{"gene":"PCDH7","run_date":"2026-04-29T11:37:58","timeline":{"discoveries":[{"year":1998,"finding":"PCDH7 (BH-protocadherin) was identified as a novel cadherin superfamily member with an extracellular domain consisting of seven cadherin motif repeats (EC1–EC7), with EC2 containing a unique 55-amino-acid insertion. Three isoforms (a, b, c) were identified with different cytoplasmic tails, and isoform c has a 47-amino-acid deletion in the EC2-3 region. The gene is predominantly expressed in brain and heart.","method":"cDNA cloning, Northern blot, Southern blot, chromosomal localization","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct cloning and structural characterization, single lab","pmids":["9615233"],"is_preprint":false},{"year":2011,"finding":"MeCP2 directly binds to the upstream regulatory region of PCDH7 in neuronal cells and represses PCDH7 promoter activity in a methyl-CpG-binding domain (MBD)-dependent manner; MBD-deleted MeCP2 fails to repress PCDH7. PCDH7 expression is upregulated upon MeCP2 reduction (siRNA) in SH-SY5Y cells and in brains of Mecp2-null mice.","method":"ChIP-on-BAC array, chromatin immunoprecipitation (ChIP), promoter-reporter assay, siRNA knockdown, Mecp2-null mouse brain analysis","journal":"BMC neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (ChIP, promoter assay, genetic null model)","pmids":["21824415"],"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 pathway activation (phospho-ERK1/2). CRISPR/Cas9-mediated somatic inactivation of PCDH7 in KrasG12D;Tp53 mice significantly reduced lung tumor development, prolonged survival, and diminished phospho-ERK1/2 activation.","method":"Transgenic gain-of-function mouse model, CRISPR/Cas9 somatic loss-of-function in vivo, immunohistochemistry for p-ERK1/2","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 — in vivo gain and loss of function with defined molecular readout (pERK), replicated in two genetic models","pmids":["30409919"],"is_preprint":false},{"year":2020,"finding":"PCDH7 directly interacts with PP1α (protein phosphatase 1α) and inactivates it, thereby preventing PP1α-mediated dephosphorylation of pMLC2 (phospho-myosin light chain 2). This increases pMLC2 levels, enhances actomyosin contractility at the intercellular region, and inhibits homotypic cell-in-cell (hoCIC) structure formation.","method":"Co-immunoprecipitation, overexpression/knockdown functional assays, western blot for pMLC2, actomyosin contractility measurements, anchorage-independent growth assay","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct protein interaction (Co-IP) with functional readout, 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, as identified by an unbiased screen of ~1,500 transmembrane proteins using purified GluN1-NTD as bait. Overexpression of PCDH7 in primary neurons and brain slice cultures increases dendritic spine density/morphology changes and reduces synaptic NMDA receptor currents, while knockdown induces opposing morphological changes.","method":"Unbiased transmembrane protein interaction screen with purified GluN1-NTD bait, overexpression and knockdown in primary neurons and brain slice cultures, electrophysiology (synaptic NMDA currents), morphological analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — unbiased screen plus functional validation in neurons, single lab","pmids":["32616769"],"is_preprint":false},{"year":2020,"finding":"PCDH7 activates ERK/c-FOS signaling in colon cancer cells; increased c-FOS binds the LNAPPCC lncRNA promoter and activates LNAPPCC expression, which in turn represses EZH2 binding to the PCDH7 promoter (reducing H3K27me3) to upregulate PCDH7, forming a positive feedback loop.","method":"Luciferase reporter assay, ChIP for EZH2 and H3K27me3, co-immunoprecipitation, RNA pulldown, ERK inhibitor treatment, siRNA knockdown, xenograft and liver metastasis models","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple biochemical and cellular methods, single lab","pmids":["32330872"],"is_preprint":false},{"year":2019,"finding":"The androgen receptor (AR) directly targets the PCDH7 gene locus (AR enrichment detected by ChIP-seq in androgen-independent prostate cancer cells). PCDH7 expression is silenced by DNMT1-mediated promoter hypermethylation in AIPC cells; DNMT1 overexpression reduces PCDH7 mRNA and protein, while DNA methyltransferase inhibitor restores PCDH7 expression.","method":"ChIP-seq