{"gene":"CDCP1","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2003,"finding":"CDCP1 (SIMA135) is a cell surface type I transmembrane glycoprotein that is tyrosine phosphorylated, with phosphorylation mediated by a Src family kinase member, as demonstrated by selective Src kinase inhibitor studies and anti-phosphotyrosine western blot analysis.","method":"Immunopurification, western blot with anti-phosphotyrosine antibody, selective kinase inhibitor studies, immunocytochemistry","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (immunopurification, western blot, inhibitor studies) in a single study establishing tyrosine phosphorylation by SFK","pmids":["12660814"],"is_preprint":false},{"year":2010,"finding":"Full-length 135 kDa CDCP1 is cleaved by serine proteases (including matriptase) at Arg-368 and Lys-369, generating a membrane-retained 70 kDa C-terminal fragment and a shed 65 kDa N-terminal ectodomain; proteolytic cleavage induces tyrosine phosphorylation of the 70 kDa fragment and recruitment of Src and PKCδ to this fragment.","method":"N-terminal sequencing of immunopurified fragments, detailed mutagenesis of cleavage sites, panel of protease inhibitors, western blot, mass spectrometry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis and N-terminal sequencing with multiple orthogonal methods (inhibitors, MS, WB) establishing mechanism in single rigorous study","pmids":["20551327"],"is_preprint":false},{"year":2011,"finding":"Proteolytic cleavage of CDCP1 by plasmin in vivo triggers a survival signaling cascade involving Src-mediated phosphorylation of the 70 kDa membrane-retained CDCP1 fragment, recruitment of PKCδ, and activation of Akt, which suppresses PARP1-mediated apoptosis; inhibiting cleavage (by antibody, serine protease inhibitors, or genetic mutation of the cleavage site) abolishes this signaling and induces apoptosis and reduces metastatic colonization.","method":"In vivo tumor models, antibody blockade, serine protease inhibitors (aprotinin), cleavage-site genetic mutagenesis, plasminogen-KO mice with plasmin rescue, western blot for phospho-Src/PKCδ/Akt/PARP1","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and pharmacological approaches in vivo establishing the cleavage-dependent signaling cascade with strong mechanistic controls","pmids":["22179830"],"is_preprint":false},{"year":2011,"finding":"CDCP1 overexpression activates Src family kinases, and its pro-metastatic activity requires CDCP1 tyrosine 734 (Y734F mutation abolishes Src activation, 3D dispersive growth in vitro, and in vivo metastasis enhancement).","method":"Stable overexpression, site-directed mutagenesis (Y734F), pharmacological Src inhibitors (PP2, dasatinib), 3D Matrigel culture, in vivo metastasis assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis combined with pharmacological inhibition and in vivo functional validation","pmids":["21220330"],"is_preprint":false},{"year":2011,"finding":"CDCP1 acts as a scaffold that competes with FAK-Y861 as an SFK substrate; stable CDCP1 expression causes SFK substrate switching from FAK-Y861 to CDCP1-Y734, dependent on CDCP1 expression level and specifically on Y734 but not Y743 or Y762; FAK does not form a trimeric complex with Src and CDCP1.","method":"Stable CDCP1 expression in HeLa cells, CDCP1 phospho-site mutagenesis, western blot for p-FAK-Y861 and p-CDCP1-Y734, CDCP1 siRNA knockdown in colon cancer lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — mutagenesis of multiple sites with reciprocal phosphorylation readouts, replicated in multiple cell types","pmids":["21994943"],"is_preprint":false},{"year":2012,"finding":"In vivo cleaved (70 kDa) CDCP1 forms a complex with activated (inside-out) β1 integrin; this complex induces FAK/PI3K/Akt phosphorylation signaling; blocking this complex (by cleavage-blocking antibody 10-D7, aprotinin, or β1 integrin shRNA) reduces FAK/Akt phosphorylation, stromal invasion, and spontaneous metastasis.","method":"Co-immunoprecipitation in cell cultures and live animals, pharmacological FAK/PI3K inhibitors, shRNA knockdown of β1 integrin, cleavage-blocking monoclonal antibody, in vivo tumor intravasation models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP in vitro and in vivo, multiple inhibitor approaches, and shRNA epistasis establishing the pathway position","pmids":["23208492"],"is_preprint":false},{"year":2012,"finding":"CDCP1 localizes to caveolin-1-containing vesicular structures and lipid rafts, co-immunoprecipitates with MT1-MMP, and is required for trafficking of MT1-MMP to invadopodia and for MT1-MMP-dependent ECM degradation and Matrigel invasion of breast cancer and melanoma cells.","method":"Co-immunoprecipitation of CDCP1 and MT1-MMP, Triton X-100 lipid raft fractionation, siRNA knockdown, immunofluorescence localization to invadopodia, ECM degradation assays, Matrigel invasion assays","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 — Co-IP plus lipid raft fractionation, siRNA with defined cellular phenotype (invadopodia function), and immunofluorescence co-localization","pmids":["23439492"],"is_preprint":false},{"year":2012,"finding":"CDCP1 is phosphorylated by Src family kinases and the phosphorylated form recruits PKCδ through PKCδ's C2 domain; this interaction promotes anchorage-independent survival signaling; antibody activation of CDCP1 induces rapid tyrosine phosphorylation by Src, requires CDCP1 bivalent clustering/dimerization, translocates CDCP1 to Triton X-100-insoluble membrane fractions, and prolonged treatment induces Src-dependent, proteasome-mediated CDCP1 internalization and degradation.","method":"Focus formation assays with NIH3T3 cells co-overexpressing Src and CDCP1, antibody treatment, Triton X-100 fractionation, proteasome inhibitors, xenograft models with western blot","journal":"Molecular oncology","confidence":"High","confidence_rationale":"Tier 2 — multiple biochemical assays (fractionation, inhibitors) and in vivo models with mechanistic controls","pmids":["24055141"],"is_preprint":false},{"year":2008,"finding":"CDCP1/Gp140 clusters in epithelial cell-cell contacts and assembles membrane microdomains (lipid rafts/TEMs) that recruit and activate SFK; active SFKs then phosphorylate CDCP1 at Y734 and also phosphorylate PKCδ, with CDCP1 acting as a transmembrane scaffold for these kinases; outside-in signals through extracellular CUB domains initiate this process.","method":"Detergent-resistant membrane fractionation, immunofluorescence co-localization, phosphorylation analysis of Y734","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 — fractionation and co-localization data with partial mechanistic follow-up; single lab","pmids":["18269919"],"is_preprint":false},{"year":2013,"finding":"HIF-2α (but not HIF-1α) transcriptionally induces CDCP1 expression and tyrosine phosphorylation under hypoxic conditions; shRNA knockdown of CDCP1 impairs cancer cell migration under hypoxia; overexpression of HIF-2α promotes xenograft tumor growth with enhanced CDCP1 expression and tyrosine phosphorylation.","method":"shRNA knockdown of HIF-2α and HIF-1α, HIF-2α overexpression, cell migration assays, xenograft tumor growth, western blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — isoform-specific knockdown (HIF-2α vs HIF-1α), overexpression, and in vivo validation","pmids":["23378636"],"is_preprint":false},{"year":2014,"finding":"Under basal conditions, CDCP1 constitutively internalizes from the cell surface and undergoes palmitoylation-dependent proteasomal degradation (palmitoylated at one or more of its four cytoplasmic cysteines); EGF/EGFR activation inhibits this degradation, promoting CDCP1 recycling to the cell surface and increased cell migration.","method":"Cycloheximide chase, palmitoylation-site mutagenesis of cytoplasmic cysteines, proteasome inhibitors, EGF treatment, cell surface biotinylation, migration assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of palmitoylation sites combined with proteasome inhibitors and functional readouts (migration, recycling)","pmids":["24681947"],"is_preprint":false},{"year":2014,"finding":"Oncogenic Ras/ERK signaling transcriptionally induces CDCP1 expression; CDCP1 is required for Ras-mediated anoikis resistance, migration, and invasion; CDCP1 knockdown or inhibition of CDCP1 phosphorylation abrogates these Ras-induced phenotypes; CDCP1 mediates activation of MMP2 and secretion of MMP9 downstream of Ras.","method":"Activated Ras expression, CDCP1 knockdown/Src inhibitor treatment, anoikis assays, migration/invasion assays, MMP2/MMP9 activity assays","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 — epistasis established by knockdown and inhibitor, multiple phenotypic readouts (anoikis, migration, invasion, MMPs)","pmids":["24939643"],"is_preprint":false},{"year":2015,"finding":"CDCP1 binds to HER2 through its intracellular domain and increases HER2's interaction with c-SRC, leading to enhanced HER2 activation, downstream signaling, and trastuzumab resistance in breast cancer cells.","method":"Co-immunoprecipitation of CDCP1 with HER2 and SRC, domain truncation mapping, cell migration/transformation assays, in vivo tumor formation, trastuzumab resistance assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — Co-IP with domain mapping, in vivo validation, and functional drug resistance readout","pmids":["25892239"],"is_preprint":false},{"year":2015,"finding":"SHP2 tyrosine phosphatase directly interacts with CDCP1 intracellular domain through residues Y734 and Y743; SHP2 knockdown increases CDCP1 phosphorylation and impairs antibody-mediated CDCP1 internalization, indicating SHP2 counteracts SFK-mediated CDCP1 phosphorylation and regulates CDCP1 cell surface availability.","method":"Co-immunoprecipitation, affinity precipitation, CDCP1 point mutants (Y734, Y743), SHP2 shRNA knockdown, flow cytometry for surface CDCP1","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and mutagenesis in single lab, but no reciprocal IP or structural validation","pmids":["25876044"],"is_preprint":false},{"year":2016,"finding":"Only cleaved CDCP1 (cCDCP1), not full-length CDCP1, is capable of homodimerization through its ectodomain; cCDCP1 homodimerization drives phosphorylation of PKCδ, ERK1/2, and p38 MAPK and induces cell migration; the extracellular portion of cleaved CDCP1 (ECC) blocks dimerization, inhibits PKCδ phosphorylation and migration, and reduces TNBC invasiveness.","method":"Overexpression of flCDCP1 vs. cCDCP1 in HEK293T, ECC competitive inhibitor, western blot for phospho-PKCδ/ERK1/2/p38, migration assays, 3D culture invasion/proliferation/apoptosis assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — domain-level dissection of dimerization requirement with functional readouts and competitive inhibitor validation","pmids":["26876198"],"is_preprint":false},{"year":2017,"finding":"CDCP1 inhibits acyl-CoA synthetase ligase (ACSL) activity and promotes fatty acid oxidation (FAO) in mitochondria, depleting cytoplasmic lipid droplets; CDCP1 knockdown increases lipid droplet abundance and reduces TNBC migration (rescued by ACSL inhibitor Triacsin C or ACSL3 co-knockdown); in vivo blocking of CDCP1 increases lipid droplet abundance and decreases metastasis.","method":"CDCP1 knockdown/overexpression, ACSL activity assays, coherent anti-Stokes Raman scattering microscopy, two-photon excited fluorescence microscopy, Triacsin C treatment, ACSL3 co-knockdown, animal models of TNBC","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — enzymatic activity assay (ACSL), optical imaging of lipid droplets, in vitro and in vivo rescue experiments with multiple orthogonal approaches","pmids":["28739932"],"is_preprint":false},{"year":2017,"finding":"CD318 (CDCP1) is a ligand for CD6; CD318-KO mice are protected in experimental autoimmune encephalomyelitis (similar to CD6-KO mice); soluble CD318 is chemoattractive to T cells and CD318 participates in