{"gene":"CDCP1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2003,"finding":"SIMA135/CDCP1 is a type I transmembrane glycoprotein located on the cell surface, with up to 40 kDa of its apparent molecular weight attributable to N-glycosylation. It is tyrosine phosphorylated in tumor cells, and selective inhibitor studies indicated that a Src kinase family member is responsible for this phosphorylation.","method":"Immunopurification, Western blot with anti-phosphotyrosine antibody, selective Src kinase inhibitor studies, deglycosylation analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods in a single lab establishing basic properties of the protein","pmids":["12660814"],"is_preprint":false},{"year":2008,"finding":"CDCP1 (Gp140) clusters in epithelial cell-cell contacts and is phosphorylated by Src Family Kinases at tyrosine 734 in response to outside-in signals. Active SFKs mediate phosphorylation of CDCP1, SFK, and PKCδ, with CDCP1 acting as a transmembrane scaffold for these kinases within membrane microdomains.","method":"Biochemical fractionation (Triton-resistant membrane domains), phosphorylation assays, cell biology experiments","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (fractionation, signaling assays) in single lab establishing scaffold function","pmids":["18269919"],"is_preprint":false},{"year":2010,"finding":"Full-length 135 kDa CDCP1 is post-translationally processed by serine protease activity (including matriptase) at two sites, Arg-368 and Lys-369, generating a C-terminal membrane-retained 70 kDa fragment and a shed N-terminal 65 kDa ectodomain. Proteolysis induces tyrosine phosphorylation of the 70 kDa fragment and recruitment of Src and PKCδ to this fragment.","method":"Immunopurification, N-terminal sequencing, detailed mutagenesis, protease inhibitor panel, Western blot, mass spectrometry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-directed mutagenesis, N-terminal sequencing, and multiple orthogonal biochemical methods in a single rigorous study","pmids":["20551327"],"is_preprint":false},{"year":2011,"finding":"CDCP1 overexpression activates Src family kinases in melanoma cells, and the Y734F point mutation in CDCP1 abolishes Src activation, dispersive 3D growth in Matrigel, and in vivo metastasis-enhancing activity, establishing that Y734 is required for CDCP1's metastasis-promoting function through SFK activation.","method":"SILAC quantitative mass spectrometry, point mutagenesis (Y734F), 3D Matrigel culture, in vivo metastasis assay, pharmacological SFK inhibitors (PP2, Dasatinib)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis, pharmacological inhibition, and in vivo experiments across multiple orthogonal methods","pmids":["21220330"],"is_preprint":false},{"year":2011,"finding":"CDCP1-Tyr-734 and FAK-Tyr-861 compete as Src family kinase (SFK) substrates. Stable CDCP1 expression causes SFK-mediated phosphorylation of CDCP1-Y734 with concomitant loss of phospho-FAK-Y861, and this substrate switching is dependent on expression level and Y734 but not Y743 or Y762. FAK does not form a trimeric complex with Src and CDCP1.","method":"Stable CDCP1 expression in HeLa cells, phosphorylation analysis (Western blot), mutagenesis (Y734F, Y743F, Y762F), siRNA knockdown, co-immunoprecipitation (negative result for trimeric complex)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with multiple phosphorylation assays and genetic knockdown, single rigorous lab study","pmids":["21994943"],"is_preprint":false},{"year":2011,"finding":"In vivo cleavage of CDCP1 by plasmin (identified as the crucial extracellular serine protease) triggers a survival signaling cascade: serine-protease-mediated 135→70 kDa CDCP1 cleavage recruits Src and PKCδ, Src-mediated phosphorylation of 70 kDa CDCP1 activates Akt, and suppresses PARP1-mediated apoptosis. Preventing CDCP1 cleavage with antibodies, protease inhibitors, or genetic mutation of the cleavage site abrogates this signaling and induces apoptosis.","method":"Anti-CDCP1 cleavage-blocking antibodies, serine protease inhibitors, genetic cleavage-site mutagenesis, plasminogen-knockout mice, lung retention model, Western blot for Src/PKCδ/Akt/PARP1","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro and in vivo approaches including genetic animal models and rescue experiments, independently convergent findings","pmids":["22179830"],"is_preprint":false},{"year":2012,"finding":"Proteolytic cleavage of CDCP1 by plasmin-like serine proteases generates a membrane-retained 70 kDa fragment that complexes preferentially with active (inside-out activated) β1 integrin, both in cell culture and in live animals. This complex activates intracellular FAK and PI3K/Akt signaling, promoting tumor cell intravasation and metastasis. Inhibition of FAK/PI3K or shRNA knockdown of β1 integrin reduces FAK/Akt phosphorylation downstream of cleaved CDCP1.","method":"Co-immunoprecipitation (cell culture and in vivo), cleavage-blocking antibody (10-D7), aprotinin (serine protease inhibition), FAK/PI3K inhibitors, β1 integrin shRNA, spontaneous metastasis assays in vivo","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in vitro and in vivo, multiple inhibitor approaches, and in vivo metastasis rescue experiments","pmids":["23208492"],"is_preprint":false},{"year":2012,"finding":"CDCP1 is required for ECM degradation by invadopodia in breast cancer and melanoma cells. CDCP1 localizes to caveolin-1-containing vesicular structures and lipid rafts and co-immunoprecipitates with MT1-MMP, regulating its trafficking and accumulation at invadopodia; siRNA knockdown of CDCP1 markedly reduces MT1-MMP-dependent ECM degradation and Matrigel invasion.","method":"siRNA knockdown, co-immunoprecipitation (CDCP1 with MT1-MMP), immunofluorescence, lipid raft fractionation (Triton X-100 insoluble fraction), Matrigel invasion assay","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, colocalization, functional knockdown with defined molecular phenotype, and fractionation in single study","pmids":["23439492"],"is_preprint":false},{"year":2013,"finding":"HIF-2α (but not HIF-1α) directly induces CDCP1 expression and tyrosine phosphorylation under hypoxia. shRNA knockdown of CDCP1 impairs cancer cell migration under hypoxic conditions, establishing CDCP1 as a downstream HIF-2α target gene mediating hypoxia-driven metastasis.","method":"shRNA knockdown of HIF-2α and HIF-1α, shRNA knockdown of CDCP1, hypoxic cell migration assay, HIF-2α overexpression in xenografts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function (shRNA) with specific migration phenotype, single lab, in vitro and in vivo","pmids":["23378636"],"is_preprint":false},{"year":2013,"finding":"Antibody-induced CDCP1 clustering/dimerization transiently induces tyrosine phosphorylation of CDCP1 by Src, causes translocation of CDCP1 to a Triton X-100 insoluble fraction of the plasma membrane (requiring bivalency of the antibody), and subsequently triggers internalization and proteasome-dependent degradation of CDCP1 in a Src-dependent manner.","method":"Focus formation assay (NIH3T3 co-transformation with CDCP1 and Src), antibody (RG7287) treatment, Western blot for CDCP1 phosphorylation and levels, detergent-resistant membrane fractionation, xenograft models","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell-based assays and in vivo xenograft models in single lab, Src-dependency established pharmacologically","pmids":["24055141"],"is_preprint":false},{"year":2014,"finding":"Oncogenic Ras/ERK signaling induces CDCP1 expression in lung cancer cells; CDCP1 knockdown or inhibition of CDCP1 phosphorylation by Src-directed therapy abrogates anoikis resistance, migration, invasion, and Ras-induced MMP2 activation/MMP9 secretion. CDCP1 is therefore required for the functional link between Ras and Src signaling.","method":"CDCP1 knockdown (siRNA/shRNA), Src-directed therapy, anoikis assay, migration assay, invasion assay, zymography (MMP2/MMP9), Ras mutant lung cancer cells","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with multiple functional readouts, pathway placement by epistasis, single lab","pmids":["24939643"],"is_preprint":false},{"year":2014,"finding":"Under basal conditions, cell-surface CDCP1 constitutively internalizes and undergoes palmitoylation-dependent proteasomal degradation, palmitoylated at one or more cytoplasmic cysteines. EGF/EGFR activation inhibits this palmitoylation-dependent degradation, promotes recycling of CDCP1 to the cell surface, and increases cell migration. Disruption of CDCP1 palmitoylation also promotes its relocalization to the cell surface and cell migration.","method":"Palmitoylation site mutagenesis (cytoplasmic cysteines), EGF treatment, proteasome inhibitors, live-cell imaging/internalization assays, cell migration assay, in vivo palmitoylation detection in tumor samples","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — palmitoylation site mutagenesis, proteasome inhibitor experiments, live-cell assays, and in vivo validation across multiple orthogonal methods","pmids":["24681947"],"is_preprint":false},{"year":2015,"finding":"CDCP1 binds to HER2 through its intracellular domain, increasing HER2 interaction with c-SRC, which enhances HER2 activation and downstream signaling and confers trastuzumab resistance in breast cancer cells.","method":"Co-immunoprecipitation (CDCP1 with HER2 and c-SRC), CDCP1 domain truncation analysis, cell migration, transformation, and in vivo tumor formation assays, trastuzumab resistance assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain mapping, multiple functional assays, and in vivo data in single rigorous study","pmids":["25892239"],"is_preprint":false},{"year":2015,"finding":"The tyrosine phosphatase SHP2 directly interacts with CDCP1 via its phosphorylated Y734 and Y743 residues (as shown by point mutants), potentially competing with SFK binding. shRNA-mediated downregulation of SHP2 results in stronger CDCP1 phosphorylation and impaired antibody-mediated CDCP1 