body of cilia, leading to Aurora A activation, which in turn phosphorylates and activates HDAC6 (a tubulin deacetylase), thereby promoting ciliary disassembly. This constitutes a nonmitotic activity of Aurora A in vertebrates.","method":"Co-immunoprecipitation, small molecule inhibitors of AurA and HDAC6, loss-of-function and overexpression experiments with defined ciliary resorption phenotype","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, pharmacological validation, necessary-and-sufficient epistasis established in multiple cell systems, replicated in subsequent studies (PMID:20864688, PMID:25139996)","pmids":["17604723"],"is_preprint":false},{"year":2005,"finding":"HEF1/NEDD9 associates with and activates Aurora A (AurA) kinase at the centrosome; overexpression causes increased centrosome numbers and multipolar spindles. Depletion causes centrosomal splitting, mono-astral spindles, and hyperactivation of Nek2, indicating HEF1 also acts earlier in the cell cycle.","method":"Co-immunoprecipitation, overexpression and siRNA knockdown with centrosome/spindle phenotype readouts","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus defined cellular phenotypes; independently replicated (PMID:17604723, PMID:16479169)","pmids":["16184168"],"is_preprint":false},{"year":2006,"finding":"NEDD9 functionally interacts with focal adhesion kinase (FAK) and modulates focal contact formation to enhance melanocyte invasion in vitro and metastasis in vivo.","method":"Biochemical co-immunoprecipitation, in vitro invasion assays, in vivo metastasis model, focal contact imaging","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional and biochemical methods in a single rigorous study, replicated across subsequent papers","pmids":["16814714"],"is_preprint":false},{"year":1996,"finding":"Cas-L/NEDD9 (pp105) is tyrosine-phosphorylated upon β1 integrin ligation in T lymphocytes and directly binds both FAK and the adaptor Crk; it also recruits Nck and SHPTP2 upon integrin engagement.","method":"Immunoprecipitation, in vitro binding assay, peptide sequencing/cloning","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — foundational biochemical characterization with multiple binding partners confirmed by reciprocal IP; independently replicated by multiple labs","pmids":["8879209"],"is_preprint":false},{"year":1998,"finding":"HEF1/NEDD9 is processed from full-length p115/p105 forms into a p55 amino-terminal fragment via caspase cleavage specifically at mitosis; p55 localizes to the mitotic spindle. Full-length forms localize to focal adhesions. HEF1 expression is cell-cycle regulated, upregulated upon growth induction. Two-hybrid screening identified the human homolog of G2/M regulator Dim1p as a p55-region interactor.","method":"Western blotting of synchronized cells, subcellular fractionation/immunofluorescence, yeast two-hybrid screen, caspase inhibitor experiments","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, immunofluorescence, two-hybrid, caspase inhibitors) in a single study; cell-cycle regulation replicated in subsequent papers","pmids":["9584194"],"is_preprint":false},{"year":2000,"finding":"Smad3 physically interacts with HEF1/NEDD9 and triggers its proteasomal degradation; TGF-β stimulation induces rapid proteasomal degradation of endogenous HEF1 in TGF-β-responsive cells. Elevated HEF1 in turn inhibits TGF-β/Smad3-mediated gene responses, suggesting a negative feedback mechanism.","method":"Co-immunoprecipitation, overexpression degradation assays, proteasome inhibitor experiments, TGF-β stimulation of endogenous protein","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus endogenous protein regulation plus pharmacological rescue; mechanism extended in PMID:15144564","pmids":["11118211"],"is_preprint":false},{"year":2004,"finding":"Smad3 recruits the APC/C ubiquitin ligase to HEF1/NEDD9 for proteasomal degradation: Smad3 directly contacts APC subunit APC10 via distinct MH2 subdomains, while HEF1 is recognized as a ubiquitination substrate by the CDH1 subunit of APC/C.","method":"Co-immunoprecipitation, domain mapping, overexpression degradation assays","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, single lab, mechanistically extends PMID:11118211","pmids":["15144564"],"is_preprint":false},{"year":2000,"finding":"HEF1/NEDD9 overexpression induces apoptosis; caspase-dependent cleavage generates 65-, 55-, and 28-kDa fragments during apoptosis. The 28-kDa C-terminal fragment drives apoptosis in a manner dependent on a divergent helix-loop-helix motif and the N-terminal 28 amino acids; it also causes cell rounding. HEF1 overexpression activates JNK, which co-localizes with HEF1.","method":"Inducible overexpression, caspase inhibitors, deletion/point mutants, immunofluorescence co-localization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, structure-function mutagenesis, multiple apoptosis readouts in a single rigorous study","pmids":["10866674"],"is_preprint":false},{"year":2001,"finding":"HEF1/NEDD9 undergoes proteolytic processing specifically in response to cell detachment; integrin receptor ligation and focal adhesion formation prevent this cleavage. A novel focal adhesion targeting domain in the HEF1 C-terminus is required for HEF1-induced cell spreading.","method":"Cell detachment/attachment assays, integrin blocking experiments, deletion mutant overexpression, immunofluorescence","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays with defined mutants, rigorous controls","pmids":["11438665"],"is_preprint":false},{"year":2002,"finding":"HEF1/NEDD9 inducible expression enhances cell speed and haptotaxis toward fibronectin in a manner partially dependent on ERK and p38 MAPK signaling pathways. HEF1 upregulates mRNAs encoding metalloproteinases, MLCK, p160ROCK, and ErbB2.","method":"Inducible expression system, cell migration/haptotaxis assays, kinase inhibitors, cDNA expression array","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible system with pharmacological pathway validation and transcriptional profiling, single lab","pmids":["11801728"],"is_preprint":false},{"year":2006,"finding":"HEF1/NEDD9 regulates the RhoA activation cycle during mitosis: increased HEF1 sustains RhoA activation causing failure at cytokinesis, while HEF1 depletion reduces RhoA activation causing defects before cleavage furrow formation. HEF1 associates with the RhoA-GEF ECT2.","method":"siRNA knockdown, overexpression, RhoA activity assays, Co-immunoprecipitation with ECT2, chemical RhoA inhibition rescue","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional genetic manipulation, biochemical interaction, pharmacological rescue; multiple orthogonal methods","pmids":["16394104"],"is_preprint":false},{"year":2001,"finding":"FAK regulates β1 integrin-dependent T cell migration through a linear β1 integrin–FAK–HEF1 effector pathway: FAK autophosphorylation and its PR1/HEF1-SH3-binding sites are required for FAK-driven migration and HEF1 tyrosine phosphorylation upon β1 integrin stimulation.","method":"Overexpression of wild-type and site-specific FAK mutants, siRNA, migration assays, phosphorylation analysis","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function mutants establishing linear pathway, single lab","pmids":["11465098"],"is_preprint":false},{"year":2006,"finding":"HEF1/NEDD9 acts as a necessary and specific downstream effector of FAK in glioblastoma cell migration and invasion: FAK overexpression increases HEF1 phosphorylation; siRNA knockdown of HEF1 (but not p130CAS) inhibits basal and PDGF-stimulated migration and invasion.","method":"siRNA knockdown, overexpression, FAK mutants (397F), transwell migration/invasion assays, Triton X-100 fractionation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective siRNA knockdown with functional rescue, FAK mutants, single lab","pmids":["16288224"],"is_preprint":false},{"year":1997,"finding":"HEF1/NEDD9 (p110HEF1) is tyrosine phosphorylated upon β1 integrin ligation in lymphoid cells and associates with CRKL via CRKL's SH2 domain; cell-type-specific differential phosphorylation of HEF1 vs. p120CBL determines different downstream CRKL complexes.","method":"Co-immunoprecipitation with SH2 domain specificity, anti-integrin stimulation, two cell line comparison","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type comparative Co-IP with SH2 domain analysis, single lab","pmids":["9162067"],"is_preprint":false},{"year":1997,"finding":"HEF1/NEDD9 is tyrosine phosphorylated downstream of BCR/ABL in leukemic cells and forms a complex with Crkl and P190Bcr/Abl; this occurs specifically for HEF1 (not p130Cas), implicating Bcr/Abl in specific interference with β1 integrin signaling via HEF1.","method":"Immunoprecipitation from transgenic mouse leukemic tissues, phosphotyrosine blotting","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical complex identified in in vivo leukemic tissue, single method","pmids":["9405482"],"is_preprint":false},{"year":1997,"finding":"HEF1/NEDD9 is tyrosine phosphorylated in human B cells upon β1 integrin or BCR ligation in a cytoskeleton-dependent manner; phosphorylated HEF1 associates with RAFTK/Pyk2 and CrkL; cytochalasin B pretreatment blocks both integrin- and BCR-induced HEF1 phosphorylation.","method":"Co-immunoprecipitation, cytochalasin B treatment, stimulation of primary and cell line B cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with pharmacological cytoskeletal disruption, primary cells and cell lines, single lab","pmids":["9020138"],"is_preprint":false},{"year":1998,"finding":"Cas-L/NEDD9 is transiently phosphorylated upon TCR/CD3 stimulation; phosphorylated Cas-L binds Crk and C3G. A Cas-L mutant lacking the SH3 domain (FAK-binding site) is phosphorylated by CD3 but not β1 integrin stimulation, indicating FAK-independent TCR signaling through Cas-L.","method":"CD3 cross-linking, immunoprecipitation, SH3-deletion mutant transfection, phospho-specific blotting","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function SH3 deletion mutant revealing pathway specificity, Co-IP, single lab","pmids":["9497377"],"is_preprint":false},{"year":1999,"finding":"The HEF1/NEDD9 C-terminal domain contains a divergent helix-loop-helix (HLH) motif that mediates HEF1 homodimerization and heterodimerization with Id2, E12, and E47 HLH proteins; this HLH is required for HEF1-induced constitutive pseudohyphal growth in yeast.","method":"Yeast two-hybrid interaction assays, deletion/mutation analysis, yeast pseudohyphal growth assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two-hybrid plus functional yeast assay with mutagenesis, single lab","pmids":["10502414"],"is_preprint":false},{"year":1999,"finding":"HEF1/NEDD9 (but not p130Cas) is tyrosine phosphorylated downstream of the calcitonin GPCR via Ca2+- and PKC-dependent mechanisms requiring an intact actin cytoskeleton; calcitonin also induces HEF1 association with paxillin and FAK.","method":"GPCR stimulation, pharmacological inhibitors (BAPTA, calphostin C, cytochalasin