{"gene":"PCDH7","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1998,"finding":"PCDH7 (BH-Pcdh) was identified as a novel cadherin superfamily member with seven extracellular cadherin-repeat domains (EC1–7), a unique 55-amino-acid insertion in EC2, and three isoforms (a, b, c) with distinct cytoplasmic tails; the gene was localized to human chromosome 4p15.","method":"cDNA cloning, Northern blot, Southern blot, chromosomal localization","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular characterization of protein structure and isoforms by cloning and expression analysis in a single foundational study","pmids":["9615233"],"is_preprint":false},{"year":2011,"finding":"MeCP2 binds to the upstream (promoter) region of PCDH7 in human neuroblastoma SH-SY5Y cells and represses PCDH7 promoter activity in an MBD-domain-dependent manner; MeCP2 knockdown increases PCDH7 expression in SH-SY5Y cells and in Mecp2-null mouse brains.","method":"Chromatin immunoprecipitation (ChIP-on-BAC array), promoter-reporter assay, siRNA knockdown, qRT-PCR in cell lines and mouse brain","journal":"BMC neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal ChIP plus functional promoter assay and in vivo validation, single lab","pmids":["21824415"],"is_preprint":false},{"year":2020,"finding":"PCDH7 directly interacts with and inactivates the protein phosphatase PP1α, thereby maintaining elevated phospho-MLC2 (pMLC2) levels; this enhanced actomyosin contractility at intercellular junctions inhibits homotypic cell-in-cell (hoCIC) structure formation and promotes anchorage-independent tumor growth.","method":"Co-immunoprecipitation (direct interaction with PP1α), overexpression and siRNA knockdown assays, western blot for pMLC2, cell-in-cell formation assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing direct interaction with PP1α plus functional gain/loss-of-function assays with defined molecular readout (pMLC2), single lab","pmids":["32457908"],"is_preprint":false},{"year":2020,"finding":"PCDH7 interacts with the N-terminal domain (NTD) of the GluN1 subunit of NMDA receptors; overexpression of PCDH7 in neurons reduces synaptic NMDA receptor currents and alters dendritic spine morphology, while knockdown produces opposing morphological changes.","method":"Unbiased transmembrane protein screen (~1,500 proteins) using purified GluN1-NTD as bait, primary neuron and brain-slice culture overexpression/knockdown, electrophysiology","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased protein-interaction screen plus functional neuronal assays (electrophysiology and morphology), single lab","pmids":["32616769"],"is_preprint":false},{"year":2018,"finding":"Enforced PCDH7 expression in a Cre-inducible transgenic mouse model significantly accelerates Kras-driven lung tumorigenesis and potentiates MAPK (ERK1/2 phospho-activation); somatic CRISPR/Cas9 inactivation of PCDH7 in Kras;Tp53 (KP) mice reduces lung tumor development, prolongs survival, and diminishes phospho-ERK1/2.","method":"Cre-inducible transgenic gain-of-function mouse model, CRISPR/Cas9 somatic loss-of-function in KP mice, tumor burden quantification, phospho-ERK1/2 western blot","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function in vivo models with defined molecular pathway readout (phospho-ERK), independently reinforced by antibody study (PMID 42234744)","pmids":["30409919"],"is_preprint":false},{"year":2020,"finding":"PCDH7 activates ERK/c-FOS signaling in colon cancer cells; the long non-coding RNA LNAPPCC relieves EZH2-mediated H3K27me3 repression at the PCDH7 promoter to activate PCDH7 expression, and PCDH7 in turn activates LNAPPCC transcription through ERK/c-FOS, forming a positive feedback loop.","method":"ChIP (EZH2 binding, H3K27me3 at PCDH7 promoter), RNA immunoprecipitation, siRNA depletion of PCDH7/LNAPPCC, ERK inhibitor treatment, western blot for phospho-ERK/c-FOS, xenograft models","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating epigenetic regulation of PCDH7 promoter plus pathway-level functional rescue, single lab","pmids":["32330872"],"is_preprint":false},{"year":2022,"finding":"PCDH7 knockdown in colon cancer cells sensitizes them to chemotherapy by inducing ferroptosis, altering autophagy, and suppressing the MEK1/2/ERK/c-FOS signaling axis; MEK1/2/ERK inhibition phenocopies PCDH7 knockdown, and ERK inhibitor abolishes PCDH7 oncogenic effects.","method":"siRNA knockdown and overexpression, MTT/colony formation assays, transwell migration/invasion, western blot (MEK1/2/ERK/c-FOS, PP1α, MLC2, pMLC2), in vivo nude mouse xenograft","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple functional assays and pathway inhibitor rescue, single lab, no direct biochemical interaction confirmation","pmids":["35926236"],"is_preprint":false},{"year":2019,"finding":"The androgen receptor (AR) binds upstream of PCDH7 (identified by ChIP-seq); PCDH7 expression is suppressed by DNMT1-mediated DNA hypermethylation in androgen-independent prostate cancer cells, and treatment with a DNA methyltransferase inhibitor restores PCDH7 expression while reducing cell growth and invasion.","method":"ChIP-seq (AR binding), bisulfite sequencing/bisulfite amplicon sequencing (methylation), DNMT1 overexpression, DNMT inhibitor treatment, CCK-8, transwell, flow cytometry","journal":"Genes & genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus methylation mapping plus functional rescue, single lab","pmids":["31872382"],"is_preprint":false},{"year":2024,"finding":"HIF1A transcriptionally activates PCDH7 in lung adenocarcinoma (confirmed by chromatin immunoprecipitation and dual-luciferase assay); PCDH7 promotes anoikis resistance by increasing triglyceride content and upregulating fatty acid synthesis enzymes FASN and ACC1.","method":"Chromatin immunoprecipitation (HIF1A binding at PCDH7 locus), dual-luciferase