for AR binding, bisulfite sequencing/BSAS for methylation, DNMT1 overexpression, DNA methyltransferase inhibitor treatment, RT-PCR, western blot","journal":"Genes & genomics","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq plus methylation analysis with multiple orthogonal methods, single lab","pmids":["31872382"],"is_preprint":false},{"year":2022,"finding":"PCDH7 promotes activation of the MEK1/2/ERK/c-FOS signaling axis in colon cancer; PCDH7 knockdown represses this pathway and sensitizes colon cancer cells to chemotherapy by inducing ferroptosis and altering autophagy. PCDH7 also regulates PP1α and pMLC2 levels to modulate hoCIC structure formation in colon cancer.","method":"siRNA knockdown, MEK inhibitor treatment, western blot, MTT and colony formation assays, in vivo nude mouse xenograft, ferroptosis and autophagy assays","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple in vitro and in vivo methods with pathway readouts, single lab","pmids":["35926236"],"is_preprint":false},{"year":2023,"finding":"In zebrafish, Pcdh7 is required for the differentiation (but not proliferation) of neural stem cells/progenitors during embryonic neurogenesis. Dopey2 and Pcdh7 mutually restrict each other's expression; Dopey2 controls proliferation while Pcdh7 controls differentiation to generate proper brain size and architecture.","method":"Zebrafish genetic knockdown/knockout, in situ hybridization, immunostaining, cell proliferation and differentiation assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function in zebrafish with defined cellular phenotype, single lab","pmids":["36936789"],"is_preprint":false},{"year":2024,"finding":"HIF1A transcriptionally activates PCDH7 expression in lung adenocarcinoma (confirmed by ChIP and dual-luciferase assay). PCDH7 in turn promotes fatty acid synthesis (upregulating FASN and ACC1 protein expression) and increases cellular triglyceride content, thereby inhibiting anoikis. This HIF1A/PCDH7 axis drives anoikis resistance in LUAD.","method":"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, western blot for FASN/ACC1, triglyceride content measurement, Caspase3 activity assay, in vivo nude mouse xenograft","journal":"Journal of biochemical and molecular toxicology","confidence":"Medium","confidence_rationale":"Tier 1-2 — direct ChIP and luciferase confirmation of transcriptional regulation plus functional metabolic readouts, single lab","pmids":["39425457"],"is_preprint":false},{"year":2025,"finding":"PCDH7 physically interacts with ZEB1 and protects ZEB1 from ubiquitin-mediated proteasomal degradation by the E3 ubiquitin ligase TRIM26. This PCDH7-mediated ZEB1 stabilization maintains E-cadherin repression, promotes EMT, and confers cisplatin resistance in lung adenocarcinoma. PCDH7 depletion restores TRIM26-mediated ZEB1 ubiquitination and degradation.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, siRNA knockdown, in vitro and in vivo functional assays, western blot","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — direct Co-IP showing physical interaction, ubiquitination assay demonstrating mechanism, single lab","pmids":["41271034"],"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, suggesting a dosage-sensitive role in epileptogenesis.","method":"CRISPR-generated null allele, brain histology, cortical layer analysis, seizure susceptibility assay (PTZ or equivalent)","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 — validated genetic null model with defined behavioral phenotype, single lab","pmids":["40870033"],"is_preprint":false}],"current_model":"PCDH7 is a transmembrane protocadherin that functions as a cell-surface signaling scaffold: it interacts with PP1α to sustain pMLC2-driven actomyosin contractility, stabilizes ZEB1 by blocking TRIM26-mediated ubiquitination to promote EMT, binds the GluN1-NTD of NMDA receptors to regulate dendritic spine morphology and synaptic currents, potentiates MAPK/ERK signaling to drive oncogenesis in vivo, is transcriptionally activated by HIF1A to promote fatty acid synthesis and anoikis resistance, and is epigenetically silenced by MeCP2 (via MBD-dependent promoter binding) or by DNMT1/AR-mediated hypermethylation in a context-dependent manner."