CD6-dependent adhesion of T cells to synovial fibroblasts.","method":"CD318-KO mice in EAU model, T cell adhesion assays, chemotaxis assays with soluble CD318, identification of antigen recognized by mAb 3A11 as CD318","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic KO in disease model replicated for both CD6 and CD318, plus functional adhesion and chemotaxis assays","pmids":["28760953"],"is_preprint":false},{"year":2018,"finding":"FBXL14 E3 ubiquitin ligase directly binds CDCP1, facilitates its ubiquitination and proteasomal degradation, suppressing CDCP1 protein stability and breast cancer metastasis; miR-17/20a controls FBXL14 expression, placing it upstream of CDCP1 regulation.","method":"Co-immunoprecipitation of FBXL14 and CDCP1, ubiquitination assays, proteasome inhibitor treatment, miR-17/20a transfection, breast cancer metastasis functional assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — Co-IP plus ubiquitination assay with functional oncological consequences","pmids":["29973690"],"is_preprint":false},{"year":2018,"finding":"Loss of CDCP1 in prostate cancer cells reduces CDK5 kinase activity by promoting SRC-mediated phosphorylation of CDK5R1/p35 at Y234, which creates a binding site for the C2 domain of PKCδ, leading to PKCδ phosphorylation of CDK5 at T77, dissociation of the CDK5/CDK5R1 complex, loss of CDK5 activity, and consequent loss of inside-out activation of β1-integrin.","method":"CDCP1 silencing, CDK5-T77 and CDK5R1-Y234 phosphorylation-site mutagenesis, Co-IP of CDK5/CDK5R1 complex, CDK5 kinase activity assays, cell adhesion/migration assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of specific phosphorylation sites, kinase activity assays, and Co-IP rescue experiments establishing the mechanism","pmids":["29511352"],"is_preprint":false},{"year":2019,"finding":"METTL3 and the m6A reader YTHDF1 promote translation of CDCP1 mRNA by recognizing m6A residues in the CDCP1 3'-UTR; ALKBH5 demethylase counteracts this; the METTL3-m6A-CDCP1 axis promotes bladder cancer cell growth and transformation.","method":"m6A profiling, METTL3/ALKBH5 knockdown, YTHDF1 RIP assays, m6A-seq, luciferase/translation reporter assays, in vitro and in vivo cancer growth assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — m6A profiling with RIP, knockdown of writer/reader/eraser, and translation reporter assays","pmids":["30796352"],"is_preprint":false},{"year":2019,"finding":"CDCP1 directly binds TGF-β1 and BMP4 via its CUB domains (measured by BIAcore surface plasmon resonance); CDCP1 enhances TGF-β1 signaling (reporter activity and phospho-Smad2 levels) in a manner dependent on Smad2 and TGFRI, but independent of Src or PKCδ; CDCP1 does not modulate BMP signaling.","method":"BIAcore surface plasmon resonance binding assay, TGF-β1/BMP reporter assays, phospho-Smad2 western blot, Smad2/TGFRI knockdown, Src/PKCδ inhibition","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1 — direct binding demonstrated by SPR plus pathway-specific functional assays with epistasis controls (Src/PKCδ independence)","pmids":["31302030"],"is_preprint":false},{"year":2019,"finding":"CDCP1 promotes Wnt signaling in colorectal cancer by facilitating translocation of β-catenin and E-cadherin to the nucleus; disruption of CDCP1 reduces nuclear/chromatin-associated β-catenin and nuclear E-cadherin, increases their sequestration at the membrane, and disrupts regulation of CRC-promoting genes.","method":"Cell fractionation, co-immunoprecipitation, confocal microscopy, immunohistochemistry of patient samples, CDCP1 loss-of-function in vitro and in vivo","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — cell fractionation, IP, microscopy, and in vivo tumor burden with multiple orthogonal approaches","pmids":["31471585"],"is_preprint":false},{"year":2019,"finding":"CDCP1 forms homophilic complexes via its extracellular CUB2 domain; deletion of the extracellular region abolishes complex formation and the ability to promote cancer cell migration; recombinant CUB2 domain protein competitively inhibits CDCP1 homophilic complex formation, SFK activation, and cell migration.","method":"CDCP1 deletion mutants, recombinant CUB2-MBP fusion protein competitive inhibition, co-immunoprecipitation, SFK activation assays, migration assays in lung adenocarcinoma and pancreatic cells","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 — domain deletion mutagenesis and competitive inhibition with defined functional output; single lab","pmids":["31524271"],"is_preprint":false},{"year":2020,"finding":"Androgen signaling suppresses CDCP1 expression; androgen deprivation combined with PTEN loss upregulates CDCP1, which then activates the SRC/MAPK pathway to promote metastatic prostate cancer progression.","method":"Androgen treatment/deprivation, PTEN loss genetic models, CDCP1 expression analysis, SRC/MAPK pathway western blot, in vivo prostate cancer progression models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (PTEN loss combined with androgen deprivation) with clear pathway activation readout and in vivo validation","pmids":["32250342"],"is_preprint":false},{"year":2021,"finding":"Urokinase plasminogen activator (uPA) is the master regulator of CDCP1 proteolysis, acting both by directly cleaving CDCP1 and by activating plasmin (which also cleaves CDCP1); uPA-mediated CDCP1 proteolysis promotes metastasis in preclinical in vivo models; co-expression of uPA and CDCP1 is predictive of poor disease outcome.","method":"Substrate-biased activity-based probe (sbABP) incorporating CDCP1 cleavage motif for protease capture/identification, in vitro cleavage assays, in vivo metastasis models, patient data analysis","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 — novel chemical biology approach (sbABP) combined with in vitro validation and in vivo disease models","pmids":["33859413"],"is_preprint":false},{"year":2021,"finding":"CDCP1 on dendritic cells (DCs) regulates IL-6 production via the Syk-MAPK signaling pathway; CDCP1-KO DCs show reduced CAWS-induced IL-6 production associated with impaired Syk-MAPK signaling; CDCP1-KO mice show attenuated coronary and aortic vasculitis in a Kawasaki disease model.","method":"CDCP1 knockout mice, DC-specific expression analysis, CAWS stimulation assays, IL-6 ELISA, Syk-MAPK western blot in WT vs. KO DCs","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined signaling readout (Syk-MAPK/IL-6) in primary DCs and in vivo disease model","pmids":["34099547"],"is_preprint":false},{"year":2021,"finding":"CDCP1 promotes compensatory renal growth downstream of HGF by recruiting Src into lipid rafts to activate STAT3 associated with the HGF receptor Met; activated STAT3 then induces matrix metalloproteinase and mitogenic factor expression; CDCP1 ablation in mice attenuates Met-STAT3 signaling and suppresses compensatory growth after unilateral nephrectomy.","method":"CDCP1 siRNA/ablation in canine kidney cells, lipid raft fractionation, Co-IP of Src/STAT3/Met, STAT3 phosphorylation assays, unilateral nephrectomy in CDCP1-ablated mice","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 — lipid raft fractionation, Co-IP, in vivo nephrectomy model with signaling readouts","pmids":["33574034"],"is_preprint":false},{"year":2022,"finding":"The two cleaved fragments of CDCP1 remain tightly associated with minimal conformational change after proteolysis; differential phage display generated antibodies that selectively recognize the proteolytic neoepitope of cleaved CDCP1 with no detectable binding to uncleaved form; biochemical and structural characterization confirmed this.","method":"Differential phage display, biochemical and biophysical characterization, structural analysis of cleaved vs. uncleaved CDCP1, antibody-drug conjugate/radionuclide/bispecific T cell engager functional studies, syngeneic pancreatic tumor model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 — structural and biophysical characterization combined with functional validation in syngeneic in vivo model","pmids":["35166238"],"is_preprint":false},{"year":2017,"finding":"CDCP1 regulates EGF/EGFR-induced cell migration; EGF/EGFR activation upregulates CDCP1 mRNA and protein via the RAS/RAF/MEK/ERK pathway (not Src), and CDCP1 relocates from cell-cell junctions to filopodia; disruption of CDCP1 by silencing or blocking antibody reduces EGF/EGFR-induced migration.","method":"CDCP1 silencing, function-blocking antibody, ERK inhibitors, EGF treatment, live-cell imaging of CDCP1 localization, migration assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — pharmacological pathway dissection (ERK vs. Src inhibitors), silencing, antibody blockade, and live imaging","pmids":["22315226"],"is_preprint":false},{"year":2017,"finding":"CDCP1 is phosphorylated by Src family kinases and recruits PKCδ through the C2 domain of PKCδ in a phosphotyrosine-dependent manner; a small molecule (glycoconjugated palladium complex Pd-Oqn) inhibits the interaction between PKCδ C2 domain and phosphorylated CDCP1, suppresses PKCδ phosphorylation (but not ERK or AKT), inhibits anchorage-independent growth and invasion in vitro, and reduces peritoneal dissemination and tumor growth in vivo.","method":"Cell-free screening, immunoprecipitation assays with PKCδ C2 domain, soft agar colony formation, invasion assays, in vivo peritoneal dissemination and orthotopic xenograft models","journal":"Cancer science","confidence":"High","confidence_rationale":"Tier 2 — cell-free biochemical screening of protein-protein interaction, Co-IP validation, specificity controls (ERK/AKT not affected), and in vivo validation","pmids":["28256037"],"is_preprint":false},{"year":2022,"finding":"CDCP1 promotes HGF-induced breast cancer cell invasion through a CDCP1-SRC-ARHGEF7-RAC1 pathway; CDCP1 coaccumulates with ARHGEF7, activates SRC, which activates ARHGEF7-RAC1 GTPase signaling, leading to lamellipodia formation and invasion.","method":"CDCP1 knockdown, ectopic MET and CDCP1 expression, Rac1 activation assays, ARHGEF7 knockdown, immunofluorescence co-localization of CDCP1 and ARHGEF7, migration/invasion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — epistasis with multiple knockdowns establishing pathway order, GTPase activity assays, and co-localization","pmids":["35085554"],"is_preprint":false},{"year":2022,"finding":"BRD4 and CBP/p300 transcription cofactors co-regulate CDCP1 gene transcription in castration-resistant prostate cancer; combined knockdown or dual inhibition reduces CDCP1 transcription and downstream PI3K/AKT and SRC/MAPK signaling more effectively than single-protein perturbation.","method":"BRD4 and CBP/p300 knockdown (individual and combined), NEO2734 dual bromodomain inhibitor, CDCP1 transcription assays, PI3K/AKT and SRC/MAPK western blot, cell proliferation/metastasis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — dual knockdown and chemical inhibition with transcriptional and signaling readouts; single lab","pmids":["35513563"],"is_preprint":false},{"year":2021,"finding":"CDCP1 on RPE cells is upregulated by IFN-γ and interacts with CD6 on T cells; CD6 stimulation of CDCP1-expressing (but not CDCP1-knockdown) RPE cells induces stress fiber formation, focal adhesion disruption, tight junction opening, and increased RPE barrier permeability permitting T cell infiltration, contributing to experimental autoimmune uveitis development.","method":"CDCP1-KO mice in EAU passive model, CDCP1-KD RPE cells, CD6 stimulation assays, tight junction immunofluorescence, T cell transmigration assays, IFN-γ stimulation","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — genetic KO in vivo combined with CDCP1-KD cell model and defined mechanistic readouts (cytoskeleton, focal adhesions, tight junctions)","pmids":["35951427"],"is_preprint":false},{"year":2021,"finding":"hsa_circ_0005358 suppresses CDCP1 expression by binding PTBP1 protein via its 215-224 sequence, sequestering