reporter assay, overexpression/knockdown, CCK-8, triglyceride content assay, western blot (FASN, ACC1), nude mouse xenograft","journal":"Journal of biochemical and molecular toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus luciferase reporter confirming direct transcriptional regulation, functional fatty acid pathway readout, single lab","pmids":["39425457"],"is_preprint":false},{"year":2025,"finding":"PCDH7 physically interacts with ZEB1 and protects it from TRIM26 E3 ligase-mediated ubiquitination and proteasomal degradation; PCDH7-mediated ZEB1 stabilization maintains E-cadherin repression, promotes EMT, and confers cisplatin resistance in lung adenocarcinoma. PCDH7 depletion restores ZEB1 ubiquitination, upregulates E-cadherin, reverses EMT, and re-sensitizes cells to cisplatin.","method":"Co-immunoprecipitation (PCDH7–ZEB1 interaction), ubiquitination assay, siRNA knockdown, overexpression, western blot (ZEB1, E-cadherin, EMT markers), in vivo xenograft and metastasis model","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing direct PCDH7–ZEB1 interaction plus ubiquitination assay defining mechanism, single lab","pmids":["41271034"],"is_preprint":false},{"year":2023,"finding":"In zebrafish embryos, Pcdh7 is responsible for the differentiation (not proliferation) of neural stem cells/progenitors; Dopey2 and Pcdh7 mutually restrict each other's expression, and loss of Pcdh7 disrupts proper neural cell arrangement in embryonic brains.","method":"Zebrafish CRISPR/morpholino mutant analysis, in situ hybridization, immunostaining of neural markers, genetic epistasis (Dopey2/Pcdh7 double mutants)","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in zebrafish with defined cellular phenotype and epistasis, single lab, ortholog study","pmids":["36936789"],"is_preprint":false},{"year":2025,"finding":"Anti-PCDH7 monoclonal antibodies (including humanized mAb7-IgG1) inhibit MAPK pathway activation downstream of PCDH7 and suppress tumor growth in multiple mutant KRAS-driven models; the humanized antibody exhibits antibody-dependent cellular cytotoxicity (ADCC) and Fc-mediated immune effector killing; a murinized version enhances cytotoxic immune cell infiltration in a syngeneic Kras model.","method":"Anti-PCDH7 mAb development and characterization, in vitro MAPK pathway (phospho-ERK) assays, in vivo syngeneic and xenograft tumor models, ADCC assay, immune cell profiling","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic antibody target validation with multiple in vivo models (syngeneic + xenograft), MAPK pathway readout, and immune effector function assay, builds on replicated MAPK finding","pmids":["42234744"],"is_preprint":false},{"year":2025,"finding":"Pcdh7 homozygous null mice generated by CRISPR deletion show no gross brain morphological defects and normal cortical layer formation, indicating PCDH7 is dispensable for gross murine brain development; however, heterozygous Pcdh7 mice show increased seizure latency in a susceptibility assay.","method":"CRISPR-generated null allele, brain morphology and histology, cortical layer analysis, seizure susceptibility assay","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean CRISPR KO with defined negative morphological phenotype and positive seizure-susceptibility phenotype, single lab","pmids":["40870033"],"is_preprint":false}],"current_model":"PCDH7 is a transmembrane protocadherin that functions as an oncogenic signaling scaffold in multiple cancer contexts: it directly binds PP1α to sustain actomyosin contractility (via pMLC2), interacts with ZEB1 to block its TRIM26-mediated ubiquitination and thereby drive EMT and chemoresistance, activates the MAPK (MEK–ERK–c-FOS) pathway to promote tumor growth, and is transcriptionally regulated by HIF1A (promoting fatty acid synthesis and anoikis resistance) and repressed by MeCP2-dependent promoter methylation; in neurons, PCDH7 interacts with the GluN1-NTD of NMDA receptors to modulate dendritic spine morphology and synaptic currents, and in neural progenitors it promotes differentiation while restraining Dopey2-driven proliferation."},"narrative":{"mechanistic_narrative":"PCDH7 is a member of the cadherin superfamily, encoding a transmembrane protocadherin with seven extracellular cadherin-repeat domains and multiple cytoplasmic-tail isoforms [PMID:9615233], that functions as an oncogenic signaling scaffold across several cancer types and as a modulator of neural cell behavior. In tumors, PCDH7 drives MAPK pathway activation: enforced expression accelerates Kras-driven lung tumorigenesis and potentiates ERK1/2 phosphorylation, whereas its inactivation reduces tumor burden and phospho-ERK [PMID:30409919], and antibody-mediated targeting of PCDH7 blocks MAPK signaling while suppressing KRAS-driven tumor growth [PMID:42234744]. Mechanistically, PCDH7 directly binds and inactivates the phosphatase PP1α to sustain phospho-MLC2 and actomyosin contractility [PMID:32457908], and engages a MEK1/2–ERK–c-FOS axis whose inhibition phenocopies PCDH7 loss and abolishes its oncogenic and chemoresistance effects [PMID:35926236]. PCDH7 also physically interacts with ZEB1, shielding it from TRIM26-mediated ubiquitination to maintain E-cadherin repression, EMT, and cisplatin resistance [PMID:41271034], and promotes anoikis resistance by upregulating fatty acid synthesis enzymes FASN and ACC1 [PMID:39425457]. Its expression is tightly controlled at the chromatin level—activated by HIF1A [PMID:39425457], repressed by MeCP2-dependent promoter binding [PMID:21824415], and silenced by DNA hypermethylation in androgen-independent prostate cancer [PMID:31872382]. In the nervous system, PCDH7 interacts with the GluN1 N-terminal domain of NMDA receptors to modulate synaptic currents and dendritic spine morphology [PMID:32616769] and contributes to neural progenitor