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of PCDH7 as a novel cadherin-superfamily member with seven extracellular cadherin repeats, three splice isoforms, and predominant brain/heart expression established the gene's structural framework and tissue context.","evidence":"cDNA cloning, Northern blot, and chromosomal mapping in human tissues","pmids":["9615233"],"confidence":"Medium","gaps":["No functional data; adhesive or signaling activity uncharacterized","Isoform-specific functions not addressed"]},{"year":2011,"claim":"Demonstrating that MeCP2 directly binds the PCDH7 promoter and represses its transcription in an MBD-dependent manner established the first regulatory mechanism controlling PCDH7 expression and linked the gene to Rett syndrome biology.","evidence":"ChIP, promoter-reporter assays, siRNA in SH-SY5Y cells, and Mecp2-null mouse brain analysis","pmids":["21824415"],"confidence":"High","gaps":["Downstream functional consequence of PCDH7 derepression in MeCP2-deficient neurons unknown","Whether PCDH7 upregulation contributes to Rett-associated phenotypes untested"]},{"year":2018,"claim":"In vivo gain- and loss-of-function studies in mouse lung showed that PCDH7 potentiates MAPK/ERK signaling and is functionally required for Kras-driven tumorigenesis, establishing PCDH7 as an oncogenic signal amplifier.","evidence":"Cre-inducible PCDH7 transgenic and CRISPR/Cas9 somatic knockout in KrasG12D;Tp53 mice with pERK readout","pmids":["30409919"],"confidence":"High","gaps":["Molecular mechanism by which PCDH7 activates ERK not defined","Whether PCDH7 directly engages RAS-RAF complexes unknown"]},{"year":2019,"claim":"Showing that the PCDH7 promoter is an AR target silenced by DNMT1-mediated hypermethylation in androgen-independent prostate cancer revealed a second epigenetic axis (distinct from MeCP2) that governs PCDH7 expression.","evidence":"ChIP-seq for AR, bisulfite sequencing, DNMT1 overexpression and inhibitor treatment in prostate cancer cells","pmids":["31872382"],"confidence":"Medium","gaps":["Functional consequence of PCDH7 re-expression in AIPC not tested","Whether AR directly recruits DNMT1 to the PCDH7 locus unclear"]},{"year":2020,"claim":"Discovery that PCDH7 physically binds and inhibits PP1α, thereby sustaining pMLC2 levels and actomyosin contractility, provided the first defined cytoplasmic signaling partner and a mechanistic link to cell mechanics.","evidence":"Co-immunoprecipitation, pMLC2 western blot, contractility and hoCIC assays in cell lines","pmids":["32457908"],"confidence":"Medium","gaps":["Interaction domain on PCDH7 not mapped","No structural or biophysical confirmation of the PP1α interaction","Single-lab finding without independent replication"]},{"year":2020,"claim":"An unbiased transmembrane-protein screen revealed that PCDH7 binds the GluN1-NTD of NMDA receptors and modulates dendritic spine morphology and synaptic NMDA currents, establishing a trans-synaptic signaling function.","evidence":"High-throughput screen with purified GluN1-NTD, overexpression/knockdown in primary neurons and brain slices, electrophysiology","pmids":["32616769"],"confidence":"Medium","gaps":["cis vs. trans interaction mode not determined","Whether PCDH7 directly modulates NMDAR gating or acts indirectly via spine remodeling unclear"]},{"year":2020,"claim":"A positive feedback loop was delineated in colon cancer whereby PCDH7 activates ERK/c-FOS, c-FOS induces LNAPPCC, and LNAPPCC de-represses the PCDH7 promoter by displacing EZH2/H3K27me3, providing a chromatin-level amplification mechanism.","evidence":"ChIP for EZH2/H3K27me3, luciferase reporters, ERK inhibitor, xenograft and metastasis models in colon cancer cells","pmids":["32330872"],"confidence":"Medium","gaps":["Relative contribution of the feedback loop vs. direct PCDH7-ERK coupling not quantified","Generalizability beyond colon cancer untested"]},{"year":2023,"claim":"Zebrafish genetic studies showed Pcdh7 is required for neural stem cell differentiation (but not proliferation) and that Dopey2 and Pcdh7 mutually regulate each other to balance brain growth, extending PCDH7 function to developmental neurogenesis.","evidence":"Zebrafish knockdown/knockout, in situ hybridization, proliferation and differentiation assays","pmids":["36936789"],"confidence":"Medium","gaps":["Downstream effectors of Pcdh7 in neural differentiation not identified","Whether mammalian neurogenesis similarly depends on PCDH7 unknown"]},{"year":2024,"claim":"Identification of HIF1A as a direct transcriptional activator of PCDH7, coupled with the finding