PTBP1 and preventing PTBP1 from stabilizing CDCP1 mRNA, thereby reducing CDCP1 protein translation and suppressing cervical cancer metastasis.","method":"RNA pull-down assay, mass spectrometry, RNA immunoprecipitation, RNA-sequencing, functional migration/invasion and in vivo metastasis assays","journal":"Molecular therapy. Nucleic acids","confidence":"High","confidence_rationale":"Tier 2 — RNA pulldown, MS, and RIP establishing the mechanism, with functional in vivo validation","pmids":["34976440"],"is_preprint":false},{"year":2023,"finding":"CDCP1 knockdown in vascular smooth muscle cells suppresses PDGFRβ/AKT signaling by promoting NEDD4-mediated ubiquitination of PDGFRβ, preventing PDGFRβ binding to clathrin and Rab5, thus inhibiting PDGFRβ endocytosis; CDCP1 thereby regulates VSMC proliferation and migration.","method":"CDCP1 knockdown, RNA-seq, Co-IP of PDGFRβ with NEDD4/clathrin/Rab5, ubiquitination assays, immunofluorescence, AKT pathway western blot, in vivo carotid stenosis model","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assays with mechanistic pathway placement; single lab","pmids":["40256729"],"is_preprint":false},{"year":2023,"finding":"CDCP1 in cardiac fibroblasts (HCFs) is induced by PDGF signaling; CDCP1 knockdown reduces HCF proliferation, decreases AKT phosphorylation, and reduces expression of soluble ST2 (a cardiac fibrosis inducer), implicating CDCP1 in regulating cardiac fibrosis.","method":"CDCP1 knockdown in HCFs, PDGF stimulation, AKT phosphorylation western blot, transcriptomic profiling, ST2 expression analysis","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 — knockdown with defined signaling (AKT) and transcriptomic readouts; single lab","pmids":["37800334"],"is_preprint":false},{"year":2012,"finding":"Structural requirements for CDCP1/Src-dependent transformation of NIH3T3 cells require intact amino- and carboxy-termini; mutation of any core intracellular tyrosine residue (Y734, Y743, or Y762) abolishes transformation; mutation of palmitoylation motif (C689,690G) strongly reduces transformation; Src binding to CDCP1 via its SH2 domain is not required for transformation, but Src myristoylation is necessary.","method":"Retrovirus-mediated co-overexpression of c-Src and CDCP1 in NIH3T3 cells, focus formation assay, systematic mutagenesis of tyrosines and palmitoylation motif, Src domain mutants (SH2-deficient, myristoylation-deficient)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis of multiple sites in a functional transformation assay","pmids":["23300860"],"is_preprint":false},{"year":2023,"finding":"CDCP1 overexpression activates MAPK/ERK pathway signaling in ex vivo urothelial carcinoma organoids from a CDCP1 transgenic mouse model; CDCP1 knockout in UC cell lines reduces MAPK/ERK activity concomitant with reduced proliferation and migration.","method":"CDCP1 transgenic mouse organoids, CRISPR/Cas9 CDCP1 knockout, MAPK/ERK western blot, proliferation/migration assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic gain- and loss-of-function in disease-relevant models; single lab","pmids":["36593286"],"is_preprint":false}],"current_model":"CDCP1 is a type I transmembrane glycoprotein that functions as a signaling scaffold at the plasma membrane: in its full-length 135 kDa form it is phosphorylated at Y734 (and Y743/Y762) by Src family kinases (SFKs), and upon proteolytic cleavage at R368/K369 by serine proteases (principally uPA and plasmin) the membrane-retained 70 kDa fragment becomes hyperphosphorylated, recruits Src and PKCδ (via PKCδ's C2 domain), forms homodimers through its CUB2 domain, and complexes with activated β1 integrin to activate downstream FAK/PI3K/Akt survival and migration signaling; CDCP1 also enhances HER2-SRC interaction, activates Wnt/β-catenin nuclear signaling, suppresses ACSL activity to redirect fatty acid metabolism toward oxidative phosphorylation, binds TGF-β1 as a co-receptor to amplify Smad2 signaling, interacts with CD6 to modulate immune cell responses, and is regulated post-translationally by palmitoylation-dependent proteasomal degradation (counteracted by EGFR/EGF activation) and by FBXL14-mediated ubiquitination, while its transcription is driven by HIF-2α under hypoxia, Ras/ERK signaling, and BRD4/CBP-p300, and its mRNA translation is enhanced by METTL3-mediated m6A modification read by YTHDF1."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing that CDCP1 is a cell-surface transmembrane glycoprotein phosphorylated by Src family kinases defined its identity as a signaling-competent receptor-like molecule.","evidence":"Immunopurification, anti-phosphotyrosine western blot, and selective Src kinase inhibitor studies in cancer cells","pmids":["12660814"],"confidence":"High","gaps":["Specific tyrosine residues not identified","Cleavage biology unknown","Downstream effectors uncharacterized"]},{"year":2008,"claim":"Identifying CDCP1 clustering in lipid raft/tetraspanin-enriched microdomains and its scaffolding of SFK and PKCδ at Y734 established it as a transmembrane signaling platform rather than a simple substrate.","evidence":"Detergent-resistant membrane fractionation and immunofluorescence co-localization in epithelial cells","pmids":["18269919"],"confidence":"Medium","gaps":["Single-lab observation without reciprocal validation of microdomain composition","Functional consequence of raft localization not tested in vivo"]},{"year":2010,"claim":"Mapping the cleavage site (R368/K369) and showing that proteolysis generates a hyperphosphorylated 70 kDa fragment that recruits Src and PKCδ resolved how CDCP1 switches from a latent to an active signaling state.","evidence":"N-terminal sequencing, site-directed mutagenesis of cleavage sites, protease inhibitor panels, mass spectrometry","pmids":["20551327"],"confidence":"High","gaps":["Identity of the physiologically relevant protease(s) in vivo not established","Stoichiometry of Src/PKCδ recruitment unknown"]},{"year":2011,"claim":"Demonstrating that Y734 phosphorylation is essential for Src activation, metastasis, and competitive SFK substrate-switching away from FAK-Y861 established Y734 as the critical regulatory site and positioned CDCP1 as a FAK-competing scaffold.","evidence":"Y734F mutagenesis, pharmacological Src inhibition (PP2, dasatinib), 3D Matrigel culture, in vivo metastasis assays, reciprocal phosphorylation analysis in multiple cell types","pmids":["21220330","21994943"],"confidence":"High","gaps":["How cellular context determines the FAK-vs-CDCP1 substrate switch is not defined","Role of Y743 and Y762 in non-transformation phenotypes unclear"]},{"year":2011,"claim":"Showing that plasmin-mediated CDCP1 cleavage in vivo triggers Src→PKCδ→Akt survival signaling and that blocking cleavage induces apoptosis and reduces metastasis established proteolysis as the critical activating event for the pro-survival cascade.","evidence":"Plasminogen-KO mice with plasmin rescue, cleavage-site mutants, antibody blockade, aprotinin, western blot for phospho-Src/PKCδ/Akt/PARP1","pmids":["22179830"],"confidence":"High","gaps":["Contribution of other serine proteases in different tissue contexts unknown","Whether cleavage is required for all CDCP1 functions (e.g. Wnt, TGF-β) not tested"]},{"year":2012,"claim":"Discovery that cleaved CDCP1 forms a complex with activated β1 integrin to induce FAK/PI3K/Akt signaling and that blocking this complex suppresses invasion and metastasis connected CDCP1 cleavage to integrin-mediated stromal invasion.","evidence":"Reciprocal Co-IP in vitro and in live animals, β1 integrin shRNA, cleavage-blocking antibody 10-D7, pharmacological FAK/PI3K inhibitors, in vivo intravasation models","pmids":["23208492"],"confidence":"High","gaps":["Whether CDCP1–β1 integrin interaction is direct or bridged by an adaptor not resolved","Integrin activation state specificity not fully mapped"]},{"year":2012,"claim":"Establishing that CDCP1 localizes to caveolin-1-containing vesicles and is required for MT1-MMP trafficking to invadopodia extended its function to protease-dependent ECM degradation and invasion beyond intracellular signaling.","evidence":"Co-IP of CDCP1 and MT1-MMP, lipid raft fractionation, siRNA knockdown, ECM degradation and Matrigel invasion assays in breast cancer and melanoma cells","pmids":["23439492"],"confidence":"High","gaps":["Direct binding between CDCP1 and MT1-MMP not confirmed","Mechanism of CDCP1-dependent trafficking of MT1-MMP to invadopodia unknown"]},{"year":2012,"claim":"Systematic mutagenesis showed all three intracellular tyrosines (Y734, Y743, Y762) and the palmitoylation motif (C689,690) are required for Src/CDCP1-dependent cell transformation, while Src SH2 domain binding to CDCP1 is dispensable, clarifying the structural determinants of oncogenic signaling.","evidence":"Retroviral co-expression in NIH3T3, focus formation assay with systematic point mutants of CDCP1 tyrosines and palmitoylation sites, Src domain mutants","pmids":["23300860"],"confidence":"High","gaps":["Structural basis of Src recruitment independent of SH2 not resolved","How palmitoylation influences membrane localization vs. stability not dissected"]},{"year":2013,"claim":"Identifying HIF-2α (not HIF-1α) as a transcriptional inducer of CDCP1 under hypoxia revealed how the tumor microenvironment upregulates CDCP1 signaling.","evidence":"Isoform-specific shRNA knockdown of HIF-2α vs HIF-1α, HIF-2α overexpression, xenograft tumor growth with CDCP1 expression analysis","pmids":["23378636"],"confidence":"High","gaps":["Direct HIF-2α binding to the CDCP1 promoter not demonstrated by ChIP","Other hypoxia-responsive regulators not excluded"]},{"year":2014,"claim":"Demonstrating that CDCP1 undergoes constitutive palmitoylation-dependent proteasomal degradation, which is counteracted by EGF/EGFR signaling that promotes CDCP1 recycling, established a post-translational regulatory circuit linking growth factor signaling to CDCP1 surface availability.","evidence":"Palmitoylation-site mutagenesis, cycloheximide chase, proteasome inhibitors, EGF treatment, surface biotinylation, migration assays","pmids":["24681947"],"confidence":"High","gaps":["Palmitoyltransferase(s) responsible not identified","How EGFR signaling specifically blocks palmitoylation-dependent degradation not defined"]},{"year":2014,"claim":"Placing CDCP1 downstream of oncogenic Ras/ERK signaling and showing its requirement for Ras-mediated anoikis resistance and MMP activation established CDCP1 as a critical effector node in the Ras pathway.","evidence":"Activated Ras expression with CDCP1 knockdown and Src inhibitors; anoikis, migration, invasion, and MMP activity assays","pmids":["24939643"],"confidence":"High","gaps":["Whether Ras directly regulates CDCP1 transcription or acts through intermediary transcription factors not fully resolved"]},{"year":2015,"claim":"Discovery that CDCP1 binds HER2 through its intracellular domain and promotes HER2–SRC interaction, leading to trastuzumab resistance, established CDCP1 as a modifier of receptor tyrosine kinase drug sensitivity.","evidence":"Co-IP with domain truncation mapping, cell migration and transformation assays, in vivo tumor formation, trastuzumab resistance readouts","pmids":["25892239"],"confidence":"High","gaps":["Structural basis of the CDCP1–HER2 intracellular interaction not defined","Whether CDCP1 modulates other HER family members not tested"]},{"year":2016,"claim":"Showing that only cleaved CDCP1 homodimerizes through the CUB2 ectodomain and that dimerization drives PKCδ/ERK/p38 phosphorylation and migration resolved the question of how proteolysis creates a dimerization-competent active species.","evidence":"Overexpression of full-length vs cleaved CDCP1, recombinant ECC competitive inhibitor blocking dimerization, western blot for downstream kinases, 3D invasion assays","pmids":["26876198"],"confidence":"High","gaps":["Direct structural evidence for CUB2-mediated