internalization.","method":"Co-immunoprecipitation, affinity precipitation, CDCP1 point mutants (Y734A, Y743A), SHP2 shRNA knockdown","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mutagenesis to define binding residues, single lab","pmids":["25876044"],"is_preprint":false},{"year":2016,"finding":"Only the cleaved form of CDCP1 (cCDCP1), not full-length CDCP1, is capable of homodimerization through its ectodomain, and only cCDCP1 induces phosphorylation of PKCδ, ERK1/2, and p38 MAPK and promotes cell migration. A blocking fragment of the cCDCP1 ectodomain (ECC) inhibits dimerization, PKCδ phosphorylation, and TNBC cell migration.","method":"Expression of full-length vs. cleaved CDCP1 constructs in HEK 293T, co-immunoprecipitation for dimerization, phosphorylation analysis (Western blot), migration rescue assay in CDCP1-shRNA TNBC lines, ECC blocking fragment","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP for dimerization, domain blocking experiment, multiple phosphorylation readouts, and functional rescue assays in a single study","pmids":["26876198"],"is_preprint":false},{"year":2017,"finding":"CDCP1 drives a 'low-lipid' phenotype in triple-negative breast cancer by interacting with and inhibiting acyl CoA-synthetase ligase (ACSL) activity, reducing acyl-CoA production and increasing fatty acid oxidation (FAO) and oxidative phosphorylation in mitochondria. CDCP1 knockdown increases lipid droplet abundance and reduces migration, rescued by the ACSL inhibitor Triacsin C or ACSL3 co-knockdown.","method":"CDCP1 knockdown and rescue experiments, coherent anti-Stokes Raman scattering (CARS) and two-photon excited fluorescence microscopy (lipid droplet imaging), ACSL activity assay, Co-IP (CDCP1 with ACSL), in vivo animal models of TNBC with blocking fragment treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — Co-IP with enzymatic activity assay, imaging-based lipid quantification, genetic rescue experiments, and in vivo validation","pmids":["28739932"],"is_preprint":false},{"year":2017,"finding":"CD318/CDCP1 is a ligand for CD6. Soluble CD318 is chemoattractive to T cells, and CD318 participates in CD6-dependent adhesion of T cells to synovial fibroblasts. CD318 knockout mice are protected in experimental autoimmune encephalomyelitis, phenocopying CD6 KO mice.","method":"Identification via mAb 3A11, CD318 knockout mice in EAU model, T cell adhesion assay, T cell chemotaxis assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout phenotype in two disease models, direct binding identification, and functional adhesion/migration assays","pmids":["28760953"],"is_preprint":false},{"year":2018,"finding":"Loss of CDCP1 reduces CDK5 kinase activity via a mechanism in which c-SRC phosphorylates CDK5R1/p35 on Y234, creating a binding site for the C2 domain of PKCδ, which in turn phosphorylates CDK5 on T77, causing dissociation of the CDK5R1/CDK5 complex and abolishing CDK5 activity. This loss of CDK5 activity reduces inside-out activation of β1 integrin, impairing cell adhesion and migration.","method":"CDCP1 siRNA silencing, phosphorylation mapping (CDK5R1-Y234, CDK5-T77), CDK5 phosphorylation site mutants (T77 and Y234), PKCδ C2 domain binding assay, β1 integrin inside-out activation assay, cell adhesion and migration assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-directed mutagenesis of two phosphorylation sites, domain binding assay, genetic knockdown, and functional rescue in a rigorous mechanistic study","pmids":["29511352"],"is_preprint":false},{"year":2018,"finding":"FBXL14 E3 ubiquitin ligase directly interacts with CDCP1 and facilitates its ubiquitination and proteasomal degradation, thereby reducing CDCP1 protein stability. miR-17/20a suppress FBXL14, establishing an upstream regulatory mechanism for CDCP1 protein levels.","method":"Co-immunoprecipitation (CDCP1 with FBXL14), ubiquitination assay, proteasome inhibitor experiments, miR-17/20a overexpression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay establishing direct interaction and functional degradation, single lab","pmids":["29973690"],"is_preprint":false},{"year":2019,"finding":"CDCP1 promotes Wnt signaling in colorectal cancer by facilitating nuclear translocation of β-catenin and E-cadherin. Disruption of CDCP1 reduces nuclear chromatin-associated β-catenin and nuclear E-cadherin, increases sequestration of these proteins at cell membranes, and disrupts regulation of CRC-promoting genes.","method":"Cell fractionation, immunoprecipitation, immunofluorescence microscopy, immunohistochemistry, CDCP1 loss-of-function, in vitro and in vivo tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, IP, imaging) with functional in vivo validation, single lab","pmids":["31471585"],"is_preprint":false},{"year":2019,"finding":"CDCP1 CUB domains bind directly to TGF-β1 and BMP4 (real-time protein interaction on BIAcore chip). CDCP1 enhances TGF-β1 signaling (reporter activity and phospho-Smad2 levels) but does not modulate BMP signaling. CDCP1 actions on TGF-β/Smad2 signaling require Smad2 and TGFRI but are independent of Src or PKCδ binding.","method":"BIAcore surface plasmon resonance (direct binding to TGF-β1 and BMP4), TGF-β reporter assay, phospho-Smad2 Western blot, siRNA knockdown of Smad2/TGFRI/Src/PKCδ","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1 / Strong — biophysical binding assay (SPR) combined with reporter assay and genetic pathway dissection, establishing direct extracellular ligand interaction","pmids":["31302030"],"is_preprint":false},{"year":2019,"finding":"CDCP1 forms a homophilic complex via its extracellular CUB2 domain; deletion of the extracellular region abolishes complex formation. The homophilic complex activates SFK on the plasma membrane and promotes cancer cell migration. A recombinant CUB2 domain protein (rMBP-CUB2) inhibits CDCP1 homophilic complex formation, SFK activation, and cancer cell migration.","method":"Deletion mutants, co-immunoprecipitation for dimerization, recombinant CUB2 domain blocking experiment, SFK phosphorylation assay, cancer cell migration assay","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion, Co-IP, domain-blocking experiment, and functional assays; single lab","pmids":["31524271"],"is_preprint":false},{"year":2019,"finding":"METTL3 and m6A reader YTHDF1 recognize m6A residues on CDCP1 3'-UTR mRNA and promote CDCP1 translation. ALKBH5 demethylase opposes this modification. Inhibition of the METTL3-m6A-CDCP1 axis reduces growth of transformed and bladder cancer cells.","method":"m6A profiling, METTL3/ALKBH5 knockdown, YTHDF1 binding assay, CDCP1 translation assay, in vitro and in vivo functional assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epitranscriptomic profiling combined with genetic loss-of-function and binding assays, single lab","pmids":["30796352"],"is_preprint":false},{"year":2021,"finding":"Urokinase (uPA) is identified as 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 disease-relevant preclinical in vivo models, and co-expression of uPA and CDCP1 is strongly predictive of poor disease outcome across multiple cancers.","method":"Substrate-biased activity-based probe (sbABP) incorporating CDCP1 cleavage motif, protease capture/isolation/identification (MS), in vivo metastasis models","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — novel chemical biology approach (activity-based probe) with protease identification by MS, validated in vivo","pmids":["33859413"],"is_preprint":false},{"year":2021,"finding":"CDCP1 on dendritic cells (DCs) is required for IL-6 production during Kawasaki disease model induction. CAWS stimulation upregulates CDCP1 on DCs, and CDCP1 KO DCs show significantly reduced IL-6 production associated with impaired Syk-MAPK signaling pathway activation.","method":"CDCP1 knockout mice, CAWS-induced Kawasaki disease model, IL-6 ELISA, immunostaining (DC subsets), Syk-MAPK pathway analysis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular and signaling phenotype, single lab, single disease model","pmids":["34099547"],"is_preprint":false},{"year":2022,"finding":"Biochemical and biophysical characterization (SPR, structural analysis) revealed that the two cleaved fragments of CDCP1 remain tightly associated with minimal conformational change after proteolysis. Antibodies that selectively bind the proteolytic neoepitope of cleaved CDCP1 (with no detectable binding to uncleaved form) potently target cleaved CDCP1-expressing cancer cells as ADC, Ab-radionuclide conjugate, and bispecific T cell engager.","method":"Biochemical characterization, biophysical analysis (SPR), structural characterization, differential phage display to generate cleavage-selective antibodies, syngeneic pancreatic tumor model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural/biophysical characterization combined with rigorous selectivity validation and in vivo functional studies","pmids":["35166238"],"is_preprint":false},{"year":2022,"finding":"CDCP1 promotes HGF-induced cell migration and invasion by activating SRC kinase; in breast cancer cells, CDCP1 facilitates MET activation by HGF and promotes lamellipodia formation. CDCP1 expression activates small GTPase Rac1 via guanine nucleotide exchange factor ARHGEF7, which co-accumulates with CDCP1, establishing a CDCP1-SRC-ARHGEF7-RAC1 pathway.","method":"CDCP1 knockdown and ectopic expression, HGF stimulation assays, Rac1 activation assay, ARHGEF7 knockdown, immunofluorescence (CDCP1/ARHGEF7 colocalization), migration/invasion assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic perturbations with GTPase activation assays and colocalization; single lab","pmids":["35085554"],"is_preprint":false},{"year":2021,"finding":"CDCP1 promotes HGF-induced compensatory renal growth by recruiting Src into lipid rafts to activate STAT3 associated with the HGF receptor Met; activated STAT3 induces expression of matrix metalloproteinases and mitogenic factors. CDCP1 ablation attenuates regenerative Met-STAT3 signaling after unilateral nephrectomy in mice.","method":"CDCP1 ablation in canine kidney