that PCDH7 upregulates FASN/ACC1 to promote fatty acid synthesis and anoikis resistance, linked PCDH7 to hypoxia-driven metabolic reprogramming in lung adenocarcinoma.","evidence":"ChIP, dual-luciferase reporter, FASN/ACC1 western blot, triglyceride measurement, caspase-3 assay, xenograft","pmids":["39425457"],"confidence":"Medium","gaps":["Mechanism connecting PCDH7 to lipogenic enzyme expression not defined","Whether fatty acid synthesis is the primary anoikis-resistance mechanism unclear"]},{"year":2025,"claim":"Demonstrating that PCDH7 physically interacts with ZEB1 and shields it from TRIM26-mediated ubiquitination and degradation revealed a non-canonical intracellular scaffolding function that drives EMT and cisplatin resistance.","evidence":"Co-IP, ubiquitination assay, proteasome inhibitor treatment, siRNA, in vitro and in vivo assays in LUAD","pmids":["41271034"],"confidence":"Medium","gaps":["Binding interface between PCDH7 and ZEB1 not mapped","Whether the PCDH7-ZEB1 interaction occurs at the membrane or in the cytoplasm unresolved"]},{"year":2025,"claim":"CRISPR-generated Pcdh7-null mice showed no gross brain morphological defects, but heterozygotes displayed increased seizure latency, revealing dosage-sensitive roles in neural excitability that are dispensable for gross cortical patterning.","evidence":"CRISPR null allele, brain histology, cortical layer analysis, seizure susceptibility assay in mice","pmids":["40870033"],"confidence":"Medium","gaps":["Mechanism underlying seizure phenotype (circuit vs. synaptic) not identified","Behavioral and cognitive phenotyping beyond seizure threshold not reported"]},{"year":null,"claim":"The mechanism by which PCDH7 couples its extracellular adhesion/receptor-binding domains to diverse intracellular pathways (ERK, PP1α, ZEB1 stabilization, lipogenesis) remains undefined; whether these represent isoform-specific functions or context-dependent activation of a common signaling hub is a central open question.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PCDH7 cytoplasmic domain or its interfaces with partners exists","Isoform-specific functions (a, b, c) have never been dissected","How PCDH7 simultaneously activates ERK and inhibits PP1α in the same cellular context is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,7]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,8,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8]}],"complexes":[],"partners":["PPP1CA","GRIN1","ZEB1","TRIM26","HIF1A","MECP2"],"other_free_text":[]},"mechanistic_narrative":"PCDH7 is a seven-repeat protocadherin that functions as a cell-surface signaling scaffold linking adhesion to intracellular signaling cascades in both neural and epithelial contexts. In the brain, PCDH7 binds the GluN1 N-terminal domain of NMDA receptors to regulate dendritic spine density and synaptic currents, is required for neural progenitor differentiation during embryonic neurogenesis, and is epigenetically silenced by MeCP2 in an MBD-dependent manner [PMID:32616769, PMID:36936789, PMID:21824415]. In epithelial and cancer cells, PCDH7 potentiates MAPK/ERK signaling to accelerate Kras-driven lung tumorigenesis, interacts with PP1α to sustain pMLC2-dependent actomyosin contractility, stabilizes ZEB1 by blocking TRIM26-mediated ubiquitination to promote EMT and cisplatin resistance, and is transcriptionally activated by HIF1A to drive fatty acid synthesis and anoikis resistance [PMID:30409919, PMID:32457908, PMID:41271034, PMID:39425457]. Heterozygous Pcdh7 mice exhibit altered seizure susceptibility, indicating a dosage-sensitive neurological role [PMID:40870033]."},"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":"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":"32616769","id":"PMC_32616769","title":"PCDH7 interacts with GluN1 and regulates dendritic spine morphology and synaptic function.","date":"2020","source":"Scientific 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research","url":"https://pubmed.ncbi.nlm.nih.gov/34012292","citation_count":12,"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":9,"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":9,"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":7,"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":5,"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":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":11995,"output_tokens":3226,"usd":0.042188},"stage2":{"model":"claude-opus-4-6","input_tokens":6596,"output_tokens":2891,"usd":0.157883},"total_usd":0.200071,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"PCDH7 (BH-protocadherin) was identified as a novel cadherin superfamily member with an extracellular domain consisting of seven cadherin motif repeats (EC1–EC7), with EC2 containing a unique 55-amino-acid insertion. Three isoforms (a, b, c) were identified with different cytoplasmic tails, and isoform c has a 47-amino-acid deletion in the EC2-3 region. The gene is predominantly expressed in brain and heart.