dimer interface lacking","Whether dimerization is required for all downstream pathways (e.g. TGF-β, integrin) not tested"]},{"year":2017,"claim":"Identification of CDCP1 as a ligand for CD6 and demonstration that CD318-KO mice are protected from autoimmune encephalomyelitis revealed an unexpected immune regulatory function for CDCP1 beyond cancer.","evidence":"CD318-KO mice in EAE model, T-cell chemotaxis with soluble CD318, CD6-dependent T-cell adhesion to synovial fibroblasts","pmids":["28760953"],"confidence":"High","gaps":["Binding affinity and stoichiometry of CDCP1–CD6 interaction not quantified","Whether CDCP1 cleavage modulates CD6 binding not examined"]},{"year":2017,"claim":"Discovering that CDCP1 suppresses ACSL activity to promote fatty acid oxidation and deplete lipid droplets uncovered a metabolic regulatory function distinct from its kinase-scaffolding role.","evidence":"CDCP1 knockdown/overexpression, ACSL enzymatic activity assays, CARS/TPEF lipid droplet imaging, ACSL3 co-knockdown rescue, in vivo TNBC metastasis models","pmids":["28739932"],"confidence":"High","gaps":["Mechanism of ACSL inhibition (direct binding vs indirect) not defined","Which ACSL isoform(s) beyond ACSL3 are involved not fully tested"]},{"year":2018,"claim":"Identifying FBXL14 as a direct E3 ubiquitin ligase for CDCP1, controlled by miR-17/20a, established a ubiquitin-proteasome degradation axis regulating CDCP1 protein levels.","evidence":"Co-IP of FBXL14 and CDCP1, ubiquitination assays, proteasome inhibitors, miR-17/20a transfection, breast cancer metastasis assays","pmids":["29973690"],"confidence":"High","gaps":["Specific lysine residues ubiquitinated on CDCP1 not mapped","Relationship between FBXL14 and palmitoylation-dependent degradation not clarified"]},{"year":2018,"claim":"Elucidating that CDCP1 loss disrupts CDK5 activity via a SRC→CDK5R1-pY234→PKCδ→CDK5-pT77 cascade, leading to loss of β1-integrin inside-out activation, connected CDCP1 scaffolding to cell adhesion regulation through CDK5.","evidence":"CDK5-T77 and CDK5R1-Y234 phosphorylation-site mutagenesis, CDK5 kinase activity assays, Co-IP of CDK5/CDK5R1, adhesion/migration assays in prostate cancer cells","pmids":["29511352"],"confidence":"High","gaps":["Whether this CDK5 mechanism operates in cell types beyond prostate cancer not known","Structural basis of PKCδ-mediated CDK5 phosphorylation at T77 not resolved"]},{"year":2019,"claim":"Demonstrating that CDCP1 directly binds TGF-β1 via CUB domains and amplifies Smad2 signaling independently of Src/PKCδ established CDCP1 as a TGF-β co-receptor with a signaling output distinct from its canonical kinase scaffold function.","evidence":"BIAcore SPR binding assays, TGF-β1/BMP reporter assays, phospho-Smad2 western blot, epistasis with Src/PKCδ inhibitors and Smad2/TGFRI knockdown","pmids":["31302030"],"confidence":"High","gaps":["Binding interface between CUB domains and TGF-β1 not structurally resolved","Physiological relevance of CDCP1–TGF-β1 interaction in vivo not tested"]},{"year":2019,"claim":"Showing that CDCP1 promotes nuclear translocation of β-catenin and E-cadherin to activate Wnt target genes revealed CDCP1 as a regulator of Wnt/β-catenin signaling in colorectal cancer.","evidence":"Cell fractionation, Co-IP, confocal microscopy, IHC of patient samples, CDCP1 loss-of-function in vitro and in vivo","pmids":["31471585"],"confidence":"High","gaps":["Mechanism by which CDCP1 facilitates β-catenin nuclear entry not defined","Whether this function depends on CDCP1 cleavage or Y734 phosphorylation not tested"]},{"year":2019,"claim":"METTL3-dependent m6A modification of CDCP1 mRNA read by YTHDF1 enhances CDCP1 translation, adding an epitranscriptomic regulatory layer to CDCP1 expression control.","evidence":"m6A profiling, METTL3/ALKBH5 knockdown, YTHDF1 RIP, luciferase/translation reporters, bladder cancer growth assays","pmids":["30796352"],"confidence":"High","gaps":["Specific m6A sites in CDCP1 3'-UTR not mapped at nucleotide resolution","Whether this regulation operates broadly across tissues not tested"]},{"year":2021,"claim":"Identification of uPA as the master protease for CDCP1 cleavage, acting both directly and via plasmin activation, resolved the long-standing question of which protease is physiologically dominant.","evidence":"Substrate-biased activity-based probe (sbABP) for protease capture, in vitro cleavage validation, in vivo metastasis models, patient co-expression analysis","pmids":["33859413"],"confidence":"High","gaps":["Tissue-specific contributions of alternative proteases (e.g., matriptase) not excluded","Whether uPA inhibition is sufficient to fully block CDCP1 cleavage in all contexts not tested"]},{"year":2021,"claim":"Demonstrating that CDCP1 on dendritic cells regulates IL-6 via Syk-MAPK signaling and that CDCP1-KO mice are protected from Kawasaki-like vasculitis expanded CDCP1 function to innate immune signaling.","evidence":"CDCP1-KO mice, DC-specific expression, CAWS stimulation, IL-6 ELISA, Syk-MAPK western blot","pmids":["34099547"],"confidence":"High","gaps":["How CDCP1 activates Syk on DCs (direct or via co-receptor) not resolved","CDCP1 cleavage status on DCs not characterized"]},{"year":2021,"claim":"Showing that CDCP1 recruits Src into lipid rafts to activate Met-STAT3 signaling and that CDCP1 ablation impairs compensatory renal growth after nephrectomy revealed a physiological non-cancer role for CDCP1 in organ homeostasis.","evidence":"CDCP1 siRNA/ablation, lipid raft fractionation, Co-IP of Src/STAT3/Met, unilateral nephrectomy in CDCP1-ablated mice","pmids":["33574034"],"confidence":"High","gaps":["Whether CDCP1 directly binds Met or acts solely through Src scaffolding not determined","Long-term renal consequences of CDCP1 loss not followed"]},{"year":2022,"claim":"Structural and biophysical characterization showing that cleaved CDCP1 fragments remain tightly associated with minimal conformational change enabled development of neoepitope-specific therapeutic antibodies distinguishing cleaved from uncleaved forms.","evidence":"Differential phage display, biophysical characterization of cleaved vs uncleaved CDCP1, ADC/radionuclide/BiTE functional studies, syngeneic pancreatic tumor model","pmids":["35166238"],"confidence":"High","gaps":["High-resolution atomic structure of cleaved CDCP1 not yet available","Whether neoepitope accessibility varies across tumor types not assessed"]},{"year":2022,"claim":"Mapping the CDCP1→SRC→ARHGEF7→RAC1 pathway downstream of HGF/Met showed how CDCP1 connects receptor tyrosine kinase activation to Rho GTPase-driven lamellipodia and invasion.","evidence":"Epistasis with CDCP1 and ARHGEF7 knockdowns, Rac1 activation assays, immunofluorescence co-localization, migration/invasion assays","pmids":["35085554"],"confidence":"High","gaps":["Whether CDCP1 directly binds ARHGEF7 or acts solely through SRC not resolved","Contribution of other GEFs not excluded"]},{"year":null,"claim":"Key unresolved questions include the high-resolution atomic structure of CDCP1 (both full-length and cleaved forms), the mechanism by which CDCP1 inhibits ACSL activity, the structural basis of CUB2-mediated homodimerization, and how CDCP1 coordinates its diverse signaling outputs (Src/PKCδ, Wnt, TGF-β, Syk) in a context-dependent manner.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure available","ACSL inhibition mechanism (direct vs indirect) unresolved","Context-dependent pathway selection logic unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,4,7,8,36]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,18]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[16,32]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6,7,8,10,28]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,3,4,5,12,14,18,20,21,23,26,30]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[16,25,32]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,17]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[15]}],"complexes":[],"partners":["SRC","PRKCД","ITGB1","ERBB2","CD6","MMP14","FBXL14","PTPN11"],"other_free_text":[]},"mechanistic_narrative":"CDCP1 is a type I transmembrane glycoprotein that functions as a signaling scaffold, integrating extracellular proteolytic cues with intracellular kinase cascades to regulate cell survival, migration, invasion, and immune cell interactions. Full-length CDCP1 (135 kDa) is phosphorylated at Y734 (and Y743/Y762) by Src family kinases; proteolytic cleavage at R368/K369 by uPA and plasmin generates a membrane-retained 70 kDa fragment that becomes hyperphosphorylated, recruits PKCδ via its C2 domain, homodimerizes through its CUB2 domain, and complexes with activated β1 integrin to drive FAK/PI3K/Akt survival signaling and suppress anoikis [PMID:20551327, PMID:22179830, PMID:33859413, PMID:26876198, PMID:23208492]. Beyond this core axis, CDCP1 enhances HER2–SRC interaction and trastuzumab resistance, promotes Wnt/β-catenin nuclear translocation, binds TGF-β1 as a co-receptor to amplify Smad2 signaling independently of Src/PKCδ, suppresses ACSL activity to redirect fatty acid metabolism toward oxidation, and serves as a ligand for the T-cell receptor CD6 to modulate immune barrier permeability and autoimmune inflammation [PMID:25892239, PMID:31471585, PMID:31302030, PMID:28739932, PMID:28760953, PMID:35951427]. CDCP1 protein levels are controlled post-translationally by palmitoylation-dependent constitutive proteasomal turnover counteracted by EGF/EGFR signaling, by FBXL14-mediated ubiquitination, and transcriptionally by HIF-2α, Ras/ERK, and BRD4/CBP-p300, while its mRNA translation is enhanced by METTL3-dependent m6A modification read by YTHDF1 [PMID:24681947, PMID:29973690, PMID:23378636, PMID:24939643, PMID:35513563, PMID:30796352]."},"prefetch_data":{"uniprot":{"accession":"Q9H5V8","full_name":"CUB domain-containing protein 1","aliases":["Membrane glycoprotein gp140","Subtractive immunization M plus HEp3-associated 135 kDa protein","SIMA135","Transmembrane and associated with src kinases"],"length_aa":836,"mass_kda":92.9,"function":"May be involved in cell adhesion and cell matrix association. May play a role in the regulation of anchorage versus migration or proliferation versus differentiation via its phosphorylation. May be a novel marker for leukemia diagnosis and for immature hematopoietic stem cell subsets. Belongs to the tetraspanin web involved in tumor progression and metastasis","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9H5V8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDCP1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CDCP1","total_profiled":1310},"omim":[{"mim_id":"611735","title":"CUB DOMAIN-CONTAINING PROTEIN 1; CDCP1","url":"https://www.omim.org/entry/611735"},{"mim_id":"607646","title":"ZINC FINGER- AND BTB DOMAIN-CONTAINING PROTEIN 7B; ZBTB7B","url":"https://www.omim.org/entry/607646"},{"mim_id":"186720","title":"CD6 ANTIGEN; CD6","url":"https://www.omim.org/entry/186720"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":35.8}],"url":"https://www.proteinatlas.org/search/CDCP1"},"hgnc":{"alias_symbol":["CD318","SIMA135"],"prev_symbol":[]},"alphafold":{"accession":"Q9H5V8","domains":[{"cath_id":"2.60.120.290","chopping":"28-219","consensus_level":"medium","plddt":89.7648,"start":28,"end":219},{"cath_id":"2.60.120.290","chopping":"543-665","consensus_level":"medium","plddt":91.8666,"start":543,"end":665}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H5V8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H5V8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H5V8-F1-predicted_aligned_error_v6.png","plddt_mean":77.