differentiation [PMID:36936789], though it is dispensable for gross murine brain development while heterozygous loss alters seizure susceptibility [PMID:40870033].","teleology":[{"year":1998,"claim":"Established the molecular identity of PCDH7 as a distinct protocadherin, defining the domain architecture and isoform diversity that frame all later functional work.","evidence":"cDNA cloning, Northern/Southern blot, and chromosomal localization","pmids":["9615233"],"confidence":"Medium","gaps":["No function assigned at discovery","Tissue-specific roles of the three cytoplasmic isoforms not resolved","No structural model of the EC2 insertion"]},{"year":2011,"claim":"Showed that PCDH7 expression is transcriptionally constrained by MeCP2, linking it to methyl-CpG-dependent gene regulation in neural cells.","evidence":"ChIP-on-BAC, promoter-reporter assay, siRNA knockdown, and qRT-PCR in SH-SY5Y cells and Mecp2-null mouse brain","pmids":["21824415"],"confidence":"Medium","gaps":["Downstream functional consequence of MeCP2 repression not tested","Direct vs indirect repression mechanism not fully separated"]},{"year":2018,"claim":"Demonstrated causally that PCDH7 drives KRAS-mutant lung tumorigenesis through MAPK activation, converting it from a structural protein into an oncogenic signaling node.","evidence":"Cre-inducible gain-of-function and CRISPR/Cas9 loss-of-function mouse models with phospho-ERK readout","pmids":["30409919"],"confidence":"High","gaps":["How a protocadherin couples to MEK/ERK was not biochemically defined","Direct upstream effector not identified"]},{"year":2019,"claim":"Identified epigenetic silencing of PCDH7 by DNMT1-mediated hypermethylation downstream of androgen receptor binding in prostate cancer, indicating context-dependent regulation.","evidence":"ChIP-seq for AR, bisulfite sequencing, DNMT1 overexpression, and DNMT inhibitor rescue","pmids":["31872382"],"confidence":"Medium","gaps":["Tumor-suppressive vs oncogenic role context not reconciled with lung cancer data","Single cell-line system"]},{"year":2020,"claim":"Defined a direct biochemical mechanism: PCDH7 binds and inactivates PP1α to sustain phospho-MLC2 and actomyosin contractility, restraining cell-in-cell formation and enabling anchorage-independent growth.","evidence":"Co-immunoprecipitation, gain/loss-of-function, pMLC2 western blot, and cell-in-cell assays","pmids":["32457908"],"confidence":"Medium","gaps":["Direct interaction not validated by reciprocal/structural approaches","Single lab"]},{"year":2020,"claim":"Revealed a neuronal function distinct from its cancer roles: PCDH7 binds the GluN1-NTD of NMDA receptors to tune synaptic currents and spine morphology.","evidence":"Unbiased ~1,500-protein transmembrane interaction screen with GluN1-NTD bait, neuronal overexpression/knockdown, and electrophysiology","pmids":["32616769"],"confidence":"Medium","gaps":["Whether interaction is direct in vivo not confirmed","Link to behavioral/circuit phenotype not established"]},{"year":2020,"claim":"Placed PCDH7 within an ERK/c-FOS positive feedback loop coupled to lncRNA LNAPPCC and EZH2/H3K27me3 chromatin regulation in colon cancer.","evidence":"ChIP (EZH2, H3K27me3), RNA immunoprecipitation, siRNA depletion, ERK inhibitor, and xenografts","pmids":["32330872"],"confidence":"Medium","gaps":["Molecular link from PCDH7 to ERK activation not biochemically defined","Generality beyond colon cancer untested"]},{"year":2022,"claim":"Connected PCDH7-driven MEK1/2/ERK/c-FOS signaling to chemoresistance via suppression of ferroptosis and modulation of autophagy.","evidence":"Knockdown/overexpression, viability and invasion assays, pathway inhibitor rescue, and xenografts","pmids":["35926236"],"confidence":"Medium","gaps":["No direct biochemical interaction confirming the signaling link","Mechanism of ferroptosis/autophagy coupling not resolved"]},{"year":2023,"claim":"Defined a developmental role: zebrafish Pcdh7 promotes neural progenitor differentiation and mutually restricts Dopey2 to control neural cell arrangement.","evidence":"Zebrafish CRISPR/morpholino mutants, in situ hybridization, immunostaining, and Dopey2/Pcdh7 epistasis","pmids":["36936789"],"confidence":"Medium","gaps":["Mechanism of Pcdh7–Dopey2 mutual repression unknown","Conservation to mammalian neurogenesis not demonstrated"]},{"year":2024,"claim":"Showed PCDH7 is a direct HIF1A target that drives anoikis resistance through enhanced fatty acid synthesis, linking it to tumor metabolic reprogramming.","evidence":"ChIP and dual-luciferase reporter for HIF1A, overexpression/knockdown, triglyceride and FASN/ACC1 assays, and xenografts","pmids":["39425457"],"confidence":"Medium","gaps":["How PCDH7 mechanistically upregulates FASN/ACC1 not defined","Single tumor type"]},{"year":2025,"claim":"Established that PCDH7 stabilizes ZEB1 by blocking TRIM26-mediated ubiquitination, providing a direct mechanism for PCDH7-driven EMT and cisplatin resistance.","evidence":"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, EMT-marker westerns, and in vivo metastasis models","pmids":["41271034"],"confidence":"Medium","gaps":["Structural basis of PCDH7–ZEB1 interaction unknown","How a transmembrane protein shields a nuclear factor not spatially resolved"]},{"year":2025,"claim":"Validated PCDH7 as an actionable surface target: anti-PCDH7 antibodies block MAPK activation and recruit Fc-mediated immune killing against KRAS-driven tumors.","evidence":"Humanized/murinized mAb development, phospho-ERK assays, syngeneic and xenograft models, ADCC, and immune profiling","pmids":["42234744"],"confidence":"High","gaps":["Epitope and ligand-blocking mechanism not fully mapped","Combination/biomarker context for clinical use undefined"]},{"year":2025,"claim":"Clarified the in vivo requirement for PCDH7 in mammalian brain: dispensable for gross development but modulating seizure susceptibility, indicating subtle neural roles.","evidence":"CRISPR-generated null mice, brain histology, cortical layer analysis, and seizure susceptibility assay","pmids":["40870033"],"confidence":"Medium","gaps":["Cellular basis of altered seizure latency not identified","Possible redundancy with other protocadherins untested"]},{"year":null,"claim":"The biochemical link between PCDH7, a transmembrane protocadherin, and intracellular MEK/ERK activation remains undefined, as does the reconciliation of its tumor-suppressive (silenced in prostate cancer) versus oncogenic roles across tissues.