D), Co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with Co-IP, single lab","pmids":["10455189"],"is_preprint":false},{"year":2000,"finding":"Calcitonin-induced tyrosine phosphorylation of HEF1/NEDD9 requires cell attachment to extracellular matrix via integrin engagement, an intact actin cytoskeleton, and c-Src kinase (specifically SH2-competent Src); overexpression of kinase-dead or SH2-lacking Src blocks HEF1 phosphorylation. Erk1/2 phosphorylation by calcitonin is largely independent of these requirements.","method":"RGD peptide blocking, poly-D-lysine vs fibronectin adhesion, Src overexpression/mutants, kinase inhibitors","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function Src mutants with multiple cellular contexts, single lab","pmids":["10954702"],"is_preprint":false},{"year":2002,"finding":"TGF-β1 potently induces HEF1/NEDD9 gene transcription in dermal fibroblasts (16-fold protein increase). The p115 HEF1 isoform results from serine/threonine phosphorylation of p105 HEF1. Adhesion-dependent tyrosine phosphorylation of p105HEF1 is mediated by Src kinase (blocked by PP1 inhibitor), while TGF-β1-induced expression is independent of adhesion.","method":"TGF-β1 stimulation, phosphatase digestion, Src inhibitor PP1, in vitro kinase assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay for Src substrate plus pharmacological dissection, single lab","pmids":["12189134"],"is_preprint":false},{"year":2005,"finding":"Cell adhesion regulates HEF1/NEDD9 Ser/Thr phosphorylation and proteasomal degradation: actin microfilament disruption activates PP2A which dephosphorylates p115HEF1 to p105HEF1, and the p115 phosphorylated form is preferentially targeted for proteasomal degradation. Adhesion protects HEF1 from degradation.","method":"Cell detachment, cytoskeletal inhibitors, PP2A inhibitors, proteasome inhibitors, phosphatase assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with multiple inhibitors, single lab","pmids":["16352661"],"is_preprint":false},{"year":2009,"finding":"In the MMTV-PyVT mammary tumor model, Nedd9-null background reduces activation of AKT, Src, FAK, and ERK in tumor cells. Cell-derived data show persistently reduced FAK activation and adhesion/migration in Nedd9-/- cells, establishing NEDD9 as a scaffolding protein supporting these pro-oncogenic kinases.","method":"Genetic knockout mouse model, western blotting of signaling proteins, cell attachment and migration assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with multiple orthogonal biochemical readouts, corroborated by cell-based assays","pmids":["19738060"],"is_preprint":false},{"year":2013,"finding":"NEDD9 binding to Aurora A kinase stabilizes AURKA protein by limiting CDH1-APC/C ubiquitin ligase binding to AURKA. NEDD9 S296E mutation disrupts binding to AURKA and leads to reduced AURKA protein levels. NEDD9 depletion increases AURKA ubiquitination and proteasomal degradation.","method":"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (S296E), proteasome inhibitor experiments, shRNA knockdown/re-expression","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, point mutant validation, ubiquitination assay, multiple orthogonal methods in single study","pmids":["23539442"],"is_preprint":false},{"year":2010,"finding":"The WW-HECT E3 ligase Smurf2 physically associates with NEDD9 and is required for NEDD9 protein stability: Smurf2 depletion causes polyubiquitination and proteasomal degradation of NEDD9, while Smurf2 overexpression upregulates NEDD9. The Smurf2/NEDD9 complex is required for Aurora A activation at G2/M and timely mitotic entry.","method":"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, Aurora A activity assays, mitotic entry timing","journal":"Cell division","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional mitotic readout, single lab","pmids":["20825672"],"is_preprint":false},{"year":2012,"finding":"NEDD9 signaling through integrin β3 leads to elevated phosphorylation of integrin β3, increased Src and FAK activity, and decreased ROCK activity (via Src-dependent phosphorylation of ROCKII Tyr722), driving elongated mesenchymal invasion. Src inhibition by dasatinib switches NEDD9-overexpressing cells from Rac-driven mesenchymal invasion to ROCK-dependent amoeboid invasion.","method":"Overexpression/knockdown of NEDD9 and integrin β3, Src inhibitor dasatinib, phosphorylation analysis, invasion assays in vitronectin-containing matrix","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic dissection of signaling pathway with invasion phenotype, single lab","pmids":["22328516"],"is_preprint":false},{"year":2014,"finding":"NEDD9 regulates cortactin (CTTN) acetylation in an Aurora A kinase (AURKA)/HDAC6-dependent manner: NEDD9 binds to CTTN and its deficiency increases CTTN acetylation and decreases CTTN-F-actin binding, disrupting lamellipodia and migration. A deacetylation-mimicking CTTN-9KR mutant rescues migration defects in NEDD9-depleted cells.","method":"Co-immunoprecipitation of NEDD9-CTTN, acetylation assays, AURKA/HDAC6 inhibitors, 9KR mutant rescue, xenograft metastasis models","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, acetylation/deacetylation assays, mutant rescue, in vivo xenograft validation; multiple orthogonal methods","pmids":["24574519"],"is_preprint":false},{"year":2014,"finding":"NEDD9 directly binds to Arf6-GAP ARAP3 and Arf6-effector GGA3, facilitating Arf6 inactivation required for targeting the MMP14/TIMP2 complex to late endosomes. Without NEDD9, MMP14 trafficking is redirected from late endosomes back to the cell surface via Arf6-dependent recycling, preventing TIMP2 disengagement and reducing MMP14 activity and tumor invasion.","method":"Co-immunoprecipitation of NEDD9-ARAP3/GGA3, Arf6 activity assays, endosomal trafficking imaging, MMP14 activity assays, xenograft models with morpholino antisense","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Co-IPs, GTPase activity assays, functional invasion rescue, in vivo validation; multiple orthogonal methods","pmids":["25241893"],"is_preprint":false},{"year":2013,"finding":"NEDD9 depletion inactivates MMP14 via TIMP2 accumulation at the cell surface, reducing collagenolytic activity of MMP2 and MMP9 and suppressing mesenchymal invasion. Re-expression of NEDD9 restores MMP14 activity. NEDD9 is required for protease-dependent invasion at the primary site but not at the metastatic site.","method":"shRNA depletion, MMP14 activity assays, TIMP2 immunostaining, in vivo xenograft, re-expression rescue","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue with biochemical endpoint, in vivo validation, single lab","pmids":["24202705"],"is_preprint":false},{"year":2012,"finding":"NEDD9 stabilizes focal adhesions and slows focal adhesion disassembly: NEDD9-/- MEFs show increased paxillin phosphorylation at focal adhesions, increased 2D migration speed, but decreased 3D collagen migration. Loss of NEDD9 suppresses β1 integrin activation and reduces adhesion strength to fibronectin despite upregulated α5β1 expression.","method":"NEDD9-/- mouse embryo fibroblasts, focal adhesion turnover assays, 2D/3D migration assays, integrin activation assays, adhesion strength measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple cellular readouts, single lab","pmids":["22509381"],"is_preprint":false},{"year":2011,"finding":"NEDD9 and BCAR1 signal through SRC to promote E-cadherin removal from the cell membrane and lysosomal degradation, without affecting E-cadherin transcription. Nedd9-/- mammary tumors show enhanced junctional E-cadherin.","method":"siRNA knockdown, Src inhibitors, membrane fractionation, lysosomal inhibitors, immunofluorescence, Nedd9-/- mouse mammary tumor model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic dissection with in vivo confirmation, single lab","pmids":["21765937"],"is_preprint":false},{"year":2000,"finding":"AND-34 (a GEF) associates with HEF1/NEDD9 via its GEF domain binding to the HEF1 C-terminus; AND-34 overexpression activates Cdc42 (but not Rac, Rho, RalA, or Rap1) in B cells, enhancing PAK1 activity and inhibiting SDF-1α-induced B cell polarization.","method":"Co-immunoprecipitation, GTPase pulldown assays, PAK1 kinase assay, overexpression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with GTPase specificity panel and functional assays, single lab","pmids":["10692442"],"is_preprint":false},{"year":2006,"finding":"Chat-H (hematopoietic isoform of Cas/HEF1-associated signal transducer) associates with HEF1/NEDD9 (CasL) and mediates serine-threonine phosphorylation of CasL; Chat-H localization to the plasma membrane and its binding to CasL are required for T cell migration and chemokine-induced Rap1 activation.","method":"Lentiviral RNAi, co-immunoprecipitation, phosphorylation analysis, Rap1 activation assay, T cell migration assay","journal":"Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating interaction, RNAi loss-of-function with chemotaxis and Rap1 readouts, single lab","pmids":["17174122"],"is_preprint":false},{"year":2012,"finding":"Abl and Arg tyrosine kinases mediate chemokine-induced tyrosine phosphorylation of HEF1/NEDD9; phosphorylated HEF1 is required for Rap1 GTPase activation, which mediates T cell adhesion and migration. T cells lacking Abl and Arg exhibit defective lymph node homing and impaired migration to inflammation sites.","method":"Abl/Arg knockout T cells, co-immunoprecipitation, Rap1 activation assay, in vivo homing assay, transwell migration","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO cells with biochemical and in vivo migration readouts, single lab","pmids":["22810897"],"is_preprint":false},{"year":2012,"finding":"LKB1 negatively regulates NEDD9 transcription by promoting cytosolic translocation of CRTC1 from the nucleus. Ectopic NEDD9 or CRTC1 expression partially reverses the inhibitory function of LKB1 on lung cancer metastasis, establishing a CRTC1-NEDD9 axis downstream of LKB1.","method":"RNAi silencing in de novo mouse lung tumor models, ectopic expression, subcellular fractionation of CRTC1, metastasis assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with mechanistic CRTC1 localization data, single lab","pmids":["23074285"],"is_preprint":false},{"year":2011,"finding":"HEF1/NEDD9 is a direct transcriptional target of canonical Wnt/β-catenin signaling: ChIP assays and promoter analyses identified three functional TCF-binding sites in the HEF1 promoter responsible for Wnt-3a/β-catenin/Dvl2-driven upregulation; shRNA knockdown of β-catenin suppresses HEF1 expression.","method":"Chromatin immunoprecipitation (ChIP), promoter luciferase assays, shRNA knockdown, Wnt-3a stimulation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with promoter dissection, multiple Wnt pathway activators, single lab","pmids":["21317929"],"is_preprint":false},{"year":2010,"finding":"VHL inactivation induces HEF1/NEDD9 and Aurora kinase A via stabilization of HIF-1 and HIF-2. HEF1/NEDD9 colocalizes with Aurora kinase A at the centrosome and enhances Aurora A's cilium-destabilizing effect; suppression of this pathway