cells, lipid raft fractionation (Src recruitment), STAT3 phosphorylation analysis (association with Met), MMP and mitogenic factor expression assay, unilateral nephrectomy mouse model","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lipid raft fractionation for Src recruitment, STAT3 pathway analysis, and in vivo nephrectomy model; single lab","pmids":["33574034"],"is_preprint":false},{"year":2022,"finding":"CDCP1 on RPE cells is upregulated by IFN-γ. CD6 stimulation of RPE cells induces increased barrier permeability, massive stress fiber formation, and focal adhesion disruption reducing tight junctions, facilitating T cell infiltration. This CD6-stimulated barrier disruption is abrogated by CDCP1 knockdown, establishing that CDCP1 mediates CD6-driven RPE cytoskeleton remodeling.","method":"CDCP1 knockdown in RPE cells, IFN-γ stimulation, CD6 stimulation, transwell T cell migration assay, RPE monolayer permeability assay, immunostaining for stress fibers and focal adhesions, EAU mouse model (CDCP1 KO)","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with defined cytoskeletal phenotype and functional barrier assay, supported by in vivo KO model; single lab","pmids":["35951427"],"is_preprint":false},{"year":2017,"finding":"CDCP1 expression is inhibited by the microRNA miR-1, which directly targets the 3'-UTR of CDCP1 mRNA. ADAM9 promotes CDCP1 expression by activating EGFR signaling, which in turn suppresses miR-1 expression, establishing an ADAM9-EGFR-miR-1-CDCP1 regulatory axis.","method":"Luciferase reporter assay (miR-1 binding to CDCP1 3'-UTR), ADAM9 knockdown, EGFR signaling analysis, miR-1 inhibitor/mimic experiments, in vivo metastasis/survival assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'-UTR reporter assay combined with genetic epistasis experiments, single lab","pmids":["28537886"],"is_preprint":false},{"year":2025,"finding":"CDCP1 knockdown in vascular smooth muscle cells (VSMCs) inhibits PDGFRβ endocytosis by promoting PDGFRβ binding to NEDD4 and its ubiquitination, and attenuating PDGFRβ binding to clathrin and Rab5. This leads to reduced AKT signaling and decreased VSMC proliferation and migration.","method":"CDCP1 siRNA knockdown, RNA-seq, co-immunoprecipitation (PDGFRβ with NEDD4, clathrin, Rab5), immunofluorescence, CCK8 proliferation assay, wound healing assay, focal carotid stenosis in vivo model","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with multiple binding partners, RNA-seq pathway analysis, functional assays, and in vivo model; single lab","pmids":["40256729"],"is_preprint":false},{"year":2012,"finding":"For CDCP1/Src-dependent cellular transformation, the intact amino- and carboxy-termini of CDCP1 are essential. Mutation of any of the three core intracellular tyrosine residues (Y734, Y743, or Y762) abolishes transformation capacity, and mutation of a palmitoylation motif (C689,690G) strongly reduces it. Src kinase 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, CDCP1 truncation and point mutants (Y734F, Y743F, Y762F, C689/690G), Src SH2 domain mutant","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis (multiple tyrosine and palmitoylation sites, domain deletions) in a rigorous transformation assay","pmids":["23300860"],"is_preprint":false},{"year":2014,"finding":"CDCP1 and the tetraspanin CD9 are co-expressed and form a low-level but detectable complex in colon cancer cells, as shown by co-sedimentation in sucrose gradients and co-immunoprecipitation. CDCP1 modulates cell-substratum adhesion and serum-induced chemotaxis in colon cancer cell lines.","method":"Co-immunoprecipitation, density gradient centrifugation, siRNA knockdown, Matrigel adhesion assay, xCELLigence chemotaxis assay","journal":"BMC cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for CDCP1/CD9 interaction, single lab, no mutagenesis or further mechanistic dissection of the complex","pmids":["25301083"],"is_preprint":false},{"year":2020,"finding":"CDCP1 is transferred from metastatic prostate cancer cells to osteoclast precursors via extracellular vesicles (EVs) and promotes osteoclastogenesis in the presence of RANKL. Functional siRNA screening of EV cargo identified CDCP1 as the specific inducer of osteoclast formation.","method":"EV characterization, functional siRNA screening of EV cargo, osteoclastogenesis assay in presence of RANKL","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional siRNA screen of EV cargo identifying CDCP1, with RANKL-dependent osteoclastogenesis assay; single lab","pmids":["36880252"],"is_preprint":false},{"year":2025,"finding":"Glycosylation of CDCP1 at N339 and N386 are identified as critical functional determinants. CDCP1 knockout reduces SRC and JUN phosphorylation (ErbB signaling pathway markers by 5.5-fold and 4.2-fold respectively) and reduces cancer cell migration. CDCP1 is selectively enriched in extracellular vesicles from highly metastatic lung cancer cells.","method":"CDCP1 knockout (KO) in lung cancer cells, intact glycopeptide enrichment with site-specific glycoform profiling, Ti4+-IMAC phosphoproteomics, site-specific glycosylation mutagenesis (N339, N386), migration assays, EV/cell co-culture","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — glycosylation mutagenesis and phosphoproteomic analysis identifying downstream signaling changes; single lab study","pmids":["40693605"],"is_preprint":false}],"current_model":"CDCP1 is a type I transmembrane glycoprotein that acts as a scaffolding receptor and signaling hub: its full-length 135 kDa form is proteolytically cleaved at R368/K369 primarily by urokinase (uPA) and plasmin, generating a membrane-retained 70 kDa fragment that homodimerizes via its CUB2 ectodomain, recruits and activates Src family kinases (phosphorylating Y734, Y743, Y762), and assembles a pro-metastatic complex with β1 integrin and PKCδ to drive FAK/PI3K/Akt survival and migration signaling, while also binding HER2 (via its intracellular domain), interacting extracellularly with TGF-β1/BMP4 as a co-receptor, facilitating MT1-MMP trafficking to invadopodia, modulating fatty acid oxidation through ACSL inhibition, and serving as a CD6 ligand on epithelial/immune cells; its activity is modulated by palmitoylation-dependent proteasomal degradation, FBXL14-mediated ubiquitination, SHP2 phosphatase interaction, and transcriptional/epitranscriptomic regulation by HIF-2α, METTL3-m6A/YTHDF1, BRD4/CBP-p300, and promoter CpG methylation."},"narrative":{"mechanistic_narrative":"CDCP1 is a type I transmembrane glycoprotein that functions as a proteolytically activated scaffolding receptor and signaling hub driving cancer cell survival, migration, invasion, and metastasis [PMID:12660814, PMID:20551327, PMID:21220330]. The full-length 135 kDa protein is cleaved at Arg-368/Lys-369 by serine proteases—with urokinase (uPA) acting as the master regulator both by cleaving CDCP1 directly and by activating plasmin—to generate a membrane-retained 70 kDa fragment and a shed ectodomain that remain tightly associated after cleavage [PMID:20551327, PMID:22179830, PMID:33859413, PMID:35166238]. Only the cleaved fragment homodimerizes through its extracellular CUB2 domain, and this homophilic complex is required to recruit and activate Src family kinases, which phosphorylate CDCP1 on the intracellular tyrosines Y734, Y743, and Y762 [PMID:26876198, PMID:31524271, PMID:23300860]. Phosphorylated Y734 is the critical residue for Src activation and metastatic behavior, and CDCP1 acts as a transmembrane platform that assembles Src and PKCδ into membrane microdomains [PMID:18269919, PMID:21220330, PMID:21994943]. Downstream, cleaved CDCP1 complexes with active β1 integrin to drive FAK and PI3K/Akt survival signaling and suppress PARP1-mediated apoptosis [PMID:22179830, PMID:23208492], promotes β1 integrin inside-out activation through a Src–PKCδ–CDK5 axis [PMID:29511352], facilitates MT1-MMP trafficking to invadopodia for ECM degradation [PMID:23439492], and engages receptor tyrosine kinase signaling by binding HER2 through its intracellular domain and potentiating MET/STAT3 and Rac1 responses to HGF [PMID:25892239, PMID:35085554, PMID:33574034]. Beyond canonical signaling, the CUB domains bind TGF-β1 directly to enhance Smad2 signaling [PMID:31302030], and CDCP1 reprograms lipid metabolism by inhibiting acyl-CoA synthetase (ACSL) activity to elevate fatty acid oxidation [PMID:28739932]. CDCP1 abundance is set by multiple converging mechanisms: constitutive palmitoylation-dependent internalization and proteasomal degradation reversed by EGFR activation [PMID:24681947], FBXL14-mediated ubiquitination [PMID:29973690], transcriptional induction by HIF-2α and Ras/ERK [PMID:23378636, PMID:24939643], and post-transcriptional control by METTL3/YTHDF1 m6A modification and miR-1 [PMID:30796352, PMID:28537886]. Independently of its oncogenic role, CDCP1 (CD318) is a ligand for CD6 that mediates T cell adhesion and chemotaxis, and CD6-driven cytoskeletal remodeling, with CDCP1-knockout mice protected in autoimmune disease models [PMID:28760953, PMID:35951427].","teleology":[{"year":2003,"claim":"Established CDCP1 as a cell-surface, heavily N-glycosylated transmembrane glycoprotein that is tyrosine phosphorylated by a Src family kinase, defining its basic biochemical identity.","evidence":"Immunopurification, anti-phosphotyrosine Western blot, Src inhibitor and deglycosylation studies in tumor cells","pmids":["12660814"],"confidence":"Medium","gaps":["Did not identify the specific SFK or the phosphorylated residues","No functional consequence of phosphorylation established"]},{"year":2008,"claim":"Showed CDCP1 acts as a transmembrane scaffold clustering at cell-cell contacts and phosphorylated at Y734 by SFKs to organize Src and PKCδ in membrane microdomains, defining its scaffolding role.","evidence":"Triton-resistant membrane fractionation and phosphorylation assays in epithelial cells","pmids":["18269919"],"confidence":"Medium","gaps":["Functional/phenotypic consequence of the scaffold not yet tested in vivo","Role of proteolysis