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified proximal effector coupling PCDH7 to MAPK","Context-dependent tumor-suppressor vs oncogene duality unresolved","No structural model of cytoplasmic-tail signaling interfaces"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,9,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10]}],"complexes":[],"partners":["PPP1CA","ZEB1","TRIM26","GRIN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60245","full_name":"Protocadherin-7","aliases":["Brain-heart protocadherin","BH-Pcdh"],"length_aa":1069,"mass_kda":116.1,"function":"","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O60245/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PCDH7","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PCDH7","total_profiled":1310},"omim":[{"mim_id":"610841","title":"STROMAL INTERACTION MOLECULE 2; STIM2","url":"https://www.omim.org/entry/610841"},{"mim_id":"607434","title":"GTP-BINDING PROTEIN 2; GTPBP2","url":"https://www.omim.org/entry/607434"},{"mim_id":"603581","title":"PROTOCADHERIN 9; PCDH9","url":"https://www.omim.org/entry/603581"},{"mim_id":"602988","title":"PROTOCADHERIN 7; PCDH7","url":"https://www.omim.org/entry/602988"},{"mim_id":"300246","title":"PROTOCADHERIN 11, X-LINKED; PCDH11X","url":"https://www.omim.org/entry/300246"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"},{"location":"Cell Junctions","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":48.2}],"url":"https://www.proteinatlas.org/search/PCDH7"},"hgnc":{"alias_symbol":["BH-Pcdh","PPP1R120"],"prev_symbol":[]},"alphafold":{"accession":"O60245","domains":[{"cath_id":"2.60.40.60","chopping":"35-135","consensus_level":"high","plddt":82.7127,"start":35,"end":135},{"cath_id":"2.60.40.60","chopping":"148-186_243-300","consensus_level":"high","plddt":87.7107,"start":148,"end":300},{"cath_id":"2.60.40.60","chopping":"308-407","consensus_level":"high","plddt":92.3967,"start":308,"end":407},{"cath_id":"2.60.40.60","chopping":"440-449_457-527","consensus_level":"high","plddt":88.917,"start":440,"end":527},{"cath_id":"2.60.40.60","chopping":"535-631","consensus_level":"medium","plddt":93.5746,"start":535,"end":631},{"cath_id":"2.60.40.60","chopping":"639-734","consensus_level":"medium","plddt":91.1945,"start":639,"end":734},{"cath_id":"2.60.40.60","chopping":"742-875","consensus_level":"high","plddt":88.8695,"start":742,"end":875}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60245","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60245-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60245-F1-predicted_aligned_error_v6.png","plddt_mean":75.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PCDH7","jax_strain_url":"https://www.jax.org/strain/search?query=PCDH7"},"sequence":{"accession":"O60245","fasta_url":"https://rest.uniprot.org/uniprotkb/O60245.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60245/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60245"}},"corpus_meta":[{"pmid":"9615233","id":"PMC_9615233","title":"Cloning, expression analysis, and chromosomal localization of BH-protocadherin (PCDH7), a novel member of the cadherin superfamily.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9615233","citation_count":71,"is_preprint":false},{"pmid":"21824415","id":"PMC_21824415","title":"The protocadherins, PCDHB1 and PCDH7, are regulated by MeCP2 in neuronal cells and brain tissues: implication for pathogenesis of Rett syndrome.","date":"2011","source":"BMC neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21824415","citation_count":57,"is_preprint":false},{"pmid":"29511597","id":"PMC_29511597","title":"AQP8 inhibits colorectal cancer growth and metastasis by down-regulating PI3K/AKT signaling and PCDH7 expression.","date":"2018","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29511597","citation_count":42,"is_preprint":false},{"pmid":"32457908","id":"PMC_32457908","title":"PCDH7 Inhibits the Formation of Homotypic Cell-in-Cell Structure.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/32457908","citation_count":35,"is_preprint":false},{"pmid":"23369722","id":"PMC_23369722","title":"Hypermethylation of the polycomb group target gene PCDH7 in bladder tumors from patients of all ages.","date":"2013","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/23369722","citation_count":26,"is_preprint":false},{"pmid":"32616769","id":"PMC_32616769","title":"PCDH7 interacts with GluN1 and regulates dendritic spine morphology and synaptic function.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32616769","citation_count":25,"is_preprint":false},{"pmid":"30409919","id":"PMC_30409919","title":"Modulation of Mutant Kras -Driven Lung Tumorigenesis In Vivo by Gain or Loss of PCDH7 Function.","date":"2018","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/30409919","citation_count":24,"is_preprint":false},{"pmid":"35280687","id":"PMC_35280687","title":"Circular RNA circDVL1 inhibits clear cell renal cell carcinoma progression through the miR-412-3p/PCDH7 axis.