improves primary cilium formation and reduces motility in VHL-defective renal cancer cells.","method":"siRNA knockdown, immunofluorescence co-localization, VHL re-expression, HIF stabilization, cilia formation assay","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic re-expression rescue with imaging and functional readouts, single lab","pmids":["20864688"],"is_preprint":false},{"year":2010,"finding":"HEF1/NEDD9 is required for VEGF-mediated head and neck cancer cell migration and invasion; VEGF promotes HEF1-dependent invadopodia formation, and HEF1 co-localizes with MT1-MMP at invadopodia.","method":"siRNA knockdown and overexpression, phosphotyrosine proteomics, invadopodia assays, co-immunolocalization","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics identification plus functional siRNA/OE studies with invadopodia imaging, single lab","pmids":["20498643"],"is_preprint":false},{"year":2018,"finding":"Oxidation of Cys18 in the SMAD3 docking region of NEDD9 impairs SMAD3-NEDD9 protein-protein interaction in vitro (demonstrated by microscale thermophoresis). Aldosterone-induced oxidant stress in pulmonary artery endothelial cells reproduces this effect, resulting in impaired NEDD9 proteolytic degradation, increased NEDD9 complex formation with NKX2-5, and increased NKX2-5 binding to the COL3A1 promoter to upregulate collagen III. NEDD9 ablation prevents fibrotic vascular remodeling in animal PAH models.","method":"Microscale thermophoresis (in vitro protein interaction), ALDO-induced oxidant stress, Co-immunoprecipitation (NEDD9-NKX2-5), ChIP (NKX2-5 on COL3A1), atomic force microscopy, NEDD9 knockout animal model","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding assay with Cys18 oxidation mechanism, multiple biochemical methods (MST, Co-IP, ChIP), in vivo KO validation","pmids":["29899023"],"is_preprint":false},{"year":2021,"finding":"NEDD9 mediates platelet adhesion to pulmonary artery endothelial cells via a NEDD9-P-selectin interaction; under hypoxia, HIF-1α-dependent NEDD9 upregulation increases surface NEDD9. Anti-NEDD9 antibody targeting the NEDD9-P-selectin interaction inhibits platelet-endothelial adhesion in vitro and reduces pulmonary thromboembolic remodeling in vivo in NEDD9-/- mice.","method":"Network medicine/proteomics identification, microscale thermophoresis, NEDD9-/- mice, anti-NEDD9 antibody functional assay, ex vivo CTEPH patient cells","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MST binding assay, genetic KO mouse model, patient-derived cells; single lab, new mechanism","pmids":["33523764"],"is_preprint":false},{"year":2016,"finding":"Cas-L/NEDD9 is phosphorylated at TCR microclusters in an actin polymerization-dependent manner and is required for transport of TCR microclusters to the center of the immunological synapse; Cas-L participates in a positive feedback loop amplifying Ca2+ signaling, inside-out integrin activation, and actomyosin contraction, acting as a mechanical transducer linking TCR to actin.","method":"siRNA knockdown, super-resolution imaging of TCR microclusters, Ca2+ imaging, integrin activation assay, traction force microscopy","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple imaging and functional readouts with siRNA knockdown, single lab","pmids":["27359298"],"is_preprint":false},{"year":2009,"finding":"Loss of Nedd9 in chick neural crest cells perturbs cell spreading, reduces focal complex density and actin filaments, and causes a graded reduction in migratory distance in vivo. Retinoic acid regulates Nedd9 expression in neural crest cells.","method":"siRNA knockdown and overexpression in chick neural crest, in ovo electroporation, immunofluorescence of focal complexes and actin","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss/gain of function with defined morphological and migratory readouts, single lab","pmids":["19464348"],"is_preprint":false},{"year":2009,"finding":"AhR/dioxin activation transcriptionally induces Nedd9/HEF1 via two xenobiotic response elements (XREs) in its promoter; RNAi knockdown of Nedd9 blocks dioxin-induced changes in adhesion, cytoskeleton reorganization, increased cell migration, E-cadherin repression, and JNK activation.","method":"XRE reporter assay, RNAi knockdown, AhR ligand stimulation, migration/adhesion assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter with functional RNAi rescue, single lab","pmids":["19648964"],"is_preprint":false},{"year":2008,"finding":"NEDD9 is directly regulated by all-trans retinoic acid (atRA) through a complex retinoic acid response element (RARE) located at -475 to -445 in the NEDD9 proximal promoter; RAR and RXR are physically bound to this RARE in cells, as shown by ChIP.","method":"Promoter luciferase assays with RARE mutations, EMSA, ChIP for RAR/RXR binding","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus promoter deletion/mutation analysis, single lab","pmids":["18585997"],"is_preprint":false},{"year":2014,"finding":"Pkd1-/-;Nedd9-/- mice show striking morphological ciliary defects with specific loss of ciliary localization of adenylyl cyclase III, and have ciliary resorption defects compatible with failure of Aurora A activation. Cystogenesis is strongly promoted in the double-mutant, indicating Nedd9 acts as a modifier of ADPKD via Aurora A-dependent ciliary maintenance.","method":"Compound Pkd1/Nedd9 genetic knockout mice, immunofluorescence of cilia, Aurora A activity analysis, cystogenesis quantification, calcium response assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo compound genetic model with ciliary imaging and signaling readouts, single lab","pmids":["25139996"],"is_preprint":false},{"year":2023,"finding":"Pan-HDAC inhibitors enhance H3K9 acetylation at the NEDD9 gene promoter via inhibition of HDAC4 activity, increasing NEDD9 expression and subsequent FAK phosphorylation activation, promoting breast cancer metastasis. FAK inhibitors can reverse this metastasis.","method":"ChIP for H3K9 acetylation at NEDD9 promoter, HDAC4 inhibition, FAK phosphorylation assays, invasion assays, preclinical metastasis models","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with promoter-specific histone acetylation, pharmacological rescue, functional invasion readout, single lab","pmids":["36604412"],"is_preprint":false},{"year":2018,"finding":"NEDD9 stimulates MMP9 secretion and invadopodia formation through its substrate domain (SD) tyrosine phosphorylation and SH3 domain; mutation of all 13 YxxP motif tyrosines plus Y629 (F14NEDD9) eliminates tyrosine phosphorylation, MMP9 secretion, and invadopodia. MICAL1 silencing also reduces MMP9 secretion, suggesting NEDD9-MICAL1 cooperation.","method":"Stable expression of NEDD9 domain mutants, MMP9 secretion assays, invadopodia formation assays, MICAL1 shRNA","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic domain mutagenesis with defined functional readouts, single lab","pmids":["29876004"],"is_preprint":false},{"year":2005,"finding":"HTLV-I Tax physically associates with Cas-L/NEDD9, binding through the serine-rich region of Cas-L; Tax increases Cas-L expression and tyrosine phosphorylation. Exogenous Cas-L inhibits Tax-mediated NF-κB transactivation but not Tax-independent NF-κB activation.","method":"Yeast two-hybrid screen, co-immunoprecipitation, NF-κB reporter assay, co-localization","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, functional NF-κB reporter assay, single lab","pmids":["15592516"],"is_preprint":false}],"current_model":"NEDD9/HEF1/CAS-L is a multi-domain Cas-family scaffolding protein that assembles signaling complexes at focal adhesions, the centrosome, and the primary cilium: it is tyrosine-phosphorylated downstream of integrins, TCR/BCR, GPCRs, and oncogenic kinases (BCR-ABL, Src), recruits Crk/CrkL, FAK, and Pyk2 to drive cell migration and invasion, activates and stabilizes Aurora A kinase at the centrosome to control mitotic progression and ciliary resorption (via HDAC6-dependent tubulin deacetylation of cortactin and ciliary axoneme), regulates the RhoA–ECT2 cycle during cell division, is processed by caspase cleavage during mitosis and apoptosis to generate subcellularly targeted fragments, is subject to proteasomal degradation controlled by Smad3/APC/C-CDH1 and Smurf2, and regulates MMP14/TIMP2 trafficking through an Arf6/ARAP3/GGA3 endosomal pathway to enable mesenchymal invasion."},"narrative":{"mechanistic_narrative":"NEDD9 (HEF1/Cas-L) is a multi-domain Cas-family scaffolding protein that assembles tyrosine-phosphorylation–dependent signaling complexes to control cell adhesion, migration, invasion, and mitotic/ciliary progression [PMID:8879209, PMID:19738060]. At focal adhesions it is tyrosine-phosphorylated upon β1 integrin ligation and engages FAK and the adaptor Crk/CrkL, also recruiting Nck, SHPTP2, and Pyk2/RAFTK, with FAK acting upstream in a linear integrin–FAK–HEF1 effector pathway that drives lymphocyte and tumor cell migration [PMID:8879209, PMID:9162067, PMID:9020138, PMID:11465098]. The same phosphorylation module is engaged downstream of TCR/BCR, the calcitonin GPCR, and the oncogenic kinases BCR-ABL and Src, channeling signals to Crk/C3G and Rap1-dependent adhesion and chemotaxis [PMID:9497377, PMID:9405482, PMID:10455189, PMID:22810897]. As a downstream effector NEDD9 supports activation of FAK, Src, AKT and ERK and stabilizes focal adhesions, while promoting mesenchymal invasion through integrin β3/Src/ROCK signaling and through control of MMP14/MMP9 protease activity—the latter via direct binding to ARAP3 and GGA3 to drive Arf6-dependent endosomal trafficking of the MMP14/TIMP2 complex [PMID:19738060, PMID:22509381, PMID:22328516, PMID:25241893, PMID:29876004]. At the centrosome and primary cilium NEDD9 binds and activates Aurora A kinase, an interaction that stabilizes Aurora A by limiting CDH1-APC/C–mediated ubiquitination and drives HDAC6-dependent tubulin/cortactin deacetylation to promote ciliary disassembly and mitotic progression [PMID:16184168, PMID:17604723, PMID:23539442, PMID:24574519]. NEDD9 additionally regulates the RhoA–ECT2 cycle during cytokinesis and is cleaved by caspases during mitosis and apoptosis into subcellularly targeted fragments [PMID:16394104, PMID:9584194, PMID:10866674]. NEDD9 abundance is set transcriptionally by Wnt/β-catenin, retinoic acid, AhR, and LKB1–CRTC1 inputs and post-translationally by proteasomal degradation controlled by Smad3/APC/C-CDH1 and by Smurf2 [PMID:21317929, PMID:18585997, PMID:23074285, PMID:11118211, PMID:15144564, PMID:20825672]. Oxidation of Cys18 in the SMAD3 docking region stabilizes NEDD9 and reroutes it into an NKX2-5/COL3A1 transcriptional program driving fibrotic pulmonary vascular remodeling, and NEDD9 mediates platelet–endothelial adhesion via P-selectin, establishing causative roles in pulmonary hypertension and thromboembolic remodeling [PMID:29899023, PMID:33523764].","teleology":[{"year":1996,"claim":"Established NEDD9 as an integrin-responsive adaptor by showing it is tyrosine-phosphorylated upon β1 integrin