\",\n      \"method\": \"cDNA cloning, Northern blot, Southern blot, chromosomal localization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct cloning and structural characterization, single lab\",\n      \"pmids\": [\"9615233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MeCP2 directly binds to the upstream regulatory region of PCDH7 in neuronal cells and represses PCDH7 promoter activity in a methyl-CpG-binding domain (MBD)-dependent manner; MBD-deleted MeCP2 fails to repress PCDH7. PCDH7 expression is upregulated upon MeCP2 reduction (siRNA) in SH-SY5Y cells and in brains of Mecp2-null mice.\",\n      \"method\": \"ChIP-on-BAC array, chromatin immunoprecipitation (ChIP), promoter-reporter assay, siRNA knockdown, Mecp2-null mouse brain analysis\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (ChIP, promoter assay, genetic null model)\",\n      \"pmids\": [\"21824415\"],\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 pathway activation (phospho-ERK1/2). CRISPR/Cas9-mediated somatic inactivation of PCDH7 in KrasG12D;Tp53 mice significantly reduced lung tumor development, prolonged survival, and diminished phospho-ERK1/2 activation.\",\n      \"method\": \"Transgenic gain-of-function mouse model, CRISPR/Cas9 somatic loss-of-function in vivo, immunohistochemistry for p-ERK1/2\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain and loss of function with defined molecular readout (pERK), replicated in two genetic models\",\n      \"pmids\": [\"30409919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PCDH7 directly interacts with PP1α (protein phosphatase 1α) and inactivates it, thereby preventing PP1α-mediated dephosphorylation of pMLC2 (phospho-myosin light chain 2). This increases pMLC2 levels, enhances actomyosin contractility at the intercellular region, and inhibits homotypic cell-in-cell (hoCIC) structure formation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown functional assays, western blot for pMLC2, actomyosin contractility measurements, anchorage-independent growth assay\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct protein interaction (Co-IP) with functional readout, 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, as identified by an unbiased screen of ~1,500 transmembrane proteins using purified GluN1-NTD as bait. Overexpression of PCDH7 in primary neurons and brain slice cultures increases dendritic spine density/morphology changes and reduces synaptic NMDA receptor currents, while knockdown induces opposing morphological changes.\",\n      \"method\": \"Unbiased transmembrane protein interaction screen with purified GluN1-NTD bait, overexpression and knockdown in primary neurons and brain slice cultures, electrophysiology (synaptic NMDA currents), morphological analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — unbiased screen plus functional validation in neurons, single lab\",\n      \"pmids\": [\"32616769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PCDH7 activates ERK/c-FOS signaling in colon cancer cells; increased c-FOS binds the LNAPPCC lncRNA promoter and activates LNAPPCC expression, which in turn represses EZH2 binding to the PCDH7 promoter (reducing H3K27me3) to upregulate PCDH7, forming a positive feedback loop.\",\n      \"method\": \"Luciferase reporter assay, ChIP for EZH2 and H3K27me3, co-immunoprecipitation, RNA pulldown, ERK inhibitor treatment, siRNA knockdown, xenograft and liver metastasis models\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple biochemical and cellular methods, single lab\",\n      \"pmids\": [\"32330872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The androgen receptor (AR) directly targets the PCDH7 gene locus (AR enrichment detected by ChIP-seq in androgen-independent prostate cancer cells). PCDH7 expression is silenced by DNMT1-mediated promoter hypermethylation in AIPC cells; DNMT1 overexpression reduces PCDH7 mRNA and protein, while DNA methyltransferase inhibitor restores PCDH7 expression.