not yet linked"]},{"year":2010,"claim":"Identified the proteolytic activation mechanism—serine protease cleavage at R368/K369 generating a membrane-retained 70 kDa fragment that recruits Src and PKCδ—establishing CDCP1 as a protease-activated receptor.","evidence":"N-terminal sequencing, site-directed mutagenesis, protease inhibitor panel and mass spectrometry","pmids":["20551327"],"confidence":"High","gaps":["The dominant physiological protease was not pinned down","Downstream survival/migration outputs not yet mapped"]},{"year":2011,"claim":"Defined Y734 as the essential residue for CDCP1-driven SFK activation and metastasis, and showed CDCP1 and FAK-Y861 compete as SFK substrates without forming a trimeric complex, clarifying signaling logic.","evidence":"SILAC mass spectrometry, Y734F/Y743F/Y762F mutagenesis, 3D Matrigel and in vivo metastasis assays, SFK inhibitors and Co-IP","pmids":["21220330","21994943"],"confidence":"High","gaps":["Did not resolve how substrate switching is controlled at endogenous expression levels","Relationship of Y734 signaling to proteolysis still implicit"]},{"year":2012,"claim":"Established the in vivo cleaved-CDCP1 survival and invasion program: plasmin cleavage recruits Src/PKCδ to activate Akt and suppress apoptosis, complexes with active β1 integrin to drive FAK/PI3K, and routes MT1-MMP to invadopodia.","evidence":"Cleavage-blocking antibodies, plasminogen-knockout mice, lung retention and spontaneous metastasis models, reciprocal Co-IP, siRNA, and invadopodia/Matrigel assays","pmids":["22179830","23208492","23439492","23300860"],"confidence":"High","gaps":["Did not establish which protease dominates across tissues","Structural basis of the cleaved fragment's activity unresolved"]},{"year":2013,"claim":"Placed CDCP1 downstream of hypoxia (HIF-2α induction) and defined antibody-induced clustering as a trigger for Src-dependent phosphorylation, internalization, and proteasomal degradation, linking expression and turnover to function.","evidence":"HIF-1α/HIF-2α shRNA, hypoxic migration assays, xenografts, antibody-clustering and detergent-resistant membrane fractionation","pmids":["23378636","24055141"],"confidence":"Medium","gaps":["Direct HIF-2α promoter occupancy not detailed","Mechanism coupling clustering to degradation incompletely defined"]},{"year":2014,"claim":"Resolved CDCP1 protein homeostasis (constitutive palmitoylation-dependent internalization/degradation reversed by EGFR) and its position downstream of oncogenic Ras/ERK linking Ras to Src signaling and MMP activation.","evidence":"Palmitoylation-site mutagenesis, EGF treatment, proteasome inhibitors, live-cell internalization assays, and Ras-mutant lung cancer knockdown with zymography","pmids":["24681947","24939643"],"confidence":"High","gaps":["Identity of palmitoyltransferase not determined","How EGFR blocks palmitoylation mechanistically unresolved"]},{"year":2015,"claim":"Expanded the interactome by showing CDCP1 binds HER2 intracellularly to enhance HER2/c-Src signaling and trastuzumab resistance, and that SHP2 binds phospho-Y734/Y743 to modulate phosphorylation and internalization.","evidence":"Reciprocal Co-IP with domain mapping, point mutants (Y734A/Y743A), SHP2 shRNA, functional and in vivo tumor assays","pmids":["25892239","25876044"],"confidence":"Medium","gaps":["SHP2 substrate specificity on CDCP1 not fully defined","Interplay between SHP2 dephosphorylation and SFK binding kinetics unclear"]},{"year":2016,"claim":"Demonstrated that only the cleaved form homodimerizes via its ectodomain to drive PKCδ/ERK/p38 phosphorylation and migration, establishing dimerization of the proteolytic fragment as the activation switch.","evidence":"Full-length vs cleaved constructs in HEK293T, Co-IP for dimerization, ectodomain blocking fragment, and migration rescue in TNBC","pmids":["26876198"],"confidence":"High","gaps":["Stoichiometry and structural geometry of the dimer not defined here","Whether dimerization precedes or follows SFK recruitment unresolved"]},{"year":2017,"claim":"Broadened CDCP1 function into metabolism (ACSL inhibition driving fatty acid oxidation), immune ligand biology (CD6 ligand mediating T cell adhesion/chemotaxis and autoimmune disease), and added miRNA/ADAM9-EGFR regulation of its expression.","evidence":"ACSL activity assays, CARS lipid imaging, genetic rescue, CD318/CD6 knockout mice in EAU, adhesion/chemotaxis assays, and miR-1 3'-UTR reporter with ADAM9 epistasis","pmids":["28739932","28760953","28537886"],"confidence":"High","gaps":["Structural basis of CDCP1-ACSL inhibition undefined","How CD6 engagement signals into CDCP1-expressing cells incompletely mapped"]},{"year":2018,"claim":"Defined a CDCP1-driven Src–PKCδ–CDK5 cascade controlling β1 integrin inside-out activation and adhesion, and added FBXL14/miR-17-20a as a ubiquitin-degradation control of CDCP1 levels.","evidence":"siRNA, CDK5R1-Y234 and CDK5-T77 phospho-site mutagenesis, PKCδ C2-domain binding, integrin activation/adhesion assays, FBXL14 Co-IP and ubiquitination assays","pmids":["29511352","29973690"],"confidence":"High","gaps":["In vivo relevance of the CDK5 arm not fully tested","FBXL14 recognition determinants on CDCP1 not mapped"]},{"year":2019,"claim":"Established direct extracellular ligand binding (CUB domains bind TGF-β1/BMP4 with selective enhancement of TGF-β/Smad2 signaling), CUB2-mediated homophilic complex formation as the SFK-activating unit, Wnt/β-catenin promotion, and m6A translational control.","evidence":"BIAcore SPR, TGF-β reporter and phospho-Smad2 assays, CUB2 deletion/blocking experiments, cell fractionation for β-catenin, and METTL3/YTHDF1/ALKBH5 m6A profiling","pmids":["31302030","31524271","31471585","30796352"],"confidence":"High","gaps":["How extracellular ligand binding integrates with proteolytic activation unresolved","Structural detail of CUB-ligand complexes lacking"]},{"year":2021,"claim":"Identified urokinase as the master protease driving CDCP1 cleavage and metastasis, and extended CDCP1 signaling to HGF/MET-STAT3 in renal regeneration and to dendritic cell IL-6/Syk-MAPK in Kawasaki disease.","evidence":"Substrate-biased activity-based probe with MS protease identification and in vivo metastasis models; lipid raft fractionation/STAT3 analysis in nephrectomy model; CDCP1 KO mice in CAWS-induced disease","pmids":["33859413","33574034","34099547"],"confidence":"High","gaps":["Relative contributions of uPA vs plasmin in different tissues not quantified","DC and renal signaling mechanisms only partially dissected"]},{"year":2022,"claim":"Structurally characterized the cleaved fragments as remaining tightly associated, enabling cleavage-selective neoepitope antibodies for targeted therapy, and defined HGF-driven CDCP1-SRC-ARHGEF7-RAC1 migration signaling and CD6-mediated RPE barrier disruption.","evidence":"SPR/structural analysis and differential phage display antibodies in syngeneic pancreatic model; Rac1 activation and ARHGEF7 colocalization assays; CDCP1 knockdown in RPE with barrier/T-cell migration assays and EAU KO model","pmids":["35166238","35085554","35951427"],"confidence":"High","gaps":["High-resolution structure of full cleaved complex not reported","Therapeutic neoepitope antibody efficacy beyond preclinical models untested"]},{"year":2025,"claim":"Defined N339/N386 glycosylation as functional determinants of CDCP1-driven SRC/JUN phosphorylation and migration, identified CDCP1 enrichment in metastatic-cell extracellular vesicles, and a CDCP1-dependent PDGFRβ endocytosis pathway in vascular smooth muscle.","evidence":"Site-specific glycosylation mutagenesis with glycoproteomics/phosphoproteomics and EV profiling in lung cancer; CDCP1 siRNA with PDGFRβ/NEDD4/clathrin/Rab5 Co-IP and carotid stenosis model","pmids":["40693605","40256729"],"confidence":"Medium","gaps":["How specific glycans modulate signaling mechanistically unresolved","Vascular and EV roles validated in single labs only"]},{"year":null,"claim":"It remains unresolved how the multiple inputs—proteolytic activation, extracellular ligand engagement, glycosylation, and degradation control—are integrated to dictate which downstream program (integrin, RTK, metabolic, or immune) CDCP1 selects in a given cell context.","evidence":"No single study in the corpus reconciles the parallel signaling, metabolic, and immune functions into a unified context-dependent model","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of the full-length or cleaved CDCP1 signaling complex","Context determinants of pathway choice undefined","Physiological (non-cancer) function only partially characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,5,14,20,21]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,6,12]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[16,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,17]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,9,21]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[7,11]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,6,12,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,6,23]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[7,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[16,24,28]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[15]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11,18]}],"complexes":[],"partners":["SRC","PRKCD","ITGB1","ERBB2","SHP2","ACSL3","CD6","FBXL14"],"other_free_text":[]}},"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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It is tyrosine phosphorylated in tumor cells, and selective inhibitor studies indicated that a Src kinase family member is responsible for this phosphorylation.\",\n      \"method\": \"Immunopurification, Western blot with anti-phosphotyrosine antibody, selective Src kinase inhibitor studies, deglycosylation analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods in a single lab establishing basic properties of the protein\",\n      \"pmids\": [\"12660814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CDCP1 (Gp140) clusters in epithelial cell-cell contacts and is phosphorylated by Src Family Kinases at tyrosine 734 in response to outside-in signals. Active SFKs mediate phosphorylation of CDCP1, SFK, and PKCδ, with CDCP1 acting as a transmembrane scaffold for these kinases within membrane microdomains.