ligation and directly binds FAK and Crk, defining its core scaffolding logic at adhesion sites.","evidence":"Immunoprecipitation, in vitro binding, and cloning in T lymphocytes","pmids":["8879209"],"confidence":"High","gaps":["Did not define the kinase directly phosphorylating NEDD9","No structural detail of binding interfaces"]},{"year":1997,"claim":"Showed the integrin-driven phosphorylation module is shared across hematopoietic receptors and oncogenic kinases, recruiting CrkL, Pyk2 and forming complexes downstream of BCR/ABL and BCR ligation.","evidence":"Co-IP with SH2-domain specificity in lymphoid and leukemic cells, including transgenic leukemic tissue","pmids":["9162067","9405482","9020138"],"confidence":"Medium","gaps":["Functional consequence of distinct CrkL complexes not resolved","Single-method complex identification in some contexts"]},{"year":1998,"claim":"Defined receptor-specific wiring (TCR vs integrin) and revealed cell-cycle-coupled caspase processing, showing full-length NEDD9 at focal adhesions and a p55 fragment at the mitotic spindle.","evidence":"SH3-deletion mutants, synchronized-cell Western blots, fractionation/IF, caspase inhibitors, yeast two-hybrid","pmids":["9497377","9584194"],"confidence":"High","gaps":["Protease responsible for mitotic cleavage not identified","Functional role of p55 at the spindle untested"]},{"year":2000,"claim":"Connected NEDD9 to apoptosis and to TGF-β/Smad3 negative feedback, and identified GPCR and GEF (AND-34) inputs, broadening its signaling and turnover control.","evidence":"Inducible overexpression with caspase inhibitors, Co-IP, proteasome inhibitors, GTPase pulldowns","pmids":["10866674","11118211","10692442","10954702"],"confidence":"High","gaps":["E3 ligase mediating Smad3-directed degradation not yet identified","Apoptotic fragment mechanism partially defined"]},{"year":2001,"claim":"Demonstrated adhesion-state control of NEDD9 stability and a focal adhesion targeting domain required for spreading, and placed NEDD9 in a linear integrin–FAK–HEF1 migration pathway.","evidence":"Detachment/attachment assays, FAK site-specific mutants, deletion mutants, migration assays","pmids":["11438665","11465098"],"confidence":"Medium","gaps":["Identity of detachment-activated protease unclear","Mechanism linking FAK autophosphorylation to NEDD9 phosphorylation not fully resolved"]},{"year":2002,"claim":"Linked NEDD9 to invasive output by showing it enhances migration via ERK/p38 and upregulates metalloproteinases and contractility genes, and is transcriptionally induced by TGF-β1.","evidence":"Inducible expression, haptotaxis assays, kinase inhibitors, cDNA arrays, Src inhibitor PP1","pmids":["11801728","12189134"],"confidence":"Medium","gaps":["Direct vs indirect transcriptional effects not distinguished","Single-lab profiling"]},{"year":2005,"claim":"Identified the centrosomal NEDD9–Aurora A axis controlling spindle and centrosome behavior, and refined Smad3-directed turnover to the APC/C-CDH1 ligase.","evidence":"Co-IP, siRNA/overexpression with centrosome/spindle phenotypes, domain mapping","pmids":["16184168","15144564","15592516"],"confidence":"High","gaps":["Mechanism of Aurora A activation by NEDD9 not yet defined at 2005","HTLV-I Tax interaction physiological relevance limited"]},{"year":2006,"claim":"Extended NEDD9 mitotic function to RhoA–ECT2 regulation during cytokinesis and confirmed it as a selective FAK effector in tumor invasion and melanoma metastasis.","evidence":"siRNA/overexpression, RhoA activity assays, Co-IP with ECT2, in vitro/in vivo invasion and metastasis models","pmids":["16394104","16288224","16814714"],"confidence":"High","gaps":["How NEDD9 modulates ECT2/RhoA GEF activity biochemically unresolved","Selectivity over p130CAS mechanistically unexplained"]},{"year":2007,"claim":"Resolved the cilia connection, showing NEDD9–Aurora A activation triggers HDAC6 to drive ciliary disassembly, a nonmitotic Aurora A function.","evidence":"Co-IP, AurA/HDAC6 inhibitors, loss/gain of function with ciliary resorption readout","pmids":["17604723"],"confidence":"High","gaps":["Stoichiometry of the NEDD9–AurA–HDAC6 module not defined","Upstream cue triggering complex assembly at the basal body unclear"]},{"year":2010,"claim":"Established NEDD9 stability is positively controlled by Smurf2 and tied the AurA/cilia axis to VHL-HIF, while a knockout model confirmed NEDD9 as a scaffold supporting AKT/Src/FAK/ERK.","evidence":"Co-IP, ubiquitination assays, VHL re-expression/HIF stabilization, MMTV-PyVT Nedd9-null model","pmids":["20825672","20864688","19738060"],"confidence":"Medium","gaps":["Opposing roles of Smurf2 vs APC/C in NEDD9 turnover not reconciled","Direct vs indirect kinase support in vivo unresolved"]},{"year":2013,"claim":"Provided the molecular basis of NEDD9-mediated Aurora A control, showing binding stabilizes Aurora A by blocking CDH1-APC/C ubiquitination, with S296 governing the interaction.","evidence":"Co-IP, ubiquitination assays, S296E mutant, proteasome inhibitors, shRNA/re-expression","pmids":["23539442"],"confidence":"High","gaps":["How S296 phosphorylation is regulated in cells not defined","Structural model of the NEDD9–AurA interface absent"]},{"year":2014,"claim":"Defined the effector arm of NEDD9-driven invasion: cortactin deacetylation via AurA/HDAC6 for lamellipodia, and Arf6/ARAP3/GGA3-dependent endosomal routing of MMP14/TIMP2 to license proteolysis.","evidence":"Co-IP, acetylation/deacetylation assays, mutant rescue, Arf6 activity assays, trafficking imaging, xenografts","pmids":["24574519","25241893","24202705","25139996"],"confidence":"High","gaps":["Coordination between cilia/centrosome and invasion functions unclear","Direct binding topology on ARAP3/GGA3 not structurally mapped"]},{"year":2018,"claim":"Identified a redox switch (Cys18 oxidation) that disables Smad3 docking, stabilizing NEDD9 and rerouting it to an NKX2-5/COL3A1 program, establishing causation in fibrotic pulmonary vascular remodeling.","evidence":"Microscale thermophoresis, oxidant-stress models, Co-IP, ChIP, NEDD9 knockout PAH models","pmids":["29899023"],"confidence":"High","gaps":["In vivo extent of Cys18 oxidation under disease conditions not quantified","How NEDD9 selects NKX2-5 over other partners unclear"]},{"year":2021,"claim":"Revealed an extracellular adhesion function: surface NEDD9 binds P-selectin to mediate platelet–endothelial adhesion under hypoxia, suggesting a therapeutic target in thromboembolic remodeling.","evidence":"Network proteomics, MST binding, NEDD9-/- mice, anti-NEDD9 antibody, CTEPH patient cells","pmids":["33523764"],"confidence":"Medium","gaps":["Mechanism of NEDD9 surface display for an adaptor protein unresolved","Single-lab new mechanism awaiting independent confirmation"]},{"year":null,"claim":"How the distinct NEDD9 pools (focal adhesion, centrosome/cilium, endosomal trafficking, cell-surface adhesion) are spatially and temporally partitioned within a single cell, and how its phosphorylation and degradation states select among partners, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of full-length NEDD9 with partners","Quantitative rules governing partner selection by phospho-state unknown","Integration of mitotic and migratory functions in vivo undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,13,22]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[39]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[23,24]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1,23,36]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,36,44]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[27]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[39]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,22,25]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,10,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[16,33,40]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[27,28,46]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[38,39]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[27]}],"complexes":["focal adhesion","NEDD9–Aurora A centrosomal complex"],"partners":["AURKA","PTK2/FAK","CRKL","ECT2","ARAP3","GGA3","CTTN","SMAD3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14511","full_name":"Enhancer of filamentation 1","aliases":["CRK-associated substrate-related protein","CAS-L","CasL","Cas scaffolding protein family member 2","CASS2","Neural precursor cell expressed developmentally down-regulated protein 9","NEDD-9","Renal carcinoma antigen NY-REN-12","p105"],"length_aa":834,"mass_kda":92.9,"function":"Scaffolding protein which plays a central coordinating role for tyrosine-kinase-based signaling related to cell adhesion (PubMed:24574519). As a focal adhesion protein, plays a role in embryonic fibroblast migration (By similarity). May play an important role in integrin beta-1 or B cell antigen receptor (BCR) mediated signaling in B- and T-cells. Integrin beta-1 stimulation leads to recruitment of various proteins including CRKL and SHPTP2 to the tyrosine phosphorylated form (PubMed:9020138). Promotes adhesion and migration of lymphocytes; as a result required for the correct migration of lymphocytes to the spleen and other secondary lymphoid organs (PubMed:17174122). Plays a role in the organization of T-cell F-actin cortical cytoskeleton and the centralization of T-cell receptor microclusters at the immunological synapse (By similarity). Negatively regulates cilia outgrowth in polarized cysts (By similarity). Modulates cilia disassembly via activation of AURKA-mediated phosphorylation of HDAC6 and subsequent deacetylation of alpha-tubulin (PubMed:17604723). Positively regulates RANKL-induced osteoclastogenesis (By similarity). Required for the maintenance of hippocampal dendritic spines in the dentate gyrus and CA1 regions, thereby involved in spatial learning and memory (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q14511/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NEDD9","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NEDD9","total_profiled":1310},"omim":[{"mim_id":"615886","title":"SCAFFOLDING CK1-ANCHORING PROTEIN G; SACK1G","url":"https://www.omim.org/entry/615886"},{"mim_id":"607129","title":"MICROTUBULE-ASSOCIATED MONOOXYGENASE, CALPONIN AND LIM DOMAINS-CONTAINING, 1; MICAL1","url":"https://www.omim.org/entry/607129"},{"mim_id":"604722","title":"SH2 DOMAIN-CONTAINING PROTEIN 3C; SH2D3C","url":"https://www.omim.org/entry/604722"},{"mim_id":"603072","title":"AURORA KINASE A; AURKA","url":"https://www.omim.org/entry/603072"},{"mim_id":"602265","title":"NEURAL PRECURSOR CELL EXPRESSED, DEVELOPMENTALLY DOWNREGULATED 9; NEDD9","url":"https://www.omim.org/entry/602265"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NEDD9"},"hgnc":{"alias_symbol":["HEF1","CAS-L","CASS2"],"prev_symbol":[]},"alphafold":{"accession":"Q14511","domains":[{"cath_id":"2.30.30.40","chopping":"7-65","consensus_level":"high","plddt":89.8869,"start":7,"end":65},{"cath_id":"1.20.120.830","chopping":"407-558","consensus_level":"high","plddt":90.0293,"start":407,"end":558},{"cath_id":"1.20.120.230","chopping":"638-649_660-685_698-834","consensus_level":"high","plddt":85.7415,"start":638,"end":834}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14511","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14511-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14511-F1-predicted_aligned_error_v6.png","plddt_mean":61.