\",\n      \"method\": \"ChIP-seq for AR binding, bisulfite sequencing/BSAS for methylation, DNMT1 overexpression, DNA methyltransferase inhibitor treatment, RT-PCR, western blot\",\n      \"journal\": \"Genes & genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq plus methylation analysis with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31872382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PCDH7 promotes activation of the MEK1/2/ERK/c-FOS signaling axis in colon cancer; PCDH7 knockdown represses this pathway and sensitizes colon cancer cells to chemotherapy by inducing ferroptosis and altering autophagy. PCDH7 also regulates PP1α and pMLC2 levels to modulate hoCIC structure formation in colon cancer.\",\n      \"method\": \"siRNA knockdown, MEK inhibitor treatment, western blot, MTT and colony formation assays, in vivo nude mouse xenograft, ferroptosis and autophagy assays\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple in vitro and in vivo methods with pathway readouts, single lab\",\n      \"pmids\": [\"35926236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In zebrafish, Pcdh7 is required for the differentiation (but not proliferation) of neural stem cells/progenitors during embryonic neurogenesis. Dopey2 and Pcdh7 mutually restrict each other's expression; Dopey2 controls proliferation while Pcdh7 controls differentiation to generate proper brain size and architecture.\",\n      \"method\": \"Zebrafish genetic knockdown/knockout, in situ hybridization, immunostaining, cell proliferation and differentiation assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function in zebrafish with defined cellular phenotype, single lab\",\n      \"pmids\": [\"36936789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HIF1A transcriptionally activates PCDH7 expression in lung adenocarcinoma (confirmed by ChIP and dual-luciferase assay). PCDH7 in turn promotes fatty acid synthesis (upregulating FASN and ACC1 protein expression) and increases cellular triglyceride content, thereby inhibiting anoikis. This HIF1A/PCDH7 axis drives anoikis resistance in LUAD.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, western blot for FASN/ACC1, triglyceride content measurement, Caspase3 activity assay, in vivo nude mouse xenograft\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — direct ChIP and luciferase confirmation of transcriptional regulation plus functional metabolic readouts, single lab\",\n      \"pmids\": [\"39425457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PCDH7 physically interacts with ZEB1 and protects ZEB1 from ubiquitin-mediated proteasomal degradation by the E3 ubiquitin ligase TRIM26. This PCDH7-mediated ZEB1 stabilization maintains E-cadherin repression, promotes EMT, and confers cisplatin resistance in lung adenocarcinoma. PCDH7 depletion restores TRIM26-mediated ZEB1 ubiquitination and degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, siRNA knockdown, in vitro and in vivo functional assays, western blot\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct Co-IP showing physical interaction, ubiquitination assay demonstrating mechanism, single lab\",\n      \"pmids\": [\"41271034\"],\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, suggesting a dosage-sensitive role in epileptogenesis.\",\n      \"method\": \"CRISPR-generated null allele, brain histology, cortical layer analysis, seizure susceptibility assay (PTZ or equivalent)\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — validated genetic null model with defined behavioral phenotype, single lab\",\n      \"pmids\": [\"40870033\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PCDH7 is a transmembrane protocadherin that functions as a cell-surface signaling scaffold: it interacts with PP1α to sustain pMLC2-driven actomyosin contractility, stabilizes ZEB1 by blocking TRIM26-mediated ubiquitination to promote EMT, binds the GluN1-NTD of NMDA receptors to regulate dendritic spine morphology and synaptic currents, potentiates MAPK/ERK signaling to drive oncogenesis in vivo, is transcriptionally activated by HIF1A to promote fatty acid synthesis and anoikis resistance, and is epigenetically silenced by MeCP2 (via MBD-dependent promoter binding) or by DNMT1/AR-mediated hypermethylation in a context-dependent manner.