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35280687","citation_count":18,"is_preprint":false},{"pmid":"35926236","id":"PMC_35926236","title":"PCDH7 knockdown potentiates colon cancer cells to chemotherapy via inducing ferroptosis and changes in autophagy through restraining MEK1/2/ERK/c-Fos axis.","date":"2022","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/35926236","citation_count":17,"is_preprint":false},{"pmid":"34012292","id":"PMC_34012292","title":"The Clinical Significance and Biological Function of PCDH7 in Cervical Cancer.","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/34012292","citation_count":13,"is_preprint":false},{"pmid":"37476411","id":"PMC_37476411","title":"PCDH7 as the key gene related to the co-occurrence of sarcopenia and osteoporosis.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37476411","citation_count":10,"is_preprint":false},{"pmid":"37538171","id":"PMC_37538171","title":"Integrative analysis illustrates the role of PCDH7 in lung cancer development, cisplatin resistance, and immunotherapy resistance: an underlying target.","date":"2023","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37538171","citation_count":10,"is_preprint":false},{"pmid":"32330872","id":"PMC_32330872","title":"Recurrence-Associated Long Non-coding RNA LNAPPCC Facilitates Colon Cancer Progression via Forming a Positive Feedback Loop with PCDH7.","date":"2020","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/32330872","citation_count":9,"is_preprint":false},{"pmid":"39425457","id":"PMC_39425457","title":"HIF1A/PCDH7 axis mediates fatty acid synthesis and metabolism to inhibit lung adenocarcinoma anoikis.","date":"2024","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/39425457","citation_count":8,"is_preprint":false},{"pmid":"38145434","id":"PMC_38145434","title":"Concurrent glomerular PCDH7 deposits in PLA2R-associated membranous nephropathy.","date":"2023","source":"CEN case reports","url":"https://pubmed.ncbi.nlm.nih.gov/38145434","citation_count":6,"is_preprint":false},{"pmid":"31872382","id":"PMC_31872382","title":"Effect of aberrantly methylated androgen receptor target gene PCDH7 on the development of androgen-independent prostate cancer cells.","date":"2019","source":"Genes & genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31872382","citation_count":4,"is_preprint":false},{"pmid":"36936789","id":"PMC_36936789","title":"Dopey2 and Pcdh7 orchestrate the development of embryonic neural stem cells/ progenitors in zebrafish.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/36936789","citation_count":3,"is_preprint":false},{"pmid":"39856454","id":"PMC_39856454","title":"Identification of cold tumor induction-related markers in pancreatic cancer and the clinical implication of PCDH7.","date":"2025","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39856454","citation_count":2,"is_preprint":false},{"pmid":"41271034","id":"PMC_41271034","title":"PCDH7 promotes EMT and chemoresistance by stabilizing ZEB1 via inhibition of TRIM26-mediated ubiquitination in lung adenocarcinoma.","date":"2025","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41271034","citation_count":0,"is_preprint":false},{"pmid":"40870033","id":"PMC_40870033","title":"Epilepsy Associated Gene, Pcdh7, Is Dispensable for Brain Development in Mice.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/40870033","citation_count":0,"is_preprint":false},{"pmid":"42234744","id":"PMC_42234744","title":"Monoclonal antibodies targeting PCDH7 inhibit tumor growth and enhance immune responses in KRAS-mutant non-small cell lung cancer.","date":"2026","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/42234744","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.29.24318222","title":"Genetic Evidence for Soluble VEGFR2 as a Protective Factor Against Macular Pucker","date":"2024-11-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.29.24318222","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13236,"output_tokens":3599,"usd":0.046846,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11218,"output_tokens":4162,"usd":0.08007,"stage2_stop_reason":"end_turn"},"total_usd":0.126916,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"PCDH7 (BH-Pcdh) was identified as a novel cadherin superfamily member with seven extracellular cadherin-repeat domains (EC1–7), a unique 55-amino-acid insertion in EC2, and three isoforms (a, b, c) with distinct cytoplasmic tails; the gene was localized to human chromosome 4p15.\",\n      \"method\": \"cDNA cloning, Northern blot, Southern blot, chromosomal localization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular characterization of protein structure and isoforms by cloning and expression analysis in a single foundational study\",\n      \"pmids\": [\"9615233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MeCP2 binds to the upstream (promoter) region of PCDH7 in human neuroblastoma SH-SY5Y cells and represses PCDH7 promoter activity in an MBD-domain-dependent manner; MeCP2 knockdown increases PCDH7 expression in SH-SY5Y cells and in Mecp2-null mouse brains.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP-on-BAC array), promoter-reporter assay, siRNA knockdown, qRT-PCR in cell lines and mouse brain\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal ChIP plus functional promoter assay and in vivo validation, single lab\",\n      \"pmids\": [\"21824415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PCDH7 directly interacts with and inactivates the protein phosphatase PP1α, thereby maintaining elevated phospho-MLC2 (pMLC2) levels; this enhanced actomyosin contractility at intercellular junctions inhibits homotypic cell-in-cell (hoCIC) structure formation and promotes anchorage-independent tumor growth.