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDCP1","jax_strain_url":"https://www.jax.org/strain/search?query=CDCP1"},"sequence":{"accession":"Q9H5V8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H5V8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H5V8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H5V8"}},"corpus_meta":[{"pmid":"28739932","id":"PMC_28739932","title":"CDCP1 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phosphorylation mediated by a Src family kinase member, as demonstrated by selective Src kinase inhibitor studies and anti-phosphotyrosine western blot analysis.\",\n      \"method\": \"Immunopurification, western blot with anti-phosphotyrosine antibody, selective kinase inhibitor studies, immunocytochemistry\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (immunopurification, western blot, inhibitor studies) in a single study establishing tyrosine phosphorylation by SFK\",\n      \"pmids\": [\"12660814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Full-length 135 kDa CDCP1 is cleaved by serine proteases (including matriptase) at Arg-368 and Lys-369, generating a membrane-retained 70 kDa C-terminal fragment and a shed 65 kDa N-terminal ectodomain; proteolytic cleavage induces tyrosine phosphorylation of the 70 kDa fragment and recruitment of Src and PKCδ to this fragment.\",\n      \"method\": \"N-terminal sequencing of immunopurified fragments, detailed mutagenesis of cleavage sites, panel of protease inhibitors, western blot, mass spectrometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis and N-terminal sequencing with multiple orthogonal methods (inhibitors, MS, WB) establishing mechanism in single rigorous study\",\n      \"pmids\": [\"20551327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Proteolytic cleavage of CDCP1 by plasmin in vivo triggers a survival signaling cascade involving Src-mediated phosphorylation of the 70 kDa membrane-retained CDCP1 fragment, recruitment of PKCδ, and activation of Akt, which suppresses PARP1-mediated apoptosis; inhibiting cleavage (by antibody, serine protease inhibitors, or genetic mutation of the cleavage site) abolishes this signaling and induces apoptosis and reduces metastatic colonization.\",\n      \"method\": \"In vivo tumor models, antibody blockade, serine protease inhibitors (aprotinin), cleavage-site genetic mutagenesis, plasminogen-KO mice with plasmin rescue, western blot for phospho-Src/PKCδ/Akt/PARP1\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological approaches in vivo establishing the cleavage-dependent signaling cascade with strong mechanistic controls\",\n      \"pmids\": [\"22179830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDCP1 overexpression activates Src family kinases, and its pro-metastatic activity requires CDCP1 tyrosine 734 (Y734F mutation abolishes Src activation, 3D dispersive growth in vitro, and in vivo metastasis enhancement).\",\n      \"method\": \"Stable overexpression, site-directed mutagenesis (Y734F), pharmacological Src inhibitors (PP2, dasatinib), 3D Matrigel culture, in vivo metastasis assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with pharmacological inhibition and in vivo functional validation\",\n      \"pmids\": [\"21220330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDCP1 acts as a scaffold that competes with FAK-Y861 as an SFK substrate; stable CDCP1 expression causes SFK substrate switching from FAK-Y861 to CDCP1-Y734, dependent on CDCP1 expression level and specifically on Y734 but not Y743 or Y762; FAK does not form a trimeric complex with Src and CDCP1.\",\n      \"method\": \"Stable CDCP1 expression in HeLa cells, CDCP1 phospho-site mutagenesis, western blot for p-FAK-Y861 and p-CDCP1-Y734, CDCP1 siRNA knockdown in colon cancer lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis of multiple sites with reciprocal phosphorylation readouts, replicated in multiple cell types\",\n      \"pmids\": [\"21994943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In vivo cleaved (70 kDa) CDCP1 forms a complex with activated (inside-out) β1 integrin; this complex induces FAK/PI3K/Akt phosphorylation signaling; blocking this complex (by cleavage-blocking antibody 10-D7, aprotinin, or β1 integrin shRNA) reduces FAK/Akt phosphorylation, stromal invasion, and spontaneous metastasis.\",\n      \"method\": \"Co-immunoprecipitation in cell cultures and live animals, pharmacological FAK/PI3K inhibitors, shRNA knockdown of β1 integrin, cleavage-blocking monoclonal antibody, in vivo tumor intravasation models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP in vitro and in vivo, multiple inhibitor approaches, and shRNA epistasis establishing the pathway position\",\n      \"pmids\": [\"23208492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CDCP1 localizes to caveolin-1-containing vesicular structures and lipid rafts, co-immunoprecipitates with MT1-MMP, and is required for trafficking of MT1-MMP to invadopodia and for MT1-MMP-dependent ECM degradation and Matrigel invasion of breast cancer and melanoma cells.\",\n      \"method\": \"Co-immunoprecipitation of CDCP1 and MT1-MMP, Triton X-100 lipid raft fractionation, siRNA knockdown, immunofluorescence localization to invadopodia, ECM degradation assays, Matrigel invasion assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus lipid raft fractionation, siRNA with defined cellular phenotype (invadopodia function), and immunofluorescence co-localization\",\n      \"pmids\": [\"23439492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CDCP1 is phosphorylated by Src family kinases and the phosphorylated form recruits PKCδ through PKCδ's C2 domain; this interaction promotes anchorage-independent survival signaling; antibody activation of CDCP1 induces rapid tyrosine phosphorylation by Src, requires CDCP1 bivalent clustering/dimerization, translocates CDCP1 to Triton X-100-insoluble membrane fractions, and prolonged treatment induces Src-dependent, proteasome-mediated CDCP1 internalization and degradation.\",\n      \"method\": \"Focus formation assays with NIH3T3 cells co-overexpressing Src and CDCP1, antibody treatment, Triton X-100 fractionation, proteasome inhibitors, xenograft models with western blot\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical assays (fractionation, inhibitors) and in vivo models with mechanistic controls\",\n      \"pmids\": [\"24055141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CDCP1/Gp140 clusters in epithelial cell-cell contacts and assembles membrane microdomains (lipid rafts/TEMs) that recruit and activate SFK; active SFKs then phosphorylate CDCP1 at Y734 and also phosphorylate PKCδ, with CDCP1 acting as a transmembrane scaffold for these kinases; outside-in signals through extracellular CUB domains initiate this process.\",\n      \"method\": \"Detergent-resistant membrane fractionation, immunofluorescence co-localization, phosphorylation analysis of Y734\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — fractionation and co-localization data with partial mechanistic follow-up; single lab\",\n      \"pmids\": [\"18269919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HIF-2α (but not HIF-1α) transcriptionally induces CDCP1 expression and tyrosine phosphorylation under hypoxic conditions; shRNA knockdown of CDCP1 impairs cancer cell migration under hypoxia; overexpression of HIF-2α promotes xenograft tumor growth with enhanced CDCP1 expression and tyrosine phosphorylation.\",\n      \"method\": \"shRNA knockdown of HIF-2α and HIF-1α, HIF-2α overexpression, cell migration assays, xenograft tumor growth, western blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific knockdown (HIF-2α vs HIF-1α), overexpression, and in vivo validation\",\n      \"pmids\": [\"23378636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Under basal conditions, CDCP1 constitutively internalizes from the cell surface and undergoes palmitoylation-dependent proteasomal degradation (palmitoylated at one or more of its four cytoplasmic cysteines); EGF/EGFR activation inhibits this degradation, promoting CDCP1 recycling to the cell surface and increased cell migration.\",\n      \"method\": \"Cycloheximide chase, palmitoylation-site mutagenesis of cytoplasmic cysteines, proteasome inhibitors, EGF treatment, cell surface biotinylation, migration assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of palmitoylation sites combined with proteasome inhibitors and functional readouts (migration, recycling)\",\n      \"pmids\": [\"24681947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Oncogenic Ras/ERK signaling transcriptionally induces CDCP1 expression; CDCP1 is required for Ras-mediated anoikis resistance, migration, and invasion; CDCP1 knockdown or inhibition of CDCP1 phosphorylation abrogates these Ras-induced phenotypes; CDCP1 mediates activation of MMP2 and secretion of MMP9 downstream of Ras.\",\n      \"method\": \"Activated Ras expression, CDCP1 knockdown/Src inhibitor treatment, anoikis assays, migration/invasion assays, MMP2/MMP9 activity assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by knockdown and inhibitor, multiple phenotypic readouts (anoikis, migration, invasion, MMPs)\",\n      \"pmids\": [\"24939643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CDCP1 binds to HER2 through its intracellular domain and increases HER2's interaction with c-SRC, leading to enhanced HER2 activation, downstream signaling, and trastuzumab resistance in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation of CDCP1 with HER2 and SRC, domain truncation mapping, cell migration/transformation assays, in vivo tumor formation, trastuzumab resistance assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with domain mapping, in vivo validation, and functional drug resistance readout\",\n      \"pmids\": [\"25892239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SHP2 tyrosine phosphatase directly interacts with CDCP1 intracellular domain through residues Y734 and Y743; SHP2 knockdown increases CDCP1 phosphorylation and impairs antibody-mediated CDCP1 internalization, indicating SHP2 counteracts SFK-mediated CDCP1 phosphorylation and regulates CDCP1 cell surface availability.\",\n      \"method\": \"Co-immunoprecipitation, affinity precipitation, CDCP1 point mutants (Y734, Y743), SHP2 shRNA knockdown, flow cytometry for surface CDCP1\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and mutagenesis in single lab, but no reciprocal IP or structural validation\",\n      \"pmids\": [\"25876044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Only cleaved CDCP1 (cCDCP1), not full-length CDCP1, is capable of homodimerization through its ectodomain; cCDCP1 homodimerization drives phosphorylation of PKCδ, ERK1/2, and p38 MAPK and induces cell migration; the extracellular portion of cleaved CDCP1 (ECC) blocks dimerization, inhibits PKCδ phosphorylation and migration, and reduces TNBC invasiveness.\",\n      \"method\": \"Overexpression of flCDCP1 vs. cCDCP1 in HEK293T, ECC competitive inhibitor, western blot for phospho-PKCδ/ERK1/2/p38, migration assays, 3D culture invasion/proliferation/apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-level dissection of dimerization requirement with functional readouts and competitive inhibitor validation\",\n      \"pmids\": [\"26876198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDCP1 inhibits acyl-CoA synthetase ligase (ACSL) activity and promotes fatty acid oxidation (FAO) in mitochondria, depleting cytoplasmic lipid droplets; CDCP1 knockdown increases lipid droplet abundance and reduces TNBC migration (rescued by ACSL inhibitor Triacsin C or ACSL3 co-knockdown); in vivo blocking of CDCP1 increases lipid droplet abundance and decreases metastasis.\",\n      \"method\": \"CDCP1 knockdown/overexpression, ACSL activity assays, coherent anti-Stokes Raman scattering microscopy, two-photon excited fluorescence microscopy, Triacsin C treatment, ACSL3 co-knockdown, animal models of TNBC\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — enzymatic activity assay (ACSL), optical imaging of lipid droplets, in vitro and in vivo rescue experiments with multiple orthogonal approaches\",\n      \"pmids\": [\"28739932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD318 (CDCP1) is a ligand for CD6; CD318-KO mice are protected in experimental autoimmune encephalomyelitis (similar to CD6-KO mice); soluble CD318 is chemoattractive to T cells and CD318 participates in CD6-dependent adhesion of T cells to synovial fibroblasts.