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PCDH7 is a seven-repeat protocadherin that functions as a cell-surface signaling scaffold linking adhesion to intracellular signaling cascades in both neural and epithelial contexts. In the brain, PCDH7 binds the GluN1 N-terminal domain of NMDA receptors to regulate dendritic spine density and synaptic currents, is required for neural progenitor differentiation during embryonic neurogenesis, and is epigenetically silenced by MeCP2 in an MBD-dependent manner [PMID:32616769, PMID:36936789, PMID:21824415]. In epithelial and cancer cells, PCDH7 potentiates MAPK/ERK signaling to accelerate Kras-driven lung tumorigenesis, interacts with PP1α to sustain pMLC2-dependent actomyosin contractility, stabilizes ZEB1 by blocking TRIM26-mediated ubiquitination to promote EMT and cisplatin resistance, and is transcriptionally activated by HIF1A to drive fatty acid synthesis and anoikis resistance [PMID:30409919, PMID:32457908, PMID:41271034, PMID:39425457]. Heterozygous Pcdh7 mice exhibit altered seizure susceptibility, indicating a dosage-sensitive neurological role [PMID:40870033].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of PCDH7 as a novel cadherin-superfamily member with seven extracellular cadherin repeats, three splice isoforms, and predominant brain/heart expression established the gene's structural framework and tissue context.\",\n      \"evidence\": \"cDNA cloning, Northern blot, and chromosomal mapping in human tissues\",\n      \"pmids\": [\"9615233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional data; adhesive or signaling activity uncharacterized\", \"Isoform-specific functions not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that MeCP2 directly binds the PCDH7 promoter and represses its transcription in an MBD-dependent manner established the first regulatory mechanism controlling PCDH7 expression and linked the gene to Rett syndrome biology.\",\n      \"evidence\": \"ChIP, promoter-reporter assays, siRNA in SH-SY5Y cells, and Mecp2-null mouse brain analysis\",\n      \"pmids\": [\"21824415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream functional consequence of PCDH7 derepression in MeCP2-deficient neurons unknown\", \"Whether PCDH7 upregulation contributes to Rett-associated phenotypes untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"In vivo gain- and loss-of-function studies in mouse lung showed that PCDH7 potentiates MAPK/ERK signaling and is functionally required for Kras-driven tumorigenesis, establishing PCDH7 as an oncogenic signal amplifier.\",\n      \"evidence\": \"Cre-inducible PCDH7 transgenic and CRISPR/Cas9 somatic knockout in KrasG12D;Tp53 mice with pERK readout\",\n      \"pmids\": [\"30409919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which PCDH7 activates ERK not defined\", \"Whether PCDH7 directly engages RAS-RAF complexes unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that the PCDH7 promoter is an AR target silenced by DNMT1-mediated hypermethylation in androgen-independent prostate cancer revealed a second epigenetic axis (distinct from MeCP2) that governs PCDH7 expression.\",\n      \"evidence\": \"ChIP-seq for AR, bisulfite sequencing, DNMT1 overexpression and inhibitor treatment in prostate cancer cells\",\n      \"pmids\": [\"31872382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of PCDH7 re-expression in AIPC not tested\", \"Whether AR directly recruits DNMT1 to the PCDH7 locus unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that PCDH7 physically binds and inhibits PP1α, thereby sustaining pMLC2 levels and actomyosin contractility, provided the first defined cytoplasmic signaling partner and a mechanistic link to cell mechanics.\",\n      \"evidence\": \"Co-immunoprecipitation, pMLC2 western blot, contractility and hoCIC assays in cell lines\",\n      \"pmids\": [\"32457908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction domain on PCDH7 not mapped\", \"No structural or biophysical confirmation of the PP1α interaction\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"An unbiased transmembrane-protein screen revealed that PCDH7 binds the GluN1-NTD of NMDA receptors and modulates dendritic spine morphology and synaptic NMDA currents, establishing a trans-synaptic signaling function.