\",\n      \"method\": \"Co-immunoprecipitation (direct interaction with PP1α), overexpression and siRNA knockdown assays, western blot for pMLC2, cell-in-cell formation assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing direct interaction with PP1α plus functional gain/loss-of-function assays with defined molecular readout (pMLC2), single lab\",\n      \"pmids\": [\"32457908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PCDH7 interacts with the N-terminal domain (NTD) of the GluN1 subunit of NMDA receptors; overexpression of PCDH7 in neurons reduces synaptic NMDA receptor currents and alters dendritic spine morphology, while knockdown produces opposing morphological changes.\",\n      \"method\": \"Unbiased transmembrane protein screen (~1,500 proteins) using purified GluN1-NTD as bait, primary neuron and brain-slice culture overexpression/knockdown, electrophysiology\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased protein-interaction screen plus functional neuronal assays (electrophysiology and morphology), single lab\",\n      \"pmids\": [\"32616769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Enforced PCDH7 expression in a Cre-inducible transgenic mouse model significantly accelerates Kras-driven lung tumorigenesis and potentiates MAPK (ERK1/2 phospho-activation); somatic CRISPR/Cas9 inactivation of PCDH7 in Kras;Tp53 (KP) mice reduces lung tumor development, prolongs survival, and diminishes phospho-ERK1/2.\",\n      \"method\": \"Cre-inducible transgenic gain-of-function mouse model, CRISPR/Cas9 somatic loss-of-function in KP mice, tumor burden quantification, phospho-ERK1/2 western blot\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function in vivo models with defined molecular pathway readout (phospho-ERK), independently reinforced by antibody study (PMID 42234744)\",\n      \"pmids\": [\"30409919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PCDH7 activates ERK/c-FOS signaling in colon cancer cells; the long non-coding RNA LNAPPCC relieves EZH2-mediated H3K27me3 repression at the PCDH7 promoter to activate PCDH7 expression, and PCDH7 in turn activates LNAPPCC transcription through ERK/c-FOS, forming a positive feedback loop.\",\n      \"method\": \"ChIP (EZH2 binding, H3K27me3 at PCDH7 promoter), RNA immunoprecipitation, siRNA depletion of PCDH7/LNAPPCC, ERK inhibitor treatment, western blot for phospho-ERK/c-FOS, xenograft models\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating epigenetic regulation of PCDH7 promoter plus pathway-level functional rescue, single lab\",\n      \"pmids\": [\"32330872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PCDH7 knockdown in colon cancer cells sensitizes them to chemotherapy by inducing ferroptosis, altering autophagy, and suppressing the MEK1/2/ERK/c-FOS signaling axis; MEK1/2/ERK inhibition phenocopies PCDH7 knockdown, and ERK inhibitor abolishes PCDH7 oncogenic effects.\",\n      \"method\": \"siRNA knockdown and overexpression, MTT/colony formation assays, transwell migration/invasion, western blot (MEK1/2/ERK/c-FOS, PP1α, MLC2, pMLC2), in vivo nude mouse xenograft\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple functional assays and pathway inhibitor rescue, single lab, no direct biochemical interaction confirmation\",\n      \"pmids\": [\"35926236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The androgen receptor (AR) binds upstream of PCDH7 (identified by ChIP-seq); PCDH7 expression is suppressed by DNMT1-mediated DNA hypermethylation in androgen-independent prostate cancer cells, and treatment with a DNA methyltransferase inhibitor restores PCDH7 expression while reducing cell growth and invasion.\",\n      \"method\": \"ChIP-seq (AR binding), bisulfite sequencing/bisulfite amplicon sequencing (methylation), DNMT1 overexpression, DNMT inhibitor treatment, CCK-8, transwell, flow cytometry\",\n      \"journal\": \"Genes & genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus methylation mapping plus functional rescue, single lab\",\n      \"pmids\": [\"31872382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HIF1A transcriptionally activates PCDH7 in lung adenocarcinoma (confirmed by chromatin immunoprecipitation and dual-luciferase assay); PCDH7 promotes anoikis resistance by increasing triglyceride content and upregulating fatty acid synthesis enzymes FASN and ACC1.\",\n      \"method\": \"Chromatin immunoprecipitation (HIF1A binding at PCDH7 locus), dual-luciferase reporter assay, overexpression/knockdown, CCK-8, triglyceride content assay, western blot (FASN, ACC1), nude mouse xenograft\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus luciferase reporter confirming direct transcriptional regulation, functional fatty acid pathway readout, single lab\",\n      \"pmids\": [\"39425457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PCDH7 physically interacts with ZEB1 and protects it from TRIM26 E3 ligase-mediated ubiquitination and proteasomal degradation; PCDH7-mediated ZEB1 stabilization maintains E-cadherin repression, promotes EMT, and confers cisplatin resistance in lung adenocarcinoma. PCDH7 depletion restores ZEB1 ubiquitination, upregulates E-cadherin, reverses EMT, and re-sensitizes cells to cisplatin.\",\n      \"method\": \"Co-immunoprecipitation (PCDH7–ZEB1 interaction), ubiquitination assay, siRNA knockdown, overexpression, western blot (ZEB1, E-cadherin, EMT markers), in vivo xenograft and metastasis model\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing direct PCDH7–ZEB1 interaction plus ubiquitination assay defining mechanism, single lab\",\n      \"pmids\": [\"41271034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In zebrafish embryos, Pcdh7 is responsible for the differentiation (not proliferation) of neural stem cells/progenitors; Dopey2 and Pcdh7 mutually restrict each other's expression, and loss of Pcdh7 disrupts proper neural cell arrangement in embryonic brains.