\",\n      \"method\": \"CD318-KO mice in EAU model, T cell adhesion assays, chemotaxis assays with soluble CD318, identification of antigen recognized by mAb 3A11 as CD318\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in disease model replicated for both CD6 and CD318, plus functional adhesion and chemotaxis assays\",\n      \"pmids\": [\"28760953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FBXL14 E3 ubiquitin ligase directly binds CDCP1, facilitates its ubiquitination and proteasomal degradation, suppressing CDCP1 protein stability and breast cancer metastasis; miR-17/20a controls FBXL14 expression, placing it upstream of CDCP1 regulation.\",\n      \"method\": \"Co-immunoprecipitation of FBXL14 and CDCP1, ubiquitination assays, proteasome inhibitor treatment, miR-17/20a transfection, breast cancer metastasis functional assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ubiquitination assay with functional oncological consequences\",\n      \"pmids\": [\"29973690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of CDCP1 in prostate cancer cells reduces CDK5 kinase activity by promoting SRC-mediated phosphorylation of CDK5R1/p35 at Y234, which creates a binding site for the C2 domain of PKCδ, leading to PKCδ phosphorylation of CDK5 at T77, dissociation of the CDK5/CDK5R1 complex, loss of CDK5 activity, and consequent loss of inside-out activation of β1-integrin.\",\n      \"method\": \"CDCP1 silencing, CDK5-T77 and CDK5R1-Y234 phosphorylation-site mutagenesis, Co-IP of CDK5/CDK5R1 complex, CDK5 kinase activity assays, cell adhesion/migration assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of specific phosphorylation sites, kinase activity assays, and Co-IP rescue experiments establishing the mechanism\",\n      \"pmids\": [\"29511352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"METTL3 and the m6A reader YTHDF1 promote translation of CDCP1 mRNA by recognizing m6A residues in the CDCP1 3'-UTR; ALKBH5 demethylase counteracts this; the METTL3-m6A-CDCP1 axis promotes bladder cancer cell growth and transformation.\",\n      \"method\": \"m6A profiling, METTL3/ALKBH5 knockdown, YTHDF1 RIP assays, m6A-seq, luciferase/translation reporter assays, in vitro and in vivo cancer growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — m6A profiling with RIP, knockdown of writer/reader/eraser, and translation reporter assays\",\n      \"pmids\": [\"30796352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDCP1 directly binds TGF-β1 and BMP4 via its CUB domains (measured by BIAcore surface plasmon resonance); CDCP1 enhances TGF-β1 signaling (reporter activity and phospho-Smad2 levels) in a manner dependent on Smad2 and TGFRI, but independent of Src or PKCδ; CDCP1 does not modulate BMP signaling.\",\n      \"method\": \"BIAcore surface plasmon resonance binding assay, TGF-β1/BMP reporter assays, phospho-Smad2 western blot, Smad2/TGFRI knockdown, Src/PKCδ inhibition\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding demonstrated by SPR plus pathway-specific functional assays with epistasis controls (Src/PKCδ independence)\",\n      \"pmids\": [\"31302030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDCP1 promotes Wnt signaling in colorectal cancer by facilitating translocation of β-catenin and E-cadherin to the nucleus; disruption of CDCP1 reduces nuclear/chromatin-associated β-catenin and nuclear E-cadherin, increases their sequestration at the membrane, and disrupts regulation of CRC-promoting genes.\",\n      \"method\": \"Cell fractionation, co-immunoprecipitation, confocal microscopy, immunohistochemistry of patient samples, CDCP1 loss-of-function in vitro and in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell fractionation, IP, microscopy, and in vivo tumor burden with multiple orthogonal approaches\",\n      \"pmids\": [\"31471585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDCP1 forms homophilic complexes via its extracellular CUB2 domain; deletion of the extracellular region abolishes complex formation and the ability to promote cancer cell migration; recombinant CUB2 domain protein competitively inhibits CDCP1 homophilic complex formation, SFK activation, and cell migration.\",\n      \"method\": \"CDCP1 deletion mutants, recombinant CUB2-MBP fusion protein competitive inhibition, co-immunoprecipitation, SFK activation assays, migration assays in lung adenocarcinoma and pancreatic cells\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain deletion mutagenesis and competitive inhibition with defined functional output; single lab\",\n      \"pmids\": [\"31524271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Androgen signaling suppresses CDCP1 expression; androgen deprivation combined with PTEN loss upregulates CDCP1, which then activates the SRC/MAPK pathway to promote metastatic prostate cancer progression.\",\n      \"method\": \"Androgen treatment/deprivation, PTEN loss genetic models, CDCP1 expression analysis, SRC/MAPK pathway western blot, in vivo prostate cancer progression models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (PTEN loss combined with androgen deprivation) with clear pathway activation readout and in vivo validation\",\n      \"pmids\": [\"32250342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Urokinase plasminogen activator (uPA) is the master regulator of CDCP1 proteolysis, acting both by directly cleaving CDCP1 and by activating plasmin (which also cleaves CDCP1); uPA-mediated CDCP1 proteolysis promotes metastasis in preclinical in vivo models; co-expression of uPA and CDCP1 is predictive of poor disease outcome.\",\n      \"method\": \"Substrate-biased activity-based probe (sbABP) incorporating CDCP1 cleavage motif for protease capture/identification, in vitro cleavage assays, in vivo metastasis models, patient data analysis\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — novel chemical biology approach (sbABP) combined with in vitro validation and in vivo disease models\",\n      \"pmids\": [\"33859413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDCP1 on dendritic cells (DCs) regulates IL-6 production via the Syk-MAPK signaling pathway; CDCP1-KO DCs show reduced CAWS-induced IL-6 production associated with impaired Syk-MAPK signaling; CDCP1-KO mice show attenuated coronary and aortic vasculitis in a Kawasaki disease model.\",\n      \"method\": \"CDCP1 knockout mice, DC-specific expression analysis, CAWS stimulation assays, IL-6 ELISA, Syk-MAPK western blot in WT vs. KO DCs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined signaling readout (Syk-MAPK/IL-6) in primary DCs and in vivo disease model\",\n      \"pmids\": [\"34099547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDCP1 promotes compensatory renal growth downstream of HGF by recruiting Src into lipid rafts to activate STAT3 associated with the HGF receptor Met; activated STAT3 then induces matrix metalloproteinase and mitogenic factor expression; CDCP1 ablation in mice attenuates Met-STAT3 signaling and suppresses compensatory growth after unilateral nephrectomy.\",\n      \"method\": \"CDCP1 siRNA/ablation in canine kidney cells, lipid raft fractionation, Co-IP of Src/STAT3/Met, STAT3 phosphorylation assays, unilateral nephrectomy in CDCP1-ablated mice\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — lipid raft fractionation, Co-IP, in vivo nephrectomy model with signaling readouts\",\n      \"pmids\": [\"33574034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The two cleaved fragments of CDCP1 remain tightly associated with minimal conformational change after proteolysis; differential phage display generated antibodies that selectively recognize the proteolytic neoepitope of cleaved CDCP1 with no detectable binding to uncleaved form; biochemical and structural characterization confirmed this.\",\n      \"method\": \"Differential phage display, biochemical and biophysical characterization, structural analysis of cleaved vs. uncleaved CDCP1, antibody-drug conjugate/radionuclide/bispecific T cell engager functional studies, syngeneic pancreatic tumor model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural and biophysical characterization combined with functional validation in syngeneic in vivo model\",\n      \"pmids\": [\"35166238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDCP1 regulates EGF/EGFR-induced cell migration; EGF/EGFR activation upregulates CDCP1 mRNA and protein via the RAS/RAF/MEK/ERK pathway (not Src), and CDCP1 relocates from cell-cell junctions to filopodia; disruption of CDCP1 by silencing or blocking antibody reduces EGF/EGFR-induced migration.\",\n      \"method\": \"CDCP1 silencing, function-blocking antibody, ERK inhibitors, EGF treatment, live-cell imaging of CDCP1 localization, migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological pathway dissection (ERK vs. Src inhibitors), silencing, antibody blockade, and live imaging\",\n      \"pmids\": [\"22315226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDCP1 is phosphorylated by Src family kinases and recruits PKCδ through the C2 domain of PKCδ in a phosphotyrosine-dependent manner; a small molecule (glycoconjugated palladium complex Pd-Oqn) inhibits the interaction between PKCδ C2 domain and phosphorylated CDCP1, suppresses PKCδ phosphorylation (but not ERK or AKT), inhibits anchorage-independent growth and invasion in vitro, and reduces peritoneal dissemination and tumor growth in vivo.\",\n      \"method\": \"Cell-free screening, immunoprecipitation assays with PKCδ C2 domain, soft agar colony formation, invasion assays, in vivo peritoneal dissemination and orthotopic xenograft models\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-free biochemical screening of protein-protein interaction, Co-IP validation, specificity controls (ERK/AKT not affected), and in vivo validation\",\n      \"pmids\": [\"28256037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDCP1 promotes HGF-induced breast cancer cell invasion through a CDCP1-SRC-ARHGEF7-RAC1 pathway; CDCP1 coaccumulates with ARHGEF7, activates SRC, which activates ARHGEF7-RAC1 GTPase signaling, leading to lamellipodia formation and invasion.\",\n      \"method\": \"CDCP1 knockdown, ectopic MET and CDCP1 expression, Rac1 activation assays, ARHGEF7 knockdown, immunofluorescence co-localization of CDCP1 and ARHGEF7, migration/invasion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with multiple knockdowns establishing pathway order, GTPase activity assays, and co-localization\",\n      \"pmids\": [\"35085554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BRD4 and CBP/p300 transcription cofactors co-regulate CDCP1 gene transcription in castration-resistant prostate cancer; combined knockdown or dual inhibition reduces CDCP1 transcription and downstream PI3K/AKT and SRC/MAPK signaling more effectively than single-protein perturbation.\",\n      \"method\": \"BRD4 and CBP/p300 knockdown (individual and combined), NEO2734 dual bromodomain inhibitor, CDCP1 transcription assays, PI3K/AKT and SRC/MAPK western blot, cell proliferation/metastasis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual knockdown and chemical inhibition with transcriptional and signaling readouts; single lab\",\n      \"pmids\": [\"35513563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDCP1 on RPE cells is upregulated by IFN-γ and interacts with CD6 on T cells; CD6 stimulation of CDCP1-expressing (but not CDCP1-knockdown) RPE cells induces stress fiber formation, focal adhesion disruption, tight junction opening, and increased RPE barrier permeability permitting T cell infiltration, contributing to experimental autoimmune uveitis development.