\",\n      \"method\": \"Biochemical fractionation (Triton-resistant membrane domains), phosphorylation assays, cell biology experiments\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (fractionation, signaling assays) in single lab establishing scaffold function\",\n      \"pmids\": [\"18269919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Full-length 135 kDa CDCP1 is post-translationally processed by serine protease activity (including matriptase) at two sites, Arg-368 and Lys-369, generating a C-terminal membrane-retained 70 kDa fragment and a shed N-terminal 65 kDa ectodomain. Proteolysis induces tyrosine phosphorylation of the 70 kDa fragment and recruitment of Src and PKCδ to this fragment.\",\n      \"method\": \"Immunopurification, N-terminal sequencing, detailed mutagenesis, protease inhibitor panel, Western blot, mass spectrometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-directed mutagenesis, N-terminal sequencing, and multiple orthogonal biochemical methods in a single rigorous study\",\n      \"pmids\": [\"20551327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDCP1 overexpression activates Src family kinases in melanoma cells, and the Y734F point mutation in CDCP1 abolishes Src activation, dispersive 3D growth in Matrigel, and in vivo metastasis-enhancing activity, establishing that Y734 is required for CDCP1's metastasis-promoting function through SFK activation.\",\n      \"method\": \"SILAC quantitative mass spectrometry, point mutagenesis (Y734F), 3D Matrigel culture, in vivo metastasis assay, pharmacological SFK inhibitors (PP2, Dasatinib)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis, pharmacological inhibition, and in vivo experiments across multiple orthogonal methods\",\n      \"pmids\": [\"21220330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDCP1-Tyr-734 and FAK-Tyr-861 compete as Src family kinase (SFK) substrates. Stable CDCP1 expression causes SFK-mediated phosphorylation of CDCP1-Y734 with concomitant loss of phospho-FAK-Y861, and this substrate switching is dependent on expression level and 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, phosphorylation analysis (Western blot), mutagenesis (Y734F, Y743F, Y762F), siRNA knockdown, co-immunoprecipitation (negative result for trimeric complex)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with multiple phosphorylation assays and genetic knockdown, single rigorous lab study\",\n      \"pmids\": [\"21994943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In vivo cleavage of CDCP1 by plasmin (identified as the crucial extracellular serine protease) triggers a survival signaling cascade: serine-protease-mediated 135→70 kDa CDCP1 cleavage recruits Src and PKCδ, Src-mediated phosphorylation of 70 kDa CDCP1 activates Akt, and suppresses PARP1-mediated apoptosis. Preventing CDCP1 cleavage with antibodies, protease inhibitors, or genetic mutation of the cleavage site abrogates this signaling and induces apoptosis.\",\n      \"method\": \"Anti-CDCP1 cleavage-blocking antibodies, serine protease inhibitors, genetic cleavage-site mutagenesis, plasminogen-knockout mice, lung retention model, Western blot for Src/PKCδ/Akt/PARP1\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro and in vivo approaches including genetic animal models and rescue experiments, independently convergent findings\",\n      \"pmids\": [\"22179830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Proteolytic cleavage of CDCP1 by plasmin-like serine proteases generates a membrane-retained 70 kDa fragment that complexes preferentially with active (inside-out activated) β1 integrin, both in cell culture and in live animals. This complex activates intracellular FAK and PI3K/Akt signaling, promoting tumor cell intravasation and metastasis. Inhibition of FAK/PI3K or shRNA knockdown of β1 integrin reduces FAK/Akt phosphorylation downstream of cleaved CDCP1.\",\n      \"method\": \"Co-immunoprecipitation (cell culture and in vivo), cleavage-blocking antibody (10-D7), aprotinin (serine protease inhibition), FAK/PI3K inhibitors, β1 integrin shRNA, spontaneous metastasis assays in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in vitro and in vivo, multiple inhibitor approaches, and in vivo metastasis rescue experiments\",\n      \"pmids\": [\"23208492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CDCP1 is required for ECM degradation by invadopodia in breast cancer and melanoma cells. CDCP1 localizes to caveolin-1-containing vesicular structures and lipid rafts and co-immunoprecipitates with MT1-MMP, regulating its trafficking and accumulation at invadopodia; siRNA knockdown of CDCP1 markedly reduces MT1-MMP-dependent ECM degradation and Matrigel invasion.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation (CDCP1 with MT1-MMP), immunofluorescence, lipid raft fractionation (Triton X-100 insoluble fraction), Matrigel invasion assay\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, colocalization, functional knockdown with defined molecular phenotype, and fractionation in single study\",\n      \"pmids\": [\"23439492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HIF-2α (but not HIF-1α) directly induces CDCP1 expression and tyrosine phosphorylation under hypoxia. shRNA knockdown of CDCP1 impairs cancer cell migration under hypoxic conditions, establishing CDCP1 as a downstream HIF-2α target gene mediating hypoxia-driven metastasis.\",\n      \"method\": \"shRNA knockdown of HIF-2α and HIF-1α, shRNA knockdown of CDCP1, hypoxic cell migration assay, HIF-2α overexpression in xenografts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function (shRNA) with specific migration phenotype, single lab, in vitro and in vivo\",\n      \"pmids\": [\"23378636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Antibody-induced CDCP1 clustering/dimerization transiently induces tyrosine phosphorylation of CDCP1 by Src, causes translocation of CDCP1 to a Triton X-100 insoluble fraction of the plasma membrane (requiring bivalency of the antibody), and subsequently triggers internalization and proteasome-dependent degradation of CDCP1 in a Src-dependent manner.\",\n      \"method\": \"Focus formation assay (NIH3T3 co-transformation with CDCP1 and Src), antibody (RG7287) treatment, Western blot for CDCP1 phosphorylation and levels, detergent-resistant membrane fractionation, xenograft models\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell-based assays and in vivo xenograft models in single lab, Src-dependency established pharmacologically\",\n      \"pmids\": [\"24055141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Oncogenic Ras/ERK signaling induces CDCP1 expression in lung cancer cells; CDCP1 knockdown or inhibition of CDCP1 phosphorylation by Src-directed therapy abrogates anoikis resistance, migration, invasion, and Ras-induced MMP2 activation/MMP9 secretion. CDCP1 is therefore required for the functional link between Ras and Src signaling.\",\n      \"method\": \"CDCP1 knockdown (siRNA/shRNA), Src-directed therapy, anoikis assay, migration assay, invasion assay, zymography (MMP2/MMP9), Ras mutant lung cancer cells\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with multiple functional readouts, pathway placement by epistasis, single lab\",\n      \"pmids\": [\"24939643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Under basal conditions, cell-surface CDCP1 constitutively internalizes and undergoes palmitoylation-dependent proteasomal degradation, palmitoylated at one or more cytoplasmic cysteines. EGF/EGFR activation inhibits this palmitoylation-dependent degradation, promotes recycling of CDCP1 to the cell surface, and increases cell migration. Disruption of CDCP1 palmitoylation also promotes its relocalization to the cell surface and cell migration.\",\n      \"method\": \"Palmitoylation site mutagenesis (cytoplasmic cysteines), EGF treatment, proteasome inhibitors, live-cell imaging/internalization assays, cell migration assay, in vivo palmitoylation detection in tumor samples\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — palmitoylation site mutagenesis, proteasome inhibitor experiments, live-cell assays, and in vivo validation across multiple orthogonal methods\",\n      \"pmids\": [\"24681947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CDCP1 binds to HER2 through its intracellular domain, increasing HER2 interaction with c-SRC, which enhances HER2 activation and downstream signaling and confers trastuzumab resistance in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (CDCP1 with HER2 and c-SRC), CDCP1 domain truncation analysis, cell migration, transformation, and in vivo tumor formation assays, trastuzumab resistance assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain mapping, multiple functional assays, and in vivo data in single rigorous study\",\n      \"pmids\": [\"25892239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The tyrosine phosphatase SHP2 directly interacts with CDCP1 via its phosphorylated Y734 and Y743 residues (as shown by point mutants), potentially competing with SFK binding. shRNA-mediated downregulation of SHP2 results in stronger CDCP1 phosphorylation and impaired antibody-mediated CDCP1 internalization.\",\n      \"method\": \"Co-immunoprecipitation, affinity precipitation, CDCP1 point mutants (Y734A, Y743A), SHP2 shRNA knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mutagenesis to define binding residues, single lab\",\n      \"pmids\": [\"25876044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Only the cleaved form of CDCP1 (cCDCP1), not full-length CDCP1, is capable of homodimerization through its ectodomain, and only cCDCP1 induces phosphorylation of PKCδ, ERK1/2, and p38 MAPK and promotes cell migration. A blocking fragment of the cCDCP1 ectodomain (ECC) inhibits dimerization, PKCδ phosphorylation, and TNBC cell migration.