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NEDD9","jax_strain_url":"https://www.jax.org/strain/search?query=NEDD9"},"sequence":{"accession":"Q14511","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14511.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14511/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14511"}},"corpus_meta":[{"pmid":"17604723","id":"PMC_17604723","title":"HEF1-dependent 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at the basal body of cilia, leading to Aurora A activation, which in turn phosphorylates and activates HDAC6 (a tubulin deacetylase), thereby promoting ciliary disassembly. This constitutes a nonmitotic activity of Aurora A in vertebrates.\",\n      \"method\": \"Co-immunoprecipitation, small molecule inhibitors of AurA and HDAC6, loss-of-function and overexpression experiments with defined ciliary resorption phenotype\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, pharmacological validation, necessary-and-sufficient epistasis established in multiple cell systems, replicated in subsequent studies (PMID:20864688, PMID:25139996)\",\n      \"pmids\": [\"17604723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HEF1/NEDD9 associates with and activates Aurora A (AurA) kinase at the centrosome; overexpression causes increased centrosome numbers and multipolar spindles. Depletion causes centrosomal splitting, mono-astral spindles, and hyperactivation of Nek2, indicating HEF1 also acts earlier in the cell cycle.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and siRNA knockdown with centrosome/spindle phenotype readouts\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus defined cellular phenotypes; independently replicated (PMID:17604723, PMID:16479169)\",\n      \"pmids\": [\"16184168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NEDD9 functionally interacts with focal adhesion kinase (FAK) and modulates focal contact formation to enhance melanocyte invasion in vitro and metastasis in vivo.\",\n      \"method\": \"Biochemical co-immunoprecipitation, in vitro invasion assays, in vivo metastasis model, focal contact imaging\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional and biochemical methods in a single rigorous study, replicated across subsequent papers\",\n      \"pmids\": [\"16814714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Cas-L/NEDD9 (pp105) is tyrosine-phosphorylated upon β1 integrin ligation in T lymphocytes and directly binds both FAK and the adaptor Crk; it also recruits Nck and SHPTP2 upon integrin engagement.\",\n      \"method\": \"Immunoprecipitation, in vitro binding assay, peptide sequencing/cloning\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — foundational biochemical characterization with multiple binding partners confirmed by reciprocal IP; independently replicated by multiple labs\",\n      \"pmids\": [\"8879209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"HEF1/NEDD9 is processed from full-length p115/p105 forms into a p55 amino-terminal fragment via caspase cleavage specifically at mitosis; p55 localizes to the mitotic spindle. Full-length forms localize to focal adhesions. HEF1 expression is cell-cycle regulated, upregulated upon growth induction. Two-hybrid screening identified the human homolog of G2/M regulator Dim1p as a p55-region interactor.\",\n      \"method\": \"Western blotting of synchronized cells, subcellular fractionation/immunofluorescence, yeast two-hybrid screen, caspase inhibitor experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, immunofluorescence, two-hybrid, caspase inhibitors) in a single study; cell-cycle regulation replicated in subsequent papers\",\n      \"pmids\": [\"9584194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Smad3 physically interacts with HEF1/NEDD9 and triggers its proteasomal degradation; TGF-β stimulation induces rapid proteasomal degradation of endogenous HEF1 in TGF-β-responsive cells. Elevated HEF1 in turn inhibits TGF-β/Smad3-mediated gene responses, suggesting a negative feedback mechanism.\",\n      \"method\": \"Co-immunoprecipitation, overexpression degradation assays, proteasome inhibitor experiments, TGF-β stimulation of endogenous protein\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus endogenous protein regulation plus pharmacological rescue; mechanism extended in PMID:15144564\",\n      \"pmids\": [\"11118211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Smad3 recruits the APC/C ubiquitin ligase to HEF1/NEDD9 for proteasomal degradation: Smad3 directly contacts APC subunit APC10 via distinct MH2 subdomains, while HEF1 is recognized as a ubiquitination substrate by the CDH1 subunit of APC/C.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, overexpression degradation assays\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, single lab, mechanistically extends PMID:11118211\",\n      \"pmids\": [\"15144564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HEF1/NEDD9 overexpression induces apoptosis; caspase-dependent cleavage generates 65-, 55-, and 28-kDa fragments during apoptosis. The 28-kDa C-terminal fragment drives apoptosis in a manner dependent on a divergent helix-loop-helix motif and the N-terminal 28 amino acids; it also causes cell rounding. HEF1 overexpression activates JNK, which co-localizes with HEF1.\",\n      \"method\": \"Inducible overexpression, caspase inhibitors, deletion/point mutants, immunofluorescence co-localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, structure-function mutagenesis, multiple apoptosis readouts in a single rigorous study\",\n      \"pmids\": [\"10866674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HEF1/NEDD9 undergoes proteolytic processing specifically in response to cell detachment; integrin receptor ligation and focal adhesion formation prevent this cleavage. A novel focal adhesion targeting domain in the HEF1 C-terminus is required for HEF1-induced cell spreading.\",\n      \"method\": \"Cell detachment/attachment assays, integrin blocking experiments, deletion mutant overexpression, immunofluorescence\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays with defined mutants, rigorous controls\",\n      \"pmids\": [\"11438665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HEF1/NEDD9 inducible expression enhances cell speed and haptotaxis toward fibronectin in a manner partially dependent on ERK and p38 MAPK signaling pathways. HEF1 upregulates mRNAs encoding metalloproteinases, MLCK, p160ROCK, and ErbB2.\",\n      \"method\": \"Inducible expression system, cell migration/haptotaxis assays, kinase inhibitors, cDNA expression array\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible system with pharmacological pathway validation and transcriptional profiling, single lab\",\n      \"pmids\": [\"11801728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HEF1/NEDD9 regulates the RhoA activation cycle during mitosis: increased HEF1 sustains RhoA activation causing failure at cytokinesis, while HEF1 depletion reduces RhoA activation causing defects before cleavage furrow formation. HEF1 associates with the RhoA-GEF ECT2.\",\n      \"method\": \"siRNA knockdown, overexpression, RhoA activity assays, Co-immunoprecipitation with ECT2, chemical RhoA inhibition rescue\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional genetic manipulation, biochemical interaction, pharmacological rescue; multiple orthogonal methods\",\n      \"pmids\": [\"16394104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"FAK regulates β1 integrin-dependent T cell migration through a linear β1 integrin–FAK–HEF1 effector pathway: FAK autophosphorylation and its PR1/HEF1-SH3-binding sites are required for FAK-driven migration and HEF1 tyrosine phosphorylation upon β1 integrin stimulation.\",\n      \"method\": \"Overexpression of wild-type and site-specific FAK mutants, siRNA, migration assays, phosphorylation analysis\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function mutants establishing linear pathway, single lab\",\n      \"pmids\": [\"11465098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HEF1/NEDD9 acts as a necessary and specific downstream effector of FAK in glioblastoma cell migration and invasion: FAK overexpression increases HEF1 phosphorylation; siRNA knockdown of HEF1 (but not p130CAS) inhibits basal and PDGF-stimulated migration and invasion.\",\n      \"method\": \"siRNA knockdown, overexpression, FAK mutants (397F), transwell migration/invasion assays, Triton X-100 fractionation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective siRNA knockdown with functional rescue, FAK mutants, single lab\",\n      \"pmids\": [\"16288224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"HEF1/NEDD9 (p110HEF1) is tyrosine phosphorylated upon β1 integrin ligation in lymphoid cells and associates with CRKL via CRKL's SH2 domain; cell-type-specific differential phosphorylation of HEF1 vs. p120CBL determines different downstream CRKL complexes.\",\n      \"method\": \"Co-immunoprecipitation with SH2 domain specificity, anti-integrin stimulation, two cell line comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type comparative Co-IP with SH2 domain analysis, single lab\",\n      \"pmids\": [\"9162067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"HEF1/NEDD9 is tyrosine phosphorylated downstream of BCR/ABL in leukemic cells and forms a complex with Crkl and P190Bcr/Abl; this occurs specifically for HEF1 (not p130Cas), implicating Bcr/Abl in specific interference with β1 integrin signaling via HEF1.\",\n      \"method\": \"Immunoprecipitation from transgenic mouse leukemic tissues, phosphotyrosine blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical complex identified in in vivo leukemic tissue, single method\",\n      \"pmids\": [\"9405482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"HEF1/NEDD9 is tyrosine phosphorylated in human B cells upon β1 integrin or BCR ligation in a cytoskeleton-dependent manner; phosphorylated HEF1 associates with RAFTK/Pyk2 and CrkL; cytochalasin B pretreatment blocks both integrin- and BCR-induced HEF1 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, cytochalasin B treatment, stimulation of primary and cell line B cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with pharmacological cytoskeletal disruption, primary cells and cell lines, single lab\",\n      \"pmids\": [\"9020138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Cas-L/NEDD9 is transiently phosphorylated upon TCR/CD3 stimulation; phosphorylated Cas-L binds Crk and C3G. A Cas-L mutant lacking the SH3 domain (FAK-binding site) is phosphorylated by CD3 but not β1 integrin stimulation, indicating FAK-independent TCR signaling through Cas-L.