\",\n      \"method\": \"CDCP1-KO mice in EAU passive model, CDCP1-KD RPE cells, CD6 stimulation assays, tight junction immunofluorescence, T cell transmigration assays, IFN-γ stimulation\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in vivo combined with CDCP1-KD cell model and defined mechanistic readouts (cytoskeleton, focal adhesions, tight junctions)\",\n      \"pmids\": [\"35951427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hsa_circ_0005358 suppresses CDCP1 expression by binding PTBP1 protein via its 215-224 sequence, sequestering PTBP1 and preventing PTBP1 from stabilizing CDCP1 mRNA, thereby reducing CDCP1 protein translation and suppressing cervical cancer metastasis.\",\n      \"method\": \"RNA pull-down assay, mass spectrometry, RNA immunoprecipitation, RNA-sequencing, functional migration/invasion and in vivo metastasis assays\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNA pulldown, MS, and RIP establishing the mechanism, with functional in vivo validation\",\n      \"pmids\": [\"34976440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDCP1 knockdown in vascular smooth muscle cells suppresses PDGFRβ/AKT signaling by promoting NEDD4-mediated ubiquitination of PDGFRβ, preventing PDGFRβ binding to clathrin and Rab5, thus inhibiting PDGFRβ endocytosis; CDCP1 thereby regulates VSMC proliferation and migration.\",\n      \"method\": \"CDCP1 knockdown, RNA-seq, Co-IP of PDGFRβ with NEDD4/clathrin/Rab5, ubiquitination assays, immunofluorescence, AKT pathway western blot, in vivo carotid stenosis model\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assays with mechanistic pathway placement; single lab\",\n      \"pmids\": [\"40256729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDCP1 in cardiac fibroblasts (HCFs) is induced by PDGF signaling; CDCP1 knockdown reduces HCF proliferation, decreases AKT phosphorylation, and reduces expression of soluble ST2 (a cardiac fibrosis inducer), implicating CDCP1 in regulating cardiac fibrosis.\",\n      \"method\": \"CDCP1 knockdown in HCFs, PDGF stimulation, AKT phosphorylation western blot, transcriptomic profiling, ST2 expression analysis\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knockdown with defined signaling (AKT) and transcriptomic readouts; single lab\",\n      \"pmids\": [\"37800334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Structural requirements for CDCP1/Src-dependent transformation of NIH3T3 cells require intact amino- and carboxy-termini; mutation of any core intracellular tyrosine residue (Y734, Y743, or Y762) abolishes transformation; mutation of palmitoylation motif (C689,690G) strongly reduces transformation; Src binding to CDCP1 via its SH2 domain is not required for transformation, but Src myristoylation is necessary.\",\n      \"method\": \"Retrovirus-mediated co-overexpression of c-Src and CDCP1 in NIH3T3 cells, focus formation assay, systematic mutagenesis of tyrosines and palmitoylation motif, Src domain mutants (SH2-deficient, myristoylation-deficient)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis of multiple sites in a functional transformation assay\",\n      \"pmids\": [\"23300860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDCP1 overexpression activates MAPK/ERK pathway signaling in ex vivo urothelial carcinoma organoids from a CDCP1 transgenic mouse model; CDCP1 knockout in UC cell lines reduces MAPK/ERK activity concomitant with reduced proliferation and migration.\",\n      \"method\": \"CDCP1 transgenic mouse organoids, CRISPR/Cas9 CDCP1 knockout, MAPK/ERK western blot, proliferation/migration assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic gain- and loss-of-function in disease-relevant models; single lab\",\n      \"pmids\": [\"36593286\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDCP1 is a type I transmembrane glycoprotein that functions as a signaling scaffold at the plasma membrane: in its full-length 135 kDa form it is phosphorylated at Y734 (and Y743/Y762) by Src family kinases (SFKs), and upon proteolytic cleavage at R368/K369 by serine proteases (principally uPA and plasmin) the membrane-retained 70 kDa fragment becomes hyperphosphorylated, recruits Src and PKCδ (via PKCδ's C2 domain), forms homodimers through its CUB2 domain, and complexes with activated β1 integrin to activate downstream FAK/PI3K/Akt survival and migration signaling; CDCP1 also enhances HER2-SRC interaction, activates Wnt/β-catenin nuclear signaling, suppresses ACSL activity to redirect fatty acid metabolism toward oxidative phosphorylation, binds TGF-β1 as a co-receptor to amplify Smad2 signaling, interacts with CD6 to modulate immune cell responses, and is regulated post-translationally by palmitoylation-dependent proteasomal degradation (counteracted by EGFR/EGF activation) and by FBXL14-mediated ubiquitination, while its transcription is driven by HIF-2α under hypoxia, Ras/ERK signaling, and BRD4/CBP-p300, and its mRNA translation is enhanced by METTL3-mediated m6A modification read by YTHDF1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CDCP1 is a type I transmembrane glycoprotein that functions as a signaling scaffold, integrating extracellular proteolytic cues with intracellular kinase cascades to regulate cell survival, migration, invasion, and immune cell interactions. Full-length CDCP1 (135 kDa) is phosphorylated at Y734 (and Y743/Y762) by Src family kinases; proteolytic cleavage at R368/K369 by uPA and plasmin generates a membrane-retained 70 kDa fragment that becomes hyperphosphorylated, recruits PKCδ via its C2 domain, homodimerizes through its CUB2 domain, and complexes with activated β1 integrin to drive FAK/PI3K/Akt survival signaling and suppress anoikis [PMID:20551327, PMID:22179830, PMID:33859413, PMID:26876198, PMID:23208492]. Beyond this core axis, CDCP1 enhances HER2–SRC interaction and trastuzumab resistance, promotes Wnt/β-catenin nuclear translocation, binds TGF-β1 as a co-receptor to amplify Smad2 signaling independently of Src/PKCδ, suppresses ACSL activity to redirect fatty acid metabolism toward oxidation, and serves as a ligand for the T-cell receptor CD6 to modulate immune barrier permeability and autoimmune inflammation [PMID:25892239, PMID:31471585, PMID:31302030, PMID:28739932, PMID:28760953, PMID:35951427]. CDCP1 protein levels are controlled post-translationally by palmitoylation-dependent constitutive proteasomal turnover counteracted by EGF/EGFR signaling, by FBXL14-mediated ubiquitination, and transcriptionally by HIF-2α, Ras/ERK, and BRD4/CBP-p300, while its mRNA translation is enhanced by METTL3-dependent m6A modification read by YTHDF1 [PMID:24681947, PMID:29973690, PMID:23378636, PMID:24939643, PMID:35513563, PMID:30796352].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that CDCP1 is a cell-surface transmembrane glycoprotein phosphorylated by Src family kinases defined its identity as a signaling-competent receptor-like molecule.\",\n      \"evidence\": \"Immunopurification, anti-phosphotyrosine western blot, and selective Src kinase inhibitor studies in cancer cells\",\n      \"pmids\": [\"12660814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific tyrosine residues not identified\", \"Cleavage biology unknown\", \"Downstream effectors uncharacterized\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying CDCP1 clustering in lipid raft/tetraspanin-enriched microdomains and its scaffolding of SFK and PKCδ at Y734 established it as a transmembrane signaling platform rather than a simple substrate.\",\n      \"evidence\": \"Detergent-resistant membrane fractionation and immunofluorescence co-localization in epithelial cells\",\n      \"pmids\": [\"18269919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab observation without reciprocal validation of microdomain composition\", \"Functional consequence of raft localization not tested in vivo\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapping the cleavage site (R368/K369) and showing that proteolysis generates a hyperphosphorylated 70 kDa fragment that recruits Src and PKCδ resolved how CDCP1 switches from a latent to an active signaling state.\",\n      \"evidence\": \"N-terminal sequencing, site-directed mutagenesis of cleavage sites, protease inhibitor panels, mass spectrometry\",\n      \"pmids\": [\"20551327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the physiologically relevant protease(s) in vivo not established\", \"Stoichiometry of Src/PKCδ recruitment unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that Y734 phosphorylation is essential for Src activation, metastasis, and competitive SFK substrate-switching away from FAK-Y861 established Y734 as the critical regulatory site and positioned CDCP1 as a FAK-competing scaffold.\",\n      \"evidence\": \"Y734F mutagenesis, pharmacological Src inhibition (PP2, dasatinib), 3D Matrigel culture, in vivo metastasis assays, reciprocal phosphorylation analysis in multiple cell types\",\n      \"pmids\": [\"21220330\", \"21994943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cellular context determines the FAK-vs-CDCP1 substrate switch is not defined\", \"Role of Y743 and Y762 in non-transformation phenotypes unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showing that plasmin-mediated CDCP1 cleavage in vivo triggers Src→PKCδ→Akt survival signaling and that blocking cleavage induces apoptosis and reduces metastasis established proteolysis as the critical activating event for the pro-survival cascade.\",\n      \"evidence\": \"Plasminogen-KO mice with plasmin rescue, cleavage-site mutants, antibody blockade, aprotinin, western blot for phospho-Src/PKCδ/Akt/PARP1\",\n      \"pmids\": [\"22179830\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of other serine proteases in different tissue contexts unknown\", \"Whether cleavage is required for all CDCP1 functions (e.g. Wnt, TGF-β) not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that cleaved CDCP1 forms a complex with activated β1 integrin to induce FAK/PI3K/Akt signaling and that blocking this complex suppresses invasion and metastasis connected CDCP1 cleavage to integrin-mediated stromal invasion.\",\n      \"evidence\": \"Reciprocal Co-IP in vitro and in live animals, β1 integrin shRNA, cleavage-blocking antibody 10-D7, pharmacological FAK/PI3K inhibitors, in vivo intravasation models\",\n      \"pmids\": [\"23208492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDCP1–β1 integrin interaction is direct or bridged by an adaptor not resolved\", \"Integrin activation state specificity not fully mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing that CDCP1 localizes to caveolin-1-containing vesicles and is required for MT1-MMP trafficking to invadopodia extended its function to protease-dependent ECM degradation and invasion beyond intracellular signaling.\",\n      \"evidence\": \"Co-IP of CDCP1 and MT1-MMP, lipid raft fractionation, siRNA knockdown, ECM degradation and Matrigel invasion assays in breast cancer and melanoma cells\",\n      \"pmids\": [\"23439492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding between CDCP1 and MT1-MMP not confirmed\", \"Mechanism of CDCP1-dependent trafficking of MT1-MMP to invadopodia unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Systematic mutagenesis showed all three intracellular tyrosines (Y734, Y743, Y762) and the palmitoylation motif (C689,690) are required for Src/CDCP1-dependent cell transformation, while Src SH2 domain binding to CDCP1 is dispensable, clarifying the structural determinants of oncogenic signaling.\",\n      \"evidence\": \"Retroviral co-expression in NIH3T3, focus formation assay with systematic point mutants of CDCP1 tyrosines and palmitoylation sites, Src domain mutants\",\n      \"pmids\": [\"23300860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Src recruitment independent of SH2 not resolved\", \"How palmitoylation influences membrane localization vs. stability not dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying HIF-2α (not HIF-1α) as a transcriptional inducer of CDCP1 under hypoxia revealed how the tumor microenvironment upregulates CDCP1 signaling.