\",\n      \"method\": \"Expression of full-length vs. cleaved CDCP1 constructs in HEK 293T, co-immunoprecipitation for dimerization, phosphorylation analysis (Western blot), migration rescue assay in CDCP1-shRNA TNBC lines, ECC blocking fragment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP for dimerization, domain blocking experiment, multiple phosphorylation readouts, and functional rescue assays in a single study\",\n      \"pmids\": [\"26876198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDCP1 drives a 'low-lipid' phenotype in triple-negative breast cancer by interacting with and inhibiting acyl CoA-synthetase ligase (ACSL) activity, reducing acyl-CoA production and increasing fatty acid oxidation (FAO) and oxidative phosphorylation in mitochondria. CDCP1 knockdown increases lipid droplet abundance and reduces migration, rescued by the ACSL inhibitor Triacsin C or ACSL3 co-knockdown.\",\n      \"method\": \"CDCP1 knockdown and rescue experiments, coherent anti-Stokes Raman scattering (CARS) and two-photon excited fluorescence microscopy (lipid droplet imaging), ACSL activity assay, Co-IP (CDCP1 with ACSL), in vivo animal models of TNBC with blocking fragment treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Co-IP with enzymatic activity assay, imaging-based lipid quantification, genetic rescue experiments, and in vivo validation\",\n      \"pmids\": [\"28739932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD318/CDCP1 is a ligand for CD6. Soluble CD318 is chemoattractive to T cells, and CD318 participates in CD6-dependent adhesion of T cells to synovial fibroblasts. CD318 knockout mice are protected in experimental autoimmune encephalomyelitis, phenocopying CD6 KO mice.\",\n      \"method\": \"Identification via mAb 3A11, CD318 knockout mice in EAU model, T cell adhesion assay, T cell chemotaxis assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout phenotype in two disease models, direct binding identification, and functional adhesion/migration assays\",\n      \"pmids\": [\"28760953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of CDCP1 reduces CDK5 kinase activity via a mechanism in which c-SRC phosphorylates CDK5R1/p35 on Y234, creating a binding site for the C2 domain of PKCδ, which in turn phosphorylates CDK5 on T77, causing dissociation of the CDK5R1/CDK5 complex and abolishing CDK5 activity. This loss of CDK5 activity reduces inside-out activation of β1 integrin, impairing cell adhesion and migration.\",\n      \"method\": \"CDCP1 siRNA silencing, phosphorylation mapping (CDK5R1-Y234, CDK5-T77), CDK5 phosphorylation site mutants (T77 and Y234), PKCδ C2 domain binding assay, β1 integrin inside-out activation assay, cell adhesion and migration assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-directed mutagenesis of two phosphorylation sites, domain binding assay, genetic knockdown, and functional rescue in a rigorous mechanistic study\",\n      \"pmids\": [\"29511352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FBXL14 E3 ubiquitin ligase directly interacts with CDCP1 and facilitates its ubiquitination and proteasomal degradation, thereby reducing CDCP1 protein stability. miR-17/20a suppress FBXL14, establishing an upstream regulatory mechanism for CDCP1 protein levels.\",\n      \"method\": \"Co-immunoprecipitation (CDCP1 with FBXL14), ubiquitination assay, proteasome inhibitor experiments, miR-17/20a overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay establishing direct interaction and functional degradation, single lab\",\n      \"pmids\": [\"29973690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDCP1 promotes Wnt signaling in colorectal cancer by facilitating nuclear translocation of β-catenin and E-cadherin. Disruption of CDCP1 reduces nuclear chromatin-associated β-catenin and nuclear E-cadherin, increases sequestration of these proteins at cell membranes, and disrupts regulation of CRC-promoting genes.\",\n      \"method\": \"Cell fractionation, immunoprecipitation, immunofluorescence microscopy, immunohistochemistry, CDCP1 loss-of-function, in vitro and in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, IP, imaging) with functional in vivo validation, single lab\",\n      \"pmids\": [\"31471585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDCP1 CUB domains bind directly to TGF-β1 and BMP4 (real-time protein interaction on BIAcore chip). CDCP1 enhances TGF-β1 signaling (reporter activity and phospho-Smad2 levels) but does not modulate BMP signaling. CDCP1 actions on TGF-β/Smad2 signaling require Smad2 and TGFRI but are independent of Src or PKCδ binding.\",\n      \"method\": \"BIAcore surface plasmon resonance (direct binding to TGF-β1 and BMP4), TGF-β reporter assay, phospho-Smad2 Western blot, siRNA knockdown of Smad2/TGFRI/Src/PKCδ\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biophysical binding assay (SPR) combined with reporter assay and genetic pathway dissection, establishing direct extracellular ligand interaction\",\n      \"pmids\": [\"31302030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDCP1 forms a homophilic complex via its extracellular CUB2 domain; deletion of the extracellular region abolishes complex formation. The homophilic complex activates SFK on the plasma membrane and promotes cancer cell migration. A recombinant CUB2 domain protein (rMBP-CUB2) inhibits CDCP1 homophilic complex formation, SFK activation, and cancer cell migration.\",\n      \"method\": \"Deletion mutants, co-immunoprecipitation for dimerization, recombinant CUB2 domain blocking experiment, SFK phosphorylation assay, cancer cell migration assay\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion, Co-IP, domain-blocking experiment, and functional assays; single lab\",\n      \"pmids\": [\"31524271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"METTL3 and m6A reader YTHDF1 recognize m6A residues on CDCP1 3'-UTR mRNA and promote CDCP1 translation. ALKBH5 demethylase opposes this modification. Inhibition of the METTL3-m6A-CDCP1 axis reduces growth of transformed and bladder cancer cells.\",\n      \"method\": \"m6A profiling, METTL3/ALKBH5 knockdown, YTHDF1 binding assay, CDCP1 translation assay, in vitro and in vivo functional assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epitranscriptomic profiling combined with genetic loss-of-function and binding assays, single lab\",\n      \"pmids\": [\"30796352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Urokinase (uPA) is identified as 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 disease-relevant preclinical in vivo models, and co-expression of uPA and CDCP1 is strongly predictive of poor disease outcome across multiple cancers.\",\n      \"method\": \"Substrate-biased activity-based probe (sbABP) incorporating CDCP1 cleavage motif, protease capture/isolation/identification (MS), in vivo metastasis models\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — novel chemical biology approach (activity-based probe) with protease identification by MS, validated in vivo\",\n      \"pmids\": [\"33859413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDCP1 on dendritic cells (DCs) is required for IL-6 production during Kawasaki disease model induction. CAWS stimulation upregulates CDCP1 on DCs, and CDCP1 KO DCs show significantly reduced IL-6 production associated with impaired Syk-MAPK signaling pathway activation.\",\n      \"method\": \"CDCP1 knockout mice, CAWS-induced Kawasaki disease model, IL-6 ELISA, immunostaining (DC subsets), Syk-MAPK pathway analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular and signaling phenotype, single lab, single disease model\",\n      \"pmids\": [\"34099547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biochemical and biophysical characterization (SPR, structural analysis) revealed that the two cleaved fragments of CDCP1 remain tightly associated with minimal conformational change after proteolysis. Antibodies that selectively bind the proteolytic neoepitope of cleaved CDCP1 (with no detectable binding to uncleaved form) potently target cleaved CDCP1-expressing cancer cells as ADC, Ab-radionuclide conjugate, and bispecific T cell engager.\",\n      \"method\": \"Biochemical characterization, biophysical analysis (SPR), structural characterization, differential phage display to generate cleavage-selective antibodies, syngeneic pancreatic tumor model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural/biophysical characterization combined with rigorous selectivity validation and in vivo functional studies\",\n      \"pmids\": [\"35166238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDCP1 promotes HGF-induced cell migration and invasion by activating SRC kinase; in breast cancer cells, CDCP1 facilitates MET activation by HGF and promotes lamellipodia formation. CDCP1 expression activates small GTPase Rac1 via guanine nucleotide exchange factor ARHGEF7, which co-accumulates with CDCP1, establishing a CDCP1-SRC-ARHGEF7-RAC1 pathway.\",\n      \"method\": \"CDCP1 knockdown and ectopic expression, HGF stimulation assays, Rac1 activation assay, ARHGEF7 knockdown, immunofluorescence (CDCP1/ARHGEF7 colocalization), migration/invasion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic perturbations with GTPase activation assays and colocalization; single lab\",\n      \"pmids\": [\"35085554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDCP1 promotes HGF-induced compensatory renal growth by recruiting Src into lipid rafts to activate STAT3 associated with the HGF receptor Met; activated STAT3 induces expression of matrix metalloproteinases and mitogenic factors. CDCP1 ablation attenuates regenerative Met-STAT3 signaling after unilateral nephrectomy in mice.