\",\n      \"method\": \"CD3 cross-linking, immunoprecipitation, SH3-deletion mutant transfection, phospho-specific blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function SH3 deletion mutant revealing pathway specificity, Co-IP, single lab\",\n      \"pmids\": [\"9497377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The HEF1/NEDD9 C-terminal domain contains a divergent helix-loop-helix (HLH) motif that mediates HEF1 homodimerization and heterodimerization with Id2, E12, and E47 HLH proteins; this HLH is required for HEF1-induced constitutive pseudohyphal growth in yeast.\",\n      \"method\": \"Yeast two-hybrid interaction assays, deletion/mutation analysis, yeast pseudohyphal growth assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two-hybrid plus functional yeast assay with mutagenesis, single lab\",\n      \"pmids\": [\"10502414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HEF1/NEDD9 (but not p130Cas) is tyrosine phosphorylated downstream of the calcitonin GPCR via Ca2+- and PKC-dependent mechanisms requiring an intact actin cytoskeleton; calcitonin also induces HEF1 association with paxillin and FAK.\",\n      \"method\": \"GPCR stimulation, pharmacological inhibitors (BAPTA, calphostin C, cytochalasin D), Co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with Co-IP, single lab\",\n      \"pmids\": [\"10455189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Calcitonin-induced tyrosine phosphorylation of HEF1/NEDD9 requires cell attachment to extracellular matrix via integrin engagement, an intact actin cytoskeleton, and c-Src kinase (specifically SH2-competent Src); overexpression of kinase-dead or SH2-lacking Src blocks HEF1 phosphorylation. Erk1/2 phosphorylation by calcitonin is largely independent of these requirements.\",\n      \"method\": \"RGD peptide blocking, poly-D-lysine vs fibronectin adhesion, Src overexpression/mutants, kinase inhibitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function Src mutants with multiple cellular contexts, single lab\",\n      \"pmids\": [\"10954702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TGF-β1 potently induces HEF1/NEDD9 gene transcription in dermal fibroblasts (16-fold protein increase). The p115 HEF1 isoform results from serine/threonine phosphorylation of p105 HEF1. Adhesion-dependent tyrosine phosphorylation of p105HEF1 is mediated by Src kinase (blocked by PP1 inhibitor), while TGF-β1-induced expression is independent of adhesion.\",\n      \"method\": \"TGF-β1 stimulation, phosphatase digestion, Src inhibitor PP1, in vitro kinase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay for Src substrate plus pharmacological dissection, single lab\",\n      \"pmids\": [\"12189134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cell adhesion regulates HEF1/NEDD9 Ser/Thr phosphorylation and proteasomal degradation: actin microfilament disruption activates PP2A which dephosphorylates p115HEF1 to p105HEF1, and the p115 phosphorylated form is preferentially targeted for proteasomal degradation. Adhesion protects HEF1 from degradation.\",\n      \"method\": \"Cell detachment, cytoskeletal inhibitors, PP2A inhibitors, proteasome inhibitors, phosphatase assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with multiple inhibitors, single lab\",\n      \"pmids\": [\"16352661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In the MMTV-PyVT mammary tumor model, Nedd9-null background reduces activation of AKT, Src, FAK, and ERK in tumor cells. Cell-derived data show persistently reduced FAK activation and adhesion/migration in Nedd9-/- cells, establishing NEDD9 as a scaffolding protein supporting these pro-oncogenic kinases.\",\n      \"method\": \"Genetic knockout mouse model, western blotting of signaling proteins, cell attachment and migration assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with multiple orthogonal biochemical readouts, corroborated by cell-based assays\",\n      \"pmids\": [\"19738060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NEDD9 binding to Aurora A kinase stabilizes AURKA protein by limiting CDH1-APC/C ubiquitin ligase binding to AURKA. NEDD9 S296E mutation disrupts binding to AURKA and leads to reduced AURKA protein levels. NEDD9 depletion increases AURKA ubiquitination and proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (S296E), proteasome inhibitor experiments, shRNA knockdown/re-expression\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, point mutant validation, ubiquitination assay, multiple orthogonal methods in single study\",\n      \"pmids\": [\"23539442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The WW-HECT E3 ligase Smurf2 physically associates with NEDD9 and is required for NEDD9 protein stability: Smurf2 depletion causes polyubiquitination and proteasomal degradation of NEDD9, while Smurf2 overexpression upregulates NEDD9. The Smurf2/NEDD9 complex is required for Aurora A activation at G2/M and timely mitotic entry.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, Aurora A activity assays, mitotic entry timing\",\n      \"journal\": \"Cell division\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional mitotic readout, single lab\",\n      \"pmids\": [\"20825672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NEDD9 signaling through integrin β3 leads to elevated phosphorylation of integrin β3, increased Src and FAK activity, and decreased ROCK activity (via Src-dependent phosphorylation of ROCKII Tyr722), driving elongated mesenchymal invasion. Src inhibition by dasatinib switches NEDD9-overexpressing cells from Rac-driven mesenchymal invasion to ROCK-dependent amoeboid invasion.\",\n      \"method\": \"Overexpression/knockdown of NEDD9 and integrin β3, Src inhibitor dasatinib, phosphorylation analysis, invasion assays in vitronectin-containing matrix\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic dissection of signaling pathway with invasion phenotype, single lab\",\n      \"pmids\": [\"22328516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NEDD9 regulates cortactin (CTTN) acetylation in an Aurora A kinase (AURKA)/HDAC6-dependent manner: NEDD9 binds to CTTN and its deficiency increases CTTN acetylation and decreases CTTN-F-actin binding, disrupting lamellipodia and migration. A deacetylation-mimicking CTTN-9KR mutant rescues migration defects in NEDD9-depleted cells.\",\n      \"method\": \"Co-immunoprecipitation of NEDD9-CTTN, acetylation assays, AURKA/HDAC6 inhibitors, 9KR mutant rescue, xenograft metastasis models\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, acetylation/deacetylation assays, mutant rescue, in vivo xenograft validation; multiple orthogonal methods\",\n      \"pmids\": [\"24574519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NEDD9 directly binds to Arf6-GAP ARAP3 and Arf6-effector GGA3, facilitating Arf6 inactivation required for targeting the MMP14/TIMP2 complex to late endosomes. Without NEDD9, MMP14 trafficking is redirected from late endosomes back to the cell surface via Arf6-dependent recycling, preventing TIMP2 disengagement and reducing MMP14 activity and tumor invasion.\",\n      \"method\": \"Co-immunoprecipitation of NEDD9-ARAP3/GGA3, Arf6 activity assays, endosomal trafficking imaging, MMP14 activity assays, xenograft models with morpholino antisense\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Co-IPs, GTPase activity assays, functional invasion rescue, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"25241893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NEDD9 depletion inactivates MMP14 via TIMP2 accumulation at the cell surface, reducing collagenolytic activity of MMP2 and MMP9 and suppressing mesenchymal invasion. Re-expression of NEDD9 restores MMP14 activity. NEDD9 is required for protease-dependent invasion at the primary site but not at the metastatic site.\",\n      \"method\": \"shRNA depletion, MMP14 activity assays, TIMP2 immunostaining, in vivo xenograft, re-expression rescue\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue with biochemical endpoint, in vivo validation, single lab\",\n      \"pmids\": [\"24202705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NEDD9 stabilizes focal adhesions and slows focal adhesion disassembly: NEDD9-/- MEFs show increased paxillin phosphorylation at focal adhesions, increased 2D migration speed, but decreased 3D collagen migration. Loss of NEDD9 suppresses β1 integrin activation and reduces adhesion strength to fibronectin despite upregulated α5β1 expression.\",\n      \"method\": \"NEDD9-/- mouse embryo fibroblasts, focal adhesion turnover assays, 2D/3D migration assays, integrin activation assays, adhesion strength measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple cellular readouts, single lab\",\n      \"pmids\": [\"22509381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NEDD9 and BCAR1 signal through SRC to promote E-cadherin removal from the cell membrane and lysosomal degradation, without affecting E-cadherin transcription. Nedd9-/- mammary tumors show enhanced junctional E-cadherin.\",\n      \"method\": \"siRNA knockdown, Src inhibitors, membrane fractionation, lysosomal inhibitors, immunofluorescence, Nedd9-/- mouse mammary tumor model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic dissection with in vivo confirmation, single lab\",\n      \"pmids\": [\"21765937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"AND-34 (a GEF) associates with HEF1/NEDD9 via its GEF domain binding to the HEF1 C-terminus; AND-34 overexpression activates Cdc42 (but not Rac, Rho, RalA, or Rap1) in B cells, enhancing PAK1 activity and inhibiting SDF-1α-induced B cell polarization.\",\n      \"method\": \"Co-immunoprecipitation, GTPase pulldown assays, PAK1 kinase assay, overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with GTPase specificity panel and functional assays, single lab\",\n      \"pmids\": [\"10692442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Chat-H (hematopoietic isoform of Cas/HEF1-associated signal transducer) associates with HEF1/NEDD9 (CasL) and mediates serine-threonine phosphorylation of CasL; Chat-H localization to the plasma membrane and its binding to CasL are required for T cell migration and chemokine-induced Rap1 activation.\",\n      \"method\": \"Lentiviral RNAi, co-immunoprecipitation, phosphorylation analysis, Rap1 activation assay, T cell migration assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating interaction, RNAi loss-of-function with chemotaxis and Rap1 readouts, single lab\",\n      \"pmids\": [\"17174122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Abl and Arg tyrosine kinases mediate chemokine-induced tyrosine phosphorylation of HEF1/NEDD9; phosphorylated HEF1 is required for Rap1 GTPase activation, which mediates T cell adhesion and migration. T cells lacking Abl and Arg exhibit defective lymph node homing and impaired migration to inflammation sites.