\",\n      \"evidence\": \"High-throughput screen with purified GluN1-NTD, overexpression/knockdown in primary neurons and brain slices, electrophysiology\",\n      \"pmids\": [\"32616769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"cis vs. trans interaction mode not determined\", \"Whether PCDH7 directly modulates NMDAR gating or acts indirectly via spine remodeling unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A positive feedback loop was delineated in colon cancer whereby PCDH7 activates ERK/c-FOS, c-FOS induces LNAPPCC, and LNAPPCC de-represses the PCDH7 promoter by displacing EZH2/H3K27me3, providing a chromatin-level amplification mechanism.\",\n      \"evidence\": \"ChIP for EZH2/H3K27me3, luciferase reporters, ERK inhibitor, xenograft and metastasis models in colon cancer cells\",\n      \"pmids\": [\"32330872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of the feedback loop vs. direct PCDH7-ERK coupling not quantified\", \"Generalizability beyond colon cancer untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Zebrafish genetic studies showed Pcdh7 is required for neural stem cell differentiation (but not proliferation) and that Dopey2 and Pcdh7 mutually regulate each other to balance brain growth, extending PCDH7 function to developmental neurogenesis.\",\n      \"evidence\": \"Zebrafish knockdown/knockout, in situ hybridization, proliferation and differentiation assays\",\n      \"pmids\": [\"36936789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of Pcdh7 in neural differentiation not identified\", \"Whether mammalian neurogenesis similarly depends on PCDH7 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of HIF1A as a direct transcriptional activator of PCDH7, coupled with the finding that PCDH7 upregulates FASN/ACC1 to promote fatty acid synthesis and anoikis resistance, linked PCDH7 to hypoxia-driven metabolic reprogramming in lung adenocarcinoma.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter, FASN/ACC1 western blot, triglyceride measurement, caspase-3 assay, xenograft\",\n      \"pmids\": [\"39425457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting PCDH7 to lipogenic enzyme expression not defined\", \"Whether fatty acid synthesis is the primary anoikis-resistance mechanism unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that PCDH7 physically interacts with ZEB1 and shields it from TRIM26-mediated ubiquitination and degradation revealed a non-canonical intracellular scaffolding function that drives EMT and cisplatin resistance.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, proteasome inhibitor treatment, siRNA, in vitro and in vivo assays in LUAD\",\n      \"pmids\": [\"41271034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface between PCDH7 and ZEB1 not mapped\", \"Whether the PCDH7-ZEB1 interaction occurs at the membrane or in the cytoplasm unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CRISPR-generated Pcdh7-null mice showed no gross brain morphological defects, but heterozygotes displayed increased seizure latency, revealing dosage-sensitive roles in neural excitability that are dispensable for gross cortical patterning.\",\n      \"evidence\": \"CRISPR null allele, brain histology, cortical layer analysis, seizure susceptibility assay in mice\",\n      \"pmids\": [\"40870033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism underlying seizure phenotype (circuit vs. synaptic) not identified\", \"Behavioral and cognitive phenotyping beyond seizure threshold not reported\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which PCDH7 couples its extracellular adhesion/receptor-binding domains to diverse intracellular pathways (ERK, PP1α, ZEB1 stabilization, lipogenesis) remains undefined; whether these represent isoform-specific functions or context-dependent activation of a common signaling hub is a central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of PCDH7 cytoplasmic domain or its interfaces with partners exists\", \"Isoform-specific functions (a, b, c) have never been dissected\", \"How PCDH7 simultaneously activates ERK and inhibits PP1α in the same cellular context is unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 7]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 8, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PPP1CA\", \"GRIN1\", \"ZEB1\", \"TRIM26\", \"HIF1A\", \"MECP2\"],\n    \"other_free_text\": []\n  }\n}\n```"}