\",\n      \"evidence\": \"Isoform-specific shRNA knockdown of HIF-2α vs HIF-1α, HIF-2α overexpression, xenograft tumor growth with CDCP1 expression analysis\",\n      \"pmids\": [\"23378636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct HIF-2α binding to the CDCP1 promoter not demonstrated by ChIP\", \"Other hypoxia-responsive regulators not excluded\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that CDCP1 undergoes constitutive palmitoylation-dependent proteasomal degradation, which is counteracted by EGF/EGFR signaling that promotes CDCP1 recycling, established a post-translational regulatory circuit linking growth factor signaling to CDCP1 surface availability.\",\n      \"evidence\": \"Palmitoylation-site mutagenesis, cycloheximide chase, proteasome inhibitors, EGF treatment, surface biotinylation, migration assays\",\n      \"pmids\": [\"24681947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoyltransferase(s) responsible not identified\", \"How EGFR signaling specifically blocks palmitoylation-dependent degradation not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placing CDCP1 downstream of oncogenic Ras/ERK signaling and showing its requirement for Ras-mediated anoikis resistance and MMP activation established CDCP1 as a critical effector node in the Ras pathway.\",\n      \"evidence\": \"Activated Ras expression with CDCP1 knockdown and Src inhibitors; anoikis, migration, invasion, and MMP activity assays\",\n      \"pmids\": [\"24939643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ras directly regulates CDCP1 transcription or acts through intermediary transcription factors not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that CDCP1 binds HER2 through its intracellular domain and promotes HER2–SRC interaction, leading to trastuzumab resistance, established CDCP1 as a modifier of receptor tyrosine kinase drug sensitivity.\",\n      \"evidence\": \"Co-IP with domain truncation mapping, cell migration and transformation assays, in vivo tumor formation, trastuzumab resistance readouts\",\n      \"pmids\": [\"25892239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the CDCP1–HER2 intracellular interaction not defined\", \"Whether CDCP1 modulates other HER family members not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing that only cleaved CDCP1 homodimerizes through the CUB2 ectodomain and that dimerization drives PKCδ/ERK/p38 phosphorylation and migration resolved the question of how proteolysis creates a dimerization-competent active species.\",\n      \"evidence\": \"Overexpression of full-length vs cleaved CDCP1, recombinant ECC competitive inhibitor blocking dimerization, western blot for downstream kinases, 3D invasion assays\",\n      \"pmids\": [\"26876198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural evidence for CUB2-mediated dimer interface lacking\", \"Whether dimerization is required for all downstream pathways (e.g. TGF-β, integrin) not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of CDCP1 as a ligand for CD6 and demonstration that CD318-KO mice are protected from autoimmune encephalomyelitis revealed an unexpected immune regulatory function for CDCP1 beyond cancer.\",\n      \"evidence\": \"CD318-KO mice in EAE model, T-cell chemotaxis with soluble CD318, CD6-dependent T-cell adhesion to synovial fibroblasts\",\n      \"pmids\": [\"28760953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding affinity and stoichiometry of CDCP1–CD6 interaction not quantified\", \"Whether CDCP1 cleavage modulates CD6 binding not examined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovering that CDCP1 suppresses ACSL activity to promote fatty acid oxidation and deplete lipid droplets uncovered a metabolic regulatory function distinct from its kinase-scaffolding role.\",\n      \"evidence\": \"CDCP1 knockdown/overexpression, ACSL enzymatic activity assays, CARS/TPEF lipid droplet imaging, ACSL3 co-knockdown rescue, in vivo TNBC metastasis models\",\n      \"pmids\": [\"28739932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ACSL inhibition (direct binding vs indirect) not defined\", \"Which ACSL isoform(s) beyond ACSL3 are involved not fully tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying FBXL14 as a direct E3 ubiquitin ligase for CDCP1, controlled by miR-17/20a, established a ubiquitin-proteasome degradation axis regulating CDCP1 protein levels.\",\n      \"evidence\": \"Co-IP of FBXL14 and CDCP1, ubiquitination assays, proteasome inhibitors, miR-17/20a transfection, breast cancer metastasis assays\",\n      \"pmids\": [\"29973690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific lysine residues ubiquitinated on CDCP1 not mapped\", \"Relationship between FBXL14 and palmitoylation-dependent degradation not clarified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Elucidating that CDCP1 loss disrupts CDK5 activity via a SRC→CDK5R1-pY234→PKCδ→CDK5-pT77 cascade, leading to loss of β1-integrin inside-out activation, connected CDCP1 scaffolding to cell adhesion regulation through CDK5.\",\n      \"evidence\": \"CDK5-T77 and CDK5R1-Y234 phosphorylation-site mutagenesis, CDK5 kinase activity assays, Co-IP of CDK5/CDK5R1, adhesion/migration assays in prostate cancer cells\",\n      \"pmids\": [\"29511352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this CDK5 mechanism operates in cell types beyond prostate cancer not known\", \"Structural basis of PKCδ-mediated CDK5 phosphorylation at T77 not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that CDCP1 directly binds TGF-β1 via CUB domains and amplifies Smad2 signaling independently of Src/PKCδ established CDCP1 as a TGF-β co-receptor with a signaling output distinct from its canonical kinase scaffold function.\",\n      \"evidence\": \"BIAcore SPR binding assays, TGF-β1/BMP reporter assays, phospho-Smad2 western blot, epistasis with Src/PKCδ inhibitors and Smad2/TGFRI knockdown\",\n      \"pmids\": [\"31302030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface between CUB domains and TGF-β1 not structurally resolved\", \"Physiological relevance of CDCP1–TGF-β1 interaction in vivo not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that CDCP1 promotes nuclear translocation of β-catenin and E-cadherin to activate Wnt target genes revealed CDCP1 as a regulator of Wnt/β-catenin signaling in colorectal cancer.\",\n      \"evidence\": \"Cell fractionation, Co-IP, confocal microscopy, IHC of patient samples, CDCP1 loss-of-function in vitro and in vivo\",\n      \"pmids\": [\"31471585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CDCP1 facilitates β-catenin nuclear entry not defined\", \"Whether this function depends on CDCP1 cleavage or Y734 phosphorylation not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"METTL3-dependent m6A modification of CDCP1 mRNA read by YTHDF1 enhances CDCP1 translation, adding an epitranscriptomic regulatory layer to CDCP1 expression control.\",\n      \"evidence\": \"m6A profiling, METTL3/ALKBH5 knockdown, YTHDF1 RIP, luciferase/translation reporters, bladder cancer growth assays\",\n      \"pmids\": [\"30796352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific m6A sites in CDCP1 3'-UTR not mapped at nucleotide resolution\", \"Whether this regulation operates broadly across tissues not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of uPA as the master protease for CDCP1 cleavage, acting both directly and via plasmin activation, resolved the long-standing question of which protease is physiologically dominant.\",\n      \"evidence\": \"Substrate-biased activity-based probe (sbABP) for protease capture, in vitro cleavage validation, in vivo metastasis models, patient co-expression analysis\",\n      \"pmids\": [\"33859413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions of alternative proteases (e.g., matriptase) not excluded\", \"Whether uPA inhibition is sufficient to fully block CDCP1 cleavage in all contexts not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that CDCP1 on dendritic cells regulates IL-6 via Syk-MAPK signaling and that CDCP1-KO mice are protected from Kawasaki-like vasculitis expanded CDCP1 function to innate immune signaling.\",\n      \"evidence\": \"CDCP1-KO mice, DC-specific expression, CAWS stimulation, IL-6 ELISA, Syk-MAPK western blot\",\n      \"pmids\": [\"34099547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDCP1 activates Syk on DCs (direct or via co-receptor) not resolved\", \"CDCP1 cleavage status on DCs not characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing that CDCP1 recruits Src into lipid rafts to activate Met-STAT3 signaling and that CDCP1 ablation impairs compensatory renal growth after nephrectomy revealed a physiological non-cancer role for CDCP1 in organ homeostasis.\",\n      \"evidence\": \"CDCP1 siRNA/ablation, lipid raft fractionation, Co-IP of Src/STAT3/Met, unilateral nephrectomy in CDCP1-ablated mice\",\n      \"pmids\": [\"33574034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDCP1 directly binds Met or acts solely through Src scaffolding not determined\", \"Long-term renal consequences of CDCP1 loss not followed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Structural and biophysical characterization showing that cleaved CDCP1 fragments remain tightly associated with minimal conformational change enabled development of neoepitope-specific therapeutic antibodies distinguishing cleaved from uncleaved forms.\",\n      \"evidence\": \"Differential phage display, biophysical characterization of cleaved vs uncleaved CDCP1, ADC/radionuclide/BiTE functional studies, syngeneic pancreatic tumor model\",\n      \"pmids\": [\"35166238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution atomic structure of cleaved CDCP1 not yet available\", \"Whether neoepitope accessibility varies across tumor types not assessed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapping the CDCP1→SRC→ARHGEF7→RAC1 pathway downstream of HGF/Met showed how CDCP1 connects receptor tyrosine kinase activation to Rho GTPase-driven lamellipodia and invasion.\",\n      \"evidence\": \"Epistasis with CDCP1 and ARHGEF7 knockdowns, Rac1 activation assays, immunofluorescence co-localization, migration/invasion assays\",\n      \"pmids\": [\"35085554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDCP1 directly binds ARHGEF7 or acts solely through SRC not resolved\", \"Contribution of other GEFs not excluded\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the high-resolution atomic structure of CDCP1 (both full-length and cleaved forms), the mechanism by which CDCP1 inhibits ACSL activity, the structural basis of CUB2-mediated homodimerization, and how CDCP1 coordinates its diverse signaling outputs (Src/PKCδ, Wnt, TGF-β, Syk) in a context-dependent manner.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure available\", \"ACSL inhibition mechanism (direct vs indirect) unresolved\", \"Context-dependent pathway selection logic unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 4, 7, 8, 36]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 18]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [16, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6, 7, 8, 10, 28]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5, 12, 14, 18, 20, 21, 23, 26, 30]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16, 25, 32]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 17]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SRC\",\n      \"PRKCД\",\n      \"ITGB1\",\n      \"ERBB2\",\n      \"CD6\",\n      \"MMP14\",\n      \"FBXL14\",\n      \"PTPN11\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}