\",\n      \"method\": \"CDCP1 ablation in canine kidney cells, lipid raft fractionation (Src recruitment), STAT3 phosphorylation analysis (association with Met), MMP and mitogenic factor expression assay, unilateral nephrectomy mouse model\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lipid raft fractionation for Src recruitment, STAT3 pathway analysis, and in vivo nephrectomy model; single lab\",\n      \"pmids\": [\"33574034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDCP1 on RPE cells is upregulated by IFN-γ. CD6 stimulation of RPE cells induces increased barrier permeability, massive stress fiber formation, and focal adhesion disruption reducing tight junctions, facilitating T cell infiltration. This CD6-stimulated barrier disruption is abrogated by CDCP1 knockdown, establishing that CDCP1 mediates CD6-driven RPE cytoskeleton remodeling.\",\n      \"method\": \"CDCP1 knockdown in RPE cells, IFN-γ stimulation, CD6 stimulation, transwell T cell migration assay, RPE monolayer permeability assay, immunostaining for stress fibers and focal adhesions, EAU mouse model (CDCP1 KO)\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with defined cytoskeletal phenotype and functional barrier assay, supported by in vivo KO model; single lab\",\n      \"pmids\": [\"35951427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDCP1 expression is inhibited by the microRNA miR-1, which directly targets the 3'-UTR of CDCP1 mRNA. ADAM9 promotes CDCP1 expression by activating EGFR signaling, which in turn suppresses miR-1 expression, establishing an ADAM9-EGFR-miR-1-CDCP1 regulatory axis.\",\n      \"method\": \"Luciferase reporter assay (miR-1 binding to CDCP1 3'-UTR), ADAM9 knockdown, EGFR signaling analysis, miR-1 inhibitor/mimic experiments, in vivo metastasis/survival assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'-UTR reporter assay combined with genetic epistasis experiments, single lab\",\n      \"pmids\": [\"28537886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDCP1 knockdown in vascular smooth muscle cells (VSMCs) inhibits PDGFRβ endocytosis by promoting PDGFRβ binding to NEDD4 and its ubiquitination, and attenuating PDGFRβ binding to clathrin and Rab5. This leads to reduced AKT signaling and decreased VSMC proliferation and migration.\",\n      \"method\": \"CDCP1 siRNA knockdown, RNA-seq, co-immunoprecipitation (PDGFRβ with NEDD4, clathrin, Rab5), immunofluorescence, CCK8 proliferation assay, wound healing assay, focal carotid stenosis in vivo model\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with multiple binding partners, RNA-seq pathway analysis, functional assays, and in vivo model; single lab\",\n      \"pmids\": [\"40256729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"For CDCP1/Src-dependent cellular transformation, the intact amino- and carboxy-termini of CDCP1 are essential. Mutation of any of the three core intracellular tyrosine residues (Y734, Y743, or Y762) abolishes transformation capacity, and mutation of a palmitoylation motif (C689,690G) strongly reduces it. Src kinase 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, CDCP1 truncation and point mutants (Y734F, Y743F, Y762F, C689/690G), Src SH2 domain mutant\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis (multiple tyrosine and palmitoylation sites, domain deletions) in a rigorous transformation assay\",\n      \"pmids\": [\"23300860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CDCP1 and the tetraspanin CD9 are co-expressed and form a low-level but detectable complex in colon cancer cells, as shown by co-sedimentation in sucrose gradients and co-immunoprecipitation. CDCP1 modulates cell-substratum adhesion and serum-induced chemotaxis in colon cancer cell lines.\",\n      \"method\": \"Co-immunoprecipitation, density gradient centrifugation, siRNA knockdown, Matrigel adhesion assay, xCELLigence chemotaxis assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for CDCP1/CD9 interaction, single lab, no mutagenesis or further mechanistic dissection of the complex\",\n      \"pmids\": [\"25301083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDCP1 is transferred from metastatic prostate cancer cells to osteoclast precursors via extracellular vesicles (EVs) and promotes osteoclastogenesis in the presence of RANKL. Functional siRNA screening of EV cargo identified CDCP1 as the specific inducer of osteoclast formation.\",\n      \"method\": \"EV characterization, functional siRNA screening of EV cargo, osteoclastogenesis assay in presence of RANKL\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional siRNA screen of EV cargo identifying CDCP1, with RANKL-dependent osteoclastogenesis assay; single lab\",\n      \"pmids\": [\"36880252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Glycosylation of CDCP1 at N339 and N386 are identified as critical functional determinants. CDCP1 knockout reduces SRC and JUN phosphorylation (ErbB signaling pathway markers by 5.5-fold and 4.2-fold respectively) and reduces cancer cell migration. CDCP1 is selectively enriched in extracellular vesicles from highly metastatic lung cancer cells.\",\n      \"method\": \"CDCP1 knockout (KO) in lung cancer cells, intact glycopeptide enrichment with site-specific glycoform profiling, Ti4+-IMAC phosphoproteomics, site-specific glycosylation mutagenesis (N339, N386), migration assays, EV/cell co-culture\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — glycosylation mutagenesis and phosphoproteomic analysis identifying downstream signaling changes; single lab study\",\n      \"pmids\": [\"40693605\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDCP1 is a type I transmembrane glycoprotein that acts as a scaffolding receptor and signaling hub: its full-length 135 kDa form is proteolytically cleaved at R368/K369 primarily by urokinase (uPA) and plasmin, generating a membrane-retained 70 kDa fragment that homodimerizes via its CUB2 ectodomain, recruits and activates Src family kinases (phosphorylating Y734, Y743, Y762), and assembles a pro-metastatic complex with β1 integrin and PKCδ to drive FAK/PI3K/Akt survival and migration signaling, while also binding HER2 (via its intracellular domain), interacting extracellularly with TGF-β1/BMP4 as a co-receptor, facilitating MT1-MMP trafficking to invadopodia, modulating fatty acid oxidation through ACSL inhibition, and serving as a CD6 ligand on epithelial/immune cells; its activity is modulated by palmitoylation-dependent proteasomal degradation, FBXL14-mediated ubiquitination, SHP2 phosphatase interaction, and transcriptional/epitranscriptomic regulation by HIF-2α, METTL3-m6A/YTHDF1, BRD4/CBP-p300, and promoter CpG methylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDCP1 is a type I transmembrane glycoprotein that functions as a proteolytically activated scaffolding receptor and signaling hub driving cancer cell survival, migration, invasion, and metastasis [#0, #2, #3]. The full-length 135 kDa protein is cleaved at Arg-368/Lys-369 by serine proteases\\u2014with urokinase (uPA) acting as the master regulator both by cleaving CDCP1 directly and by activating plasmin\\u2014to generate a membrane-retained 70 kDa fragment and a shed ectodomain that remain tightly associated after cleavage [#2, #5, #23, #25]. Only the cleaved fragment homodimerizes through its extracellular CUB2 domain, and this homophilic complex is required to recruit and activate Src family kinases, which phosphorylate CDCP1 on the intracellular tyrosines Y734, Y743, and Y762 [#14, #21, #31]. Phosphorylated Y734 is the critical residue for Src activation and metastatic behavior, and CDCP1 acts as a transmembrane platform that assembles Src and PKC\\u03b4 into membrane microdomains [#1, #3, #4]. Downstream, cleaved CDCP1 complexes with active \\u03b21 integrin to drive FAK and PI3K/Akt survival signaling and suppress PARP1-mediated apoptosis [#5, #6], promotes \\u03b21 integrin inside-out activation through a Src\\u2013PKC\\u03b4\\u2013CDK5 axis [#17], facilitates MT1-MMP trafficking to invadopodia for ECM degradation [#7], and engages receptor tyrosine kinase signaling by binding HER2 through its intracellular domain and potentiating MET/STAT3 and Rac1 responses to HGF [#12, #26, #27]. Beyond canonical signaling, the CUB domains bind TGF-\\u03b21 directly to enhance Smad2 signaling [#20], and CDCP1 reprograms lipid metabolism by inhibiting acyl-CoA synthetase (ACSL) activity to elevate fatty acid oxidation [#15]. CDCP1 abundance is set by multiple converging mechanisms: constitutive palmitoylation-dependent internalization and proteasomal degradation reversed by EGFR activation [#11], FBXL14-mediated ubiquitination [#18], transcriptional induction by HIF-2\\u03b1 and Ras/ERK [#8, #10], and post-transcriptional control by METTL3/YTHDF1 m6A modification and miR-1 [#22, #29]. Independently of its oncogenic role, CDCP1 (CD318) is a ligand for CD6 that mediates T cell adhesion and chemotaxis, and CD6-driven cytoskeletal remodeling, with CDCP1-knockout mice protected in autoimmune disease models [#16, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established CDCP1 as a cell-surface, heavily N-glycosylated transmembrane glycoprotein that is tyrosine phosphorylated by a Src family kinase, defining its basic biochemical identity.\",\n      \"evidence\": \"Immunopurification, anti-phosphotyrosine Western blot, Src inhibitor and deglycosylation studies in tumor cells\",\n      \"pmids\": [\"12660814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the specific SFK or the phosphorylated residues\", \"No functional consequence of phosphorylation established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed CDCP1 acts as a transmembrane scaffold clustering at cell-cell contacts and phosphorylated at Y734 by SFKs to organize Src and PKC\\u03b4 in membrane microdomains, defining its scaffolding role.\",\n      \"evidence\": \"Triton-resistant membrane fractionation and phosphorylation assays in epithelial cells\",\n      \"pmids\": [\"18269919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional/phenotypic consequence of the scaffold not yet tested in vivo\", \"Role of proteolysis not yet linked\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the proteolytic activation mechanism\\u2014serine protease cleavage at R368/K369 generating a membrane-retained 70 kDa fragment that recruits Src and PKC\\u03b4\\u2014establishing CDCP1 as a protease-activated receptor.