\",\n      \"method\": \"Abl/Arg knockout T cells, co-immunoprecipitation, Rap1 activation assay, in vivo homing assay, transwell migration\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO cells with biochemical and in vivo migration readouts, single lab\",\n      \"pmids\": [\"22810897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LKB1 negatively regulates NEDD9 transcription by promoting cytosolic translocation of CRTC1 from the nucleus. Ectopic NEDD9 or CRTC1 expression partially reverses the inhibitory function of LKB1 on lung cancer metastasis, establishing a CRTC1-NEDD9 axis downstream of LKB1.\",\n      \"method\": \"RNAi silencing in de novo mouse lung tumor models, ectopic expression, subcellular fractionation of CRTC1, metastasis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with mechanistic CRTC1 localization data, single lab\",\n      \"pmids\": [\"23074285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HEF1/NEDD9 is a direct transcriptional target of canonical Wnt/β-catenin signaling: ChIP assays and promoter analyses identified three functional TCF-binding sites in the HEF1 promoter responsible for Wnt-3a/β-catenin/Dvl2-driven upregulation; shRNA knockdown of β-catenin suppresses HEF1 expression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), promoter luciferase assays, shRNA knockdown, Wnt-3a stimulation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with promoter dissection, multiple Wnt pathway activators, single lab\",\n      \"pmids\": [\"21317929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"VHL inactivation induces HEF1/NEDD9 and Aurora kinase A via stabilization of HIF-1 and HIF-2. HEF1/NEDD9 colocalizes with Aurora kinase A at the centrosome and enhances Aurora A's cilium-destabilizing effect; suppression of this pathway improves primary cilium formation and reduces motility in VHL-defective renal cancer cells.\",\n      \"method\": \"siRNA knockdown, immunofluorescence co-localization, VHL re-expression, HIF stabilization, cilia formation assay\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic re-expression rescue with imaging and functional readouts, single lab\",\n      \"pmids\": [\"20864688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HEF1/NEDD9 is required for VEGF-mediated head and neck cancer cell migration and invasion; VEGF promotes HEF1-dependent invadopodia formation, and HEF1 co-localizes with MT1-MMP at invadopodia.\",\n      \"method\": \"siRNA knockdown and overexpression, phosphotyrosine proteomics, invadopodia assays, co-immunolocalization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics identification plus functional siRNA/OE studies with invadopodia imaging, single lab\",\n      \"pmids\": [\"20498643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Oxidation of Cys18 in the SMAD3 docking region of NEDD9 impairs SMAD3-NEDD9 protein-protein interaction in vitro (demonstrated by microscale thermophoresis). Aldosterone-induced oxidant stress in pulmonary artery endothelial cells reproduces this effect, resulting in impaired NEDD9 proteolytic degradation, increased NEDD9 complex formation with NKX2-5, and increased NKX2-5 binding to the COL3A1 promoter to upregulate collagen III. NEDD9 ablation prevents fibrotic vascular remodeling in animal PAH models.\",\n      \"method\": \"Microscale thermophoresis (in vitro protein interaction), ALDO-induced oxidant stress, Co-immunoprecipitation (NEDD9-NKX2-5), ChIP (NKX2-5 on COL3A1), atomic force microscopy, NEDD9 knockout animal model\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding assay with Cys18 oxidation mechanism, multiple biochemical methods (MST, Co-IP, ChIP), in vivo KO validation\",\n      \"pmids\": [\"29899023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NEDD9 mediates platelet adhesion to pulmonary artery endothelial cells via a NEDD9-P-selectin interaction; under hypoxia, HIF-1α-dependent NEDD9 upregulation increases surface NEDD9. Anti-NEDD9 antibody targeting the NEDD9-P-selectin interaction inhibits platelet-endothelial adhesion in vitro and reduces pulmonary thromboembolic remodeling in vivo in NEDD9-/- mice.\",\n      \"method\": \"Network medicine/proteomics identification, microscale thermophoresis, NEDD9-/- mice, anti-NEDD9 antibody functional assay, ex vivo CTEPH patient cells\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MST binding assay, genetic KO mouse model, patient-derived cells; single lab, new mechanism\",\n      \"pmids\": [\"33523764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cas-L/NEDD9 is phosphorylated at TCR microclusters in an actin polymerization-dependent manner and is required for transport of TCR microclusters to the center of the immunological synapse; Cas-L participates in a positive feedback loop amplifying Ca2+ signaling, inside-out integrin activation, and actomyosin contraction, acting as a mechanical transducer linking TCR to actin.\",\n      \"method\": \"siRNA knockdown, super-resolution imaging of TCR microclusters, Ca2+ imaging, integrin activation assay, traction force microscopy\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple imaging and functional readouts with siRNA knockdown, single lab\",\n      \"pmids\": [\"27359298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Loss of Nedd9 in chick neural crest cells perturbs cell spreading, reduces focal complex density and actin filaments, and causes a graded reduction in migratory distance in vivo. Retinoic acid regulates Nedd9 expression in neural crest cells.\",\n      \"method\": \"siRNA knockdown and overexpression in chick neural crest, in ovo electroporation, immunofluorescence of focal complexes and actin\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss/gain of function with defined morphological and migratory readouts, single lab\",\n      \"pmids\": [\"19464348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"AhR/dioxin activation transcriptionally induces Nedd9/HEF1 via two xenobiotic response elements (XREs) in its promoter; RNAi knockdown of Nedd9 blocks dioxin-induced changes in adhesion, cytoskeleton reorganization, increased cell migration, E-cadherin repression, and JNK activation.\",\n      \"method\": \"XRE reporter assay, RNAi knockdown, AhR ligand stimulation, migration/adhesion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter with functional RNAi rescue, single lab\",\n      \"pmids\": [\"19648964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NEDD9 is directly regulated by all-trans retinoic acid (atRA) through a complex retinoic acid response element (RARE) located at -475 to -445 in the NEDD9 proximal promoter; RAR and RXR are physically bound to this RARE in cells, as shown by ChIP.\",\n      \"method\": \"Promoter luciferase assays with RARE mutations, EMSA, ChIP for RAR/RXR binding\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus promoter deletion/mutation analysis, single lab\",\n      \"pmids\": [\"18585997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Pkd1-/-;Nedd9-/- mice show striking morphological ciliary defects with specific loss of ciliary localization of adenylyl cyclase III, and have ciliary resorption defects compatible with failure of Aurora A activation. Cystogenesis is strongly promoted in the double-mutant, indicating Nedd9 acts as a modifier of ADPKD via Aurora A-dependent ciliary maintenance.\",\n      \"method\": \"Compound Pkd1/Nedd9 genetic knockout mice, immunofluorescence of cilia, Aurora A activity analysis, cystogenesis quantification, calcium response assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo compound genetic model with ciliary imaging and signaling readouts, single lab\",\n      \"pmids\": [\"25139996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Pan-HDAC inhibitors enhance H3K9 acetylation at the NEDD9 gene promoter via inhibition of HDAC4 activity, increasing NEDD9 expression and subsequent FAK phosphorylation activation, promoting breast cancer metastasis. FAK inhibitors can reverse this metastasis.\",\n      \"method\": \"ChIP for H3K9 acetylation at NEDD9 promoter, HDAC4 inhibition, FAK phosphorylation assays, invasion assays, preclinical metastasis models\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with promoter-specific histone acetylation, pharmacological rescue, functional invasion readout, single lab\",\n      \"pmids\": [\"36604412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NEDD9 stimulates MMP9 secretion and invadopodia formation through its substrate domain (SD) tyrosine phosphorylation and SH3 domain; mutation of all 13 YxxP motif tyrosines plus Y629 (F14NEDD9) eliminates tyrosine phosphorylation, MMP9 secretion, and invadopodia. MICAL1 silencing also reduces MMP9 secretion, suggesting NEDD9-MICAL1 cooperation.\",\n      \"method\": \"Stable expression of NEDD9 domain mutants, MMP9 secretion assays, invadopodia formation assays, MICAL1 shRNA\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain mutagenesis with defined functional readouts, single lab\",\n      \"pmids\": [\"29876004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HTLV-I Tax physically associates with Cas-L/NEDD9, binding through the serine-rich region of Cas-L; Tax increases Cas-L expression and tyrosine phosphorylation. Exogenous Cas-L inhibits Tax-mediated NF-κB transactivation but not Tax-independent NF-κB activation.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, NF-κB reporter assay, co-localization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, functional NF-κB reporter assay, single lab\",\n      \"pmids\": [\"15592516\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NEDD9/HEF1/CAS-L is a multi-domain Cas-family scaffolding protein that assembles signaling complexes at focal adhesions, the centrosome, and the primary cilium: it is tyrosine-phosphorylated downstream of integrins, TCR/BCR, GPCRs, and oncogenic kinases (BCR-ABL, Src), recruits Crk/CrkL, FAK, and Pyk2 to drive cell migration and invasion, activates and stabilizes Aurora A kinase at the centrosome to control mitotic progression and ciliary resorption (via HDAC6-dependent tubulin deacetylation of cortactin and ciliary axoneme), regulates the RhoA–ECT2 cycle during cell division, is processed by caspase cleavage during mitosis and apoptosis to generate subcellularly targeted fragments, is subject to proteasomal degradation controlled by Smad3/APC/C-CDH1 and Smurf2, and regulates MMP14/TIMP2 trafficking through an Arf6/ARAP3/GGA3 endosomal pathway to enable mesenchymal invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NEDD9 (HEF1/Cas-L) is a multi-domain Cas-family scaffolding protein that assembles tyrosine-phosphorylation–dependent signaling complexes to control cell adhesion, migration, invasion, and mitotic/ciliary progression [#3, #22]. At focal adhesions it is tyrosine-phosphorylated upon \\u03b21 integrin ligation and engages FAK and the adaptor Crk/CrkL, also recruiting Nck, SHPTP2, and Pyk2/RAFTK, with FAK acting upstream in a linear integrin\\u2013FAK\\u2013HEF1 effector pathway that drives lymphocyte and tumor cell migration [#3, #13, #15, #11]. The