\",\n      \"method\": \"Zebrafish CRISPR/morpholino mutant analysis, in situ hybridization, immunostaining of neural markers, genetic epistasis (Dopey2/Pcdh7 double mutants)\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in zebrafish with defined cellular phenotype and epistasis, single lab, ortholog study\",\n      \"pmids\": [\"36936789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Anti-PCDH7 monoclonal antibodies (including humanized mAb7-IgG1) inhibit MAPK pathway activation downstream of PCDH7 and suppress tumor growth in multiple mutant KRAS-driven models; the humanized antibody exhibits antibody-dependent cellular cytotoxicity (ADCC) and Fc-mediated immune effector killing; a murinized version enhances cytotoxic immune cell infiltration in a syngeneic Kras model.\",\n      \"method\": \"Anti-PCDH7 mAb development and characterization, in vitro MAPK pathway (phospho-ERK) assays, in vivo syngeneic and xenograft tumor models, ADCC assay, immune cell profiling\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic antibody target validation with multiple in vivo models (syngeneic + xenograft), MAPK pathway readout, and immune effector function assay, builds on replicated MAPK finding\",\n      \"pmids\": [\"42234744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Pcdh7 homozygous null mice generated by CRISPR deletion show no gross brain morphological defects and normal cortical layer formation, indicating PCDH7 is dispensable for gross murine brain development; however, heterozygous Pcdh7 mice show increased seizure latency in a susceptibility assay.\",\n      \"method\": \"CRISPR-generated null allele, brain morphology and histology, cortical layer analysis, seizure susceptibility assay\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean CRISPR KO with defined negative morphological phenotype and positive seizure-susceptibility phenotype, single lab\",\n      \"pmids\": [\"40870033\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PCDH7 is a transmembrane protocadherin that functions as an oncogenic signaling scaffold in multiple cancer contexts: it directly binds PP1α to sustain actomyosin contractility (via pMLC2), interacts with ZEB1 to block its TRIM26-mediated ubiquitination and thereby drive EMT and chemoresistance, activates the MAPK (MEK–ERK–c-FOS) pathway to promote tumor growth, and is transcriptionally regulated by HIF1A (promoting fatty acid synthesis and anoikis resistance) and repressed by MeCP2-dependent promoter methylation; in neurons, PCDH7 interacts with the GluN1-NTD of NMDA receptors to modulate dendritic spine morphology and synaptic currents, and in neural progenitors it promotes differentiation while restraining Dopey2-driven proliferation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PCDH7 is a member of the cadherin superfamily, encoding a transmembrane protocadherin with seven extracellular cadherin-repeat domains and multiple cytoplasmic-tail isoforms [#0], that functions as an oncogenic signaling scaffold across several cancer types and as a modulator of neural cell behavior. In tumors, PCDH7 drives MAPK pathway activation: enforced expression accelerates Kras-driven lung tumorigenesis and potentiates ERK1/2 phosphorylation, whereas its inactivation reduces tumor burden and phospho-ERK [#4], and antibody-mediated targeting of PCDH7 blocks MAPK signaling while suppressing KRAS-driven tumor growth [#11]. Mechanistically, PCDH7 directly binds and inactivates the phosphatase PP1\\u03b1 to sustain phospho-MLC2 and actomyosin contractility [#2], and engages a MEK1/2\\u2013ERK\\u2013c-FOS axis whose inhibition phenocopies PCDH7 loss and abolishes its oncogenic and chemoresistance effects [#6]. PCDH7 also physically interacts with ZEB1, shielding it from TRIM26-mediated ubiquitination to maintain E-cadherin repression, EMT, and cisplatin resistance [#9], and promotes anoikis resistance by upregulating fatty acid synthesis enzymes FASN and ACC1 [#8]. Its expression is tightly controlled at the chromatin level\\u2014activated by HIF1A [#8], repressed by MeCP2-dependent promoter binding [#1], and silenced by DNA hypermethylation in androgen-independent prostate cancer [#7]. In the nervous system, PCDH7 interacts with the GluN1 N-terminal domain of NMDA receptors to modulate synaptic currents and dendritic spine morphology [#3] and contributes to neural progenitor differentiation [#10], though it is dispensable for gross murine brain development while heterozygous loss alters seizure susceptibility [#12].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the molecular identity of PCDH7 as a distinct protocadherin, defining the domain architecture and isoform diversity that frame all later functional work.\",\n      \"evidence\": \"cDNA cloning, Northern/Southern blot, and chromosomal localization\",\n      \"pmids\": [\"9615233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No function assigned at discovery\", \"Tissue-specific roles of the three cytoplasmic isoforms not resolved\", \"No structural model of the EC2 insertion\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed that PCDH7 expression is transcriptionally constrained by MeCP2, linking it to methyl-CpG-dependent gene regulation in neural cells.\",\n      \"evidence\": \"ChIP-on-BAC, promoter-reporter assay, siRNA knockdown, and qRT-PCR in SH-SY5Y cells and Mecp2-null mouse brain\",\n      \"pmids\": [\"21824415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream functional consequence of MeCP2 repression not tested\", \"Direct vs indirect repression mechanism not fully separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated causally that PCDH7 drives KRAS-mutant lung tumorigenesis through MAPK activation, converting it from a structural protein into an oncogenic signaling node.\",\n      \"evidence\": \"Cre-inducible gain-of-function and CRISPR/Cas9 loss-of-function mouse models with phospho-ERK readout\",\n      \"pmids\": [\"30409919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a protocadherin couples to MEK/ERK was not biochemically defined\", \"Direct upstream effector not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified epigenetic silencing of PCDH7 by DNMT1-mediated hypermethylation downstream of androgen receptor binding in prostate cancer, indicating context-dependent regulation.