\",\n      \"evidence\": \"N-terminal sequencing, site-directed mutagenesis, protease inhibitor panel and mass spectrometry\",\n      \"pmids\": [\"20551327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The dominant physiological protease was not pinned down\", \"Downstream survival/migration outputs not yet mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined Y734 as the essential residue for CDCP1-driven SFK activation and metastasis, and showed CDCP1 and FAK-Y861 compete as SFK substrates without forming a trimeric complex, clarifying signaling logic.\",\n      \"evidence\": \"SILAC mass spectrometry, Y734F/Y743F/Y762F mutagenesis, 3D Matrigel and in vivo metastasis assays, SFK inhibitors and Co-IP\",\n      \"pmids\": [\"21220330\", \"21994943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how substrate switching is controlled at endogenous expression levels\", \"Relationship of Y734 signaling to proteolysis still implicit\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the in vivo cleaved-CDCP1 survival and invasion program: plasmin cleavage recruits Src/PKC\\u03b4 to activate Akt and suppress apoptosis, complexes with active \\u03b21 integrin to drive FAK/PI3K, and routes MT1-MMP to invadopodia.\",\n      \"evidence\": \"Cleavage-blocking antibodies, plasminogen-knockout mice, lung retention and spontaneous metastasis models, reciprocal Co-IP, siRNA, and invadopodia/Matrigel assays\",\n      \"pmids\": [\"22179830\", \"23208492\", \"23439492\", \"23300860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish which protease dominates across tissues\", \"Structural basis of the cleaved fragment's activity unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed CDCP1 downstream of hypoxia (HIF-2\\u03b1 induction) and defined antibody-induced clustering as a trigger for Src-dependent phosphorylation, internalization, and proteasomal degradation, linking expression and turnover to function.\",\n      \"evidence\": \"HIF-1\\u03b1/HIF-2\\u03b1 shRNA, hypoxic migration assays, xenografts, antibody-clustering and detergent-resistant membrane fractionation\",\n      \"pmids\": [\"23378636\", \"24055141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HIF-2\\u03b1 promoter occupancy not detailed\", \"Mechanism coupling clustering to degradation incompletely defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved CDCP1 protein homeostasis (constitutive palmitoylation-dependent internalization/degradation reversed by EGFR) and its position downstream of oncogenic Ras/ERK linking Ras to Src signaling and MMP activation.\",\n      \"evidence\": \"Palmitoylation-site mutagenesis, EGF treatment, proteasome inhibitors, live-cell internalization assays, and Ras-mutant lung cancer knockdown with zymography\",\n      \"pmids\": [\"24681947\", \"24939643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of palmitoyltransferase not determined\", \"How EGFR blocks palmitoylation mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Expanded the interactome by showing CDCP1 binds HER2 intracellularly to enhance HER2/c-Src signaling and trastuzumab resistance, and that SHP2 binds phospho-Y734/Y743 to modulate phosphorylation and internalization.\",\n      \"evidence\": \"Reciprocal Co-IP with domain mapping, point mutants (Y734A/Y743A), SHP2 shRNA, functional and in vivo tumor assays\",\n      \"pmids\": [\"25892239\", \"25876044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SHP2 substrate specificity on CDCP1 not fully defined\", \"Interplay between SHP2 dephosphorylation and SFK binding kinetics unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that only the cleaved form homodimerizes via its ectodomain to drive PKC\\u03b4/ERK/p38 phosphorylation and migration, establishing dimerization of the proteolytic fragment as the activation switch.\",\n      \"evidence\": \"Full-length vs cleaved constructs in HEK293T, Co-IP for dimerization, ectodomain blocking fragment, and migration rescue in TNBC\",\n      \"pmids\": [\"26876198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural geometry of the dimer not defined here\", \"Whether dimerization precedes or follows SFK recruitment unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Broadened CDCP1 function into metabolism (ACSL inhibition driving fatty acid oxidation), immune ligand biology (CD6 ligand mediating T cell adhesion/chemotaxis and autoimmune disease), and added miRNA/ADAM9-EGFR regulation of its expression.\",\n      \"evidence\": \"ACSL activity assays, CARS lipid imaging, genetic rescue, CD318/CD6 knockout mice in EAU, adhesion/chemotaxis assays, and miR-1 3'-UTR reporter with ADAM9 epistasis\",\n      \"pmids\": [\"28739932\", \"28760953\", \"28537886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CDCP1-ACSL inhibition undefined\", \"How CD6 engagement signals into CDCP1-expressing cells incompletely mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a CDCP1-driven Src\\u2013PKC\\u03b4\\u2013CDK5 cascade controlling \\u03b21 integrin inside-out activation and adhesion, and added FBXL14/miR-17-20a as a ubiquitin-degradation control of CDCP1 levels.\",\n      \"evidence\": \"siRNA, CDK5R1-Y234 and CDK5-T77 phospho-site mutagenesis, PKC\\u03b4 C2-domain binding, integrin activation/adhesion assays, FBXL14 Co-IP and ubiquitination assays\",\n      \"pmids\": [\"29511352\", \"29973690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of the CDK5 arm not fully tested\", \"FBXL14 recognition determinants on CDCP1 not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established direct extracellular ligand binding (CUB domains bind TGF-\\u03b21/BMP4 with selective enhancement of TGF-\\u03b2/Smad2 signaling), CUB2-mediated homophilic complex formation as the SFK-activating unit, Wnt/\\u03b2-catenin promotion, and m6A translational control.\",\n      \"evidence\": \"BIAcore SPR, TGF-\\u03b2 reporter and phospho-Smad2 assays, CUB2 deletion/blocking experiments, cell fractionation for \\u03b2-catenin, and METTL3/YTHDF1/ALKBH5 m6A profiling\",\n      \"pmids\": [\"31302030\", \"31524271\", \"31471585\", \"30796352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How extracellular ligand binding integrates with proteolytic activation unresolved\", \"Structural detail of CUB-ligand complexes lacking\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified urokinase as the master protease driving CDCP1 cleavage and metastasis, and extended CDCP1 signaling to HGF/MET-STAT3 in renal regeneration and to dendritic cell IL-6/Syk-MAPK in Kawasaki disease.\",\n      \"evidence\": \"Substrate-biased activity-based probe with MS protease identification and in vivo metastasis models; lipid raft fractionation/STAT3 analysis in nephrectomy model; CDCP1 KO mice in CAWS-induced disease\",\n      \"pmids\": [\"33859413\", \"33574034\", \"34099547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of uPA vs plasmin in different tissues not quantified\", \"DC and renal signaling mechanisms only partially dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Structurally characterized the cleaved fragments as remaining tightly associated, enabling cleavage-selective neoepitope antibodies for targeted therapy, and defined HGF-driven CDCP1-SRC-ARHGEF7-RAC1 migration signaling and CD6-mediated RPE barrier disruption.\",\n      \"evidence\": \"SPR/structural analysis and differential phage display antibodies in syngeneic pancreatic model; Rac1 activation and ARHGEF7 colocalization assays; CDCP1 knockdown in RPE with barrier/T-cell migration assays and EAU KO model\",\n      \"pmids\": [\"35166238\", \"35085554\", \"35951427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of full cleaved complex not reported\", \"Therapeutic neoepitope antibody efficacy beyond preclinical models untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined N339/N386 glycosylation as functional determinants of CDCP1-driven SRC/JUN phosphorylation and migration, identified CDCP1 enrichment in metastatic-cell extracellular vesicles, and a CDCP1-dependent PDGFR\\u03b2 endocytosis pathway in vascular smooth muscle.\",\n      \"evidence\": \"Site-specific glycosylation mutagenesis with glycoproteomics/phosphoproteomics and EV profiling in lung cancer; CDCP1 siRNA with PDGFR\\u03b2/NEDD4/clathrin/Rab5 Co-IP and carotid stenosis model\",\n      \"pmids\": [\"40693605\", \"40256729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How specific glycans modulate signaling mechanistically unresolved\", \"Vascular and EV roles validated in single labs only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the multiple inputs\\u2014proteolytic activation, extracellular ligand engagement, glycosylation, and degradation control\\u2014are integrated to dictate which downstream program (integrin, RTK, metabolic, or immune) CDCP1 selects in a given cell context.\",\n      \"evidence\": \"No single study in the corpus reconciles the parallel signaling, metabolic, and immune functions into a unified context-dependent model\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of the full-length or cleaved CDCP1 signaling complex\", \"Context determinants of pathway choice undefined\", \"Physiological (non-cancer) function only partially characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 5, 14, 20, 21]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 6, 12]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [16, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 9, 21]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 6, 12, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 6, 23]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16, 24, 28]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SRC\", \"PRKCD\", \"ITGB1\", \"ERBB2\", \"SHP2\", \"ACSL3\", \"CD6\", \"FBXL14\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}