same phosphorylation module is engaged downstream of TCR/BCR, the calcitonin GPCR, and the oncogenic kinases BCR-ABL and Src, channeling signals to Crk/C3G and Rap1-dependent adhesion and chemotaxis [#16, #14, #18, #33]. As a downstream effector NEDD9 supports activation of FAK, Src, AKT and ERK and stabilizes focal adhesions, while promoting mesenchymal invasion through integrin \\u03b23/Src/ROCK signaling and through control of MMP14/MMP9 protease activity\\u2014the latter via direct binding to ARAP3 and GGA3 to drive Arf6-dependent endosomal trafficking of the MMP14/TIMP2 complex [#22, #29, #25, #27, #46]. At the centrosome and primary cilium NEDD9 binds and activates Aurora A kinase, an interaction that stabilizes Aurora A by limiting CDH1-APC/C–mediated ubiquitination and drives HDAC6-dependent tubulin/cortactin deacetylation to promote ciliary disassembly and mitotic progression [#1, #0, #23, #26]. NEDD9 additionally regulates the RhoA\\u2013ECT2 cycle during cytokinesis and is cleaved by caspases during mitosis and apoptosis into subcellularly targeted fragments [#10, #4, #7]. NEDD9 abundance is set transcriptionally by Wnt/\\u03b2-catenin, retinoic acid, AhR, and LKB1\\u2013CRTC1 inputs and post-translationally by proteasomal degradation controlled by Smad3/APC/C-CDH1 and by Smurf2 [#35, #43, #34, #5, #6, #24]. Oxidation of Cys18 in the SMAD3 docking region stabilizes NEDD9 and reroutes it into an NKX2-5/COL3A1 transcriptional program driving fibrotic pulmonary vascular remodeling, and NEDD9 mediates platelet\\u2013endothelial adhesion via P-selectin, establishing causative roles in pulmonary hypertension and thromboembolic remodeling [#38, #39].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established NEDD9 as an integrin-responsive adaptor by showing it is tyrosine-phosphorylated upon \\u03b21 integrin ligation and directly binds FAK and Crk, defining its core scaffolding logic at adhesion sites.\",\n      \"evidence\": \"Immunoprecipitation, in vitro binding, and cloning in T lymphocytes\",\n      \"pmids\": [\"8879209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the kinase directly phosphorylating NEDD9\", \"No structural detail of binding interfaces\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed the integrin-driven phosphorylation module is shared across hematopoietic receptors and oncogenic kinases, recruiting CrkL, Pyk2 and forming complexes downstream of BCR/ABL and BCR ligation.\",\n      \"evidence\": \"Co-IP with SH2-domain specificity in lymphoid and leukemic cells, including transgenic leukemic tissue\",\n      \"pmids\": [\"9162067\", \"9405482\", \"9020138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of distinct CrkL complexes not resolved\", \"Single-method complex identification in some contexts\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined receptor-specific wiring (TCR vs integrin) and revealed cell-cycle-coupled caspase processing, showing full-length NEDD9 at focal adhesions and a p55 fragment at the mitotic spindle.\",\n      \"evidence\": \"SH3-deletion mutants, synchronized-cell Western blots, fractionation/IF, caspase inhibitors, yeast two-hybrid\",\n      \"pmids\": [\"9497377\", \"9584194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for mitotic cleavage not identified\", \"Functional role of p55 at the spindle untested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Connected NEDD9 to apoptosis and to TGF-\\u03b2/Smad3 negative feedback, and identified GPCR and GEF (AND-34) inputs, broadening its signaling and turnover control.\",\n      \"evidence\": \"Inducible overexpression with caspase inhibitors, Co-IP, proteasome inhibitors, GTPase pulldowns\",\n      \"pmids\": [\"10866674\", \"11118211\", \"10692442\", \"10954702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating Smad3-directed degradation not yet identified\", \"Apoptotic fragment mechanism partially defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated adhesion-state control of NEDD9 stability and a focal adhesion targeting domain required for spreading, and placed NEDD9 in a linear integrin\\u2013FAK\\u2013HEF1 migration pathway.\",\n      \"evidence\": \"Detachment/attachment assays, FAK site-specific mutants, deletion mutants, migration assays\",\n      \"pmids\": [\"11438665\", \"11465098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of detachment-activated protease unclear\", \"Mechanism linking FAK autophosphorylation to NEDD9 phosphorylation not fully resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked NEDD9 to invasive output by showing it enhances migration via ERK/p38 and upregulates metalloproteinases and contractility genes, and is transcriptionally induced by TGF-\\u03b21.\",\n      \"evidence\": \"Inducible expression, haptotaxis assays, kinase inhibitors, cDNA arrays, Src inhibitor PP1\",\n      \"pmids\": [\"11801728\", \"12189134\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect transcriptional effects not distinguished\", \"Single-lab profiling\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified the centrosomal NEDD9\\u2013Aurora A axis controlling spindle and centrosome behavior, and refined Smad3-directed turnover to the APC/C-CDH1 ligase.\",\n      \"evidence\": \"Co-IP, siRNA/overexpression with centrosome/spindle phenotypes, domain mapping\",\n      \"pmids\": [\"16184168\", \"15144564\", \"15592516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Aurora A activation by NEDD9 not yet defined at 2005\", \"HTLV-I Tax interaction physiological relevance limited\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended NEDD9 mitotic function to RhoA\\u2013ECT2 regulation during cytokinesis and confirmed it as a selective FAK effector in tumor invasion and melanoma metastasis.\",\n      \"evidence\": \"siRNA/overexpression, RhoA activity assays, Co-IP with ECT2, in vitro/in vivo invasion and metastasis models\",\n      \"pmids\": [\"16394104\", \"16288224\", \"16814714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NEDD9 modulates ECT2/RhoA GEF activity biochemically unresolved\", \"Selectivity over p130CAS mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the cilia connection, showing NEDD9\\u2013Aurora A activation triggers HDAC6 to drive ciliary disassembly, a nonmitotic Aurora A function.\",\n      \"evidence\": \"Co-IP, AurA/HDAC6 inhibitors, loss/gain of function with ciliary resorption readout\",\n      \"pmids\": [\"17604723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the NEDD9\\u2013AurA\\u2013HDAC6 module not defined\", \"Upstream cue triggering complex assembly at the basal body unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established NEDD9 stability is positively controlled by Smurf2 and tied the AurA/cilia axis to VHL-HIF, while a knockout model confirmed NEDD9 as a scaffold supporting AKT/Src/FAK/ERK.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, VHL re-expression/HIF stabilization, MMTV-PyVT Nedd9-null model\",\n      \"pmids\": [\"20825672\", \"20864688\", \"19738060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing roles of Smurf2 vs APC/C in NEDD9 turnover not reconciled\", \"Direct vs indirect kinase support in vivo unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the molecular basis of NEDD9-mediated Aurora A control, showing binding stabilizes Aurora A by blocking CDH1-APC/C ubiquitination, with S296 governing the interaction.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, S296E mutant, proteasome inhibitors, shRNA/re-expression\",\n      \"pmids\": [\"23539442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How S296 phosphorylation is regulated in cells not defined\", \"Structural model of the NEDD9\\u2013AurA interface absent\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the effector arm of NEDD9-driven invasion: cortactin deacetylation via AurA/HDAC6 for lamellipodia, and Arf6/ARAP3/GGA3-dependent endosomal routing of MMP14/TIMP2 to license proteolysis.\",\n      \"evidence\": \"Co-IP, acetylation/deacetylation assays, mutant rescue, Arf6 activity assays, trafficking imaging, xenografts\",\n      \"pmids\": [\"24574519\", \"25241893\", \"24202705\", \"25139996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination between cilia/centrosome and invasion functions unclear\", \"Direct binding topology on ARAP3/GGA3 not structurally mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a redox switch (Cys18 oxidation) that disables Smad3 docking, stabilizing NEDD9 and rerouting it to an NKX2-5/COL3A1 program, establishing causation in fibrotic pulmonary vascular remodeling.\",\n      \"evidence\": \"Microscale thermophoresis, oxidant-stress models, Co-IP, ChIP, NEDD9 knockout PAH models\",\n      \"pmids\": [\"29899023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo extent of Cys18 oxidation under disease conditions not quantified\", \"How NEDD9 selects NKX2-5 over other partners unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed an extracellular adhesion function: surface NEDD9 binds P-selectin to mediate platelet\\u2013endothelial adhesion under hypoxia, suggesting a therapeutic target in thromboembolic remodeling.\",\n      \"evidence\": \"Network proteomics, MST binding, NEDD9-/- mice, anti-NEDD9 antibody, CTEPH patient cells\",\n      \"pmids\": [\"33523764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of NEDD9 surface display for an adaptor protein unresolved\", \"Single-lab new mechanism awaiting independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct NEDD9 pools (focal adhesion, centrosome/cilium, endosomal trafficking, cell-surface adhesion) are spatially and temporally partitioned within a single cell, and how its phosphorylation and degradation states select among partners, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of full-length NEDD9 with partners\", \"Quantitative rules governing partner selection by phospho-state unknown\", \"Integration of mitotic and migratory functions in vivo undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 13, 22]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [39]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [23, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [4, 8, 29]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1, 23, 36]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 36, 44]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [27]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [39]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 22, 25]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 10, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16, 33, 40]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [27, 28, 46]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [38, 39]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"complexes\": [\"focal adhesion\", \"NEDD9\\u2013Aurora A centrosomal complex\"],\n    \"partners\": [\"AURKA\", \"PTK2/FAK\", \"CRKL\", \"ECT2\", \"ARAP3\", \"GGA3\", \"CTTN\", \"SMAD3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}