\",\n      \"evidence\": \"ChIP-seq for AR, bisulfite sequencing, DNMT1 overexpression, and DNMT inhibitor rescue\",\n      \"pmids\": [\"31872382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tumor-suppressive vs oncogenic role context not reconciled with lung cancer data\", \"Single cell-line system\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a direct biochemical mechanism: PCDH7 binds and inactivates PP1\\u03b1 to sustain phospho-MLC2 and actomyosin contractility, restraining cell-in-cell formation and enabling anchorage-independent growth.\",\n      \"evidence\": \"Co-immunoprecipitation, gain/loss-of-function, pMLC2 western blot, and cell-in-cell assays\",\n      \"pmids\": [\"32457908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction not validated by reciprocal/structural approaches\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a neuronal function distinct from its cancer roles: PCDH7 binds the GluN1-NTD of NMDA receptors to tune synaptic currents and spine morphology.\",\n      \"evidence\": \"Unbiased ~1,500-protein transmembrane interaction screen with GluN1-NTD bait, neuronal overexpression/knockdown, and electrophysiology\",\n      \"pmids\": [\"32616769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether interaction is direct in vivo not confirmed\", \"Link to behavioral/circuit phenotype not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed PCDH7 within an ERK/c-FOS positive feedback loop coupled to lncRNA LNAPPCC and EZH2/H3K27me3 chromatin regulation in colon cancer.\",\n      \"evidence\": \"ChIP (EZH2, H3K27me3), RNA immunoprecipitation, siRNA depletion, ERK inhibitor, and xenografts\",\n      \"pmids\": [\"32330872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link from PCDH7 to ERK activation not biochemically defined\", \"Generality beyond colon cancer untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected PCDH7-driven MEK1/2/ERK/c-FOS signaling to chemoresistance via suppression of ferroptosis and modulation of autophagy.\",\n      \"evidence\": \"Knockdown/overexpression, viability and invasion assays, pathway inhibitor rescue, and xenografts\",\n      \"pmids\": [\"35926236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical interaction confirming the signaling link\", \"Mechanism of ferroptosis/autophagy coupling not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a developmental role: zebrafish Pcdh7 promotes neural progenitor differentiation and mutually restricts Dopey2 to control neural cell arrangement.\",\n      \"evidence\": \"Zebrafish CRISPR/morpholino mutants, in situ hybridization, immunostaining, and Dopey2/Pcdh7 epistasis\",\n      \"pmids\": [\"36936789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Pcdh7\\u2013Dopey2 mutual repression unknown\", \"Conservation to mammalian neurogenesis not demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed PCDH7 is a direct HIF1A target that drives anoikis resistance through enhanced fatty acid synthesis, linking it to tumor metabolic reprogramming.\",\n      \"evidence\": \"ChIP and dual-luciferase reporter for HIF1A, overexpression/knockdown, triglyceride and FASN/ACC1 assays, and xenografts\",\n      \"pmids\": [\"39425457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PCDH7 mechanistically upregulates FASN/ACC1 not defined\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established that PCDH7 stabilizes ZEB1 by blocking TRIM26-mediated ubiquitination, providing a direct mechanism for PCDH7-driven EMT and cisplatin resistance.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, EMT-marker westerns, and in vivo metastasis models\",\n      \"pmids\": [\"41271034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of PCDH7\\u2013ZEB1 interaction unknown\", \"How a transmembrane protein shields a nuclear factor not spatially resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Validated PCDH7 as an actionable surface target: anti-PCDH7 antibodies block MAPK activation and recruit Fc-mediated immune killing against KRAS-driven tumors.\",\n      \"evidence\": \"Humanized/murinized mAb development, phospho-ERK assays, syngeneic and xenograft models, ADCC, and immune profiling\",\n      \"pmids\": [\"42234744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Epitope and ligand-blocking mechanism not fully mapped\", \"Combination/biomarker context for clinical use undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Clarified the in vivo requirement for PCDH7 in mammalian brain: dispensable for gross development but modulating seizure susceptibility, indicating subtle neural roles.\",\n      \"evidence\": \"CRISPR-generated null mice, brain histology, cortical layer analysis, and seizure susceptibility assay\",\n      \"pmids\": [\"40870033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular basis of altered seizure latency not identified\", \"Possible redundancy with other protocadherins untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical link between PCDH7, a transmembrane protocadherin, and intracellular MEK/ERK activation remains undefined, as does the reconciliation of its tumor-suppressive (silenced in prostate cancer) versus oncogenic roles across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified proximal effector coupling PCDH7 to MAPK\", \"Context-dependent tumor-suppressor vs oncogene duality unresolved\", \"No structural model of cytoplasmic-tail signaling interfaces\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 9, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PPP1CA\", \"ZEB1\", \"TRIM26\", \"GRIN1\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}