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PCDH7

Protocadherin-7 · UniProt O60245

Length
1069 aa
Mass
116.1 kDa
Annotated
2026-06-10
21 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 Medium

    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

    PMID:9615233

    Open questions at the time
    • No function assigned at discovery
    • Tissue-specific roles of the three cytoplasmic isoforms not resolved
    • No structural model of the EC2 insertion
  2. 2011 Medium

    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

    PMID:21824415

    Open questions at the time
    • Downstream functional consequence of MeCP2 repression not tested
    • Direct vs indirect repression mechanism not fully separated
  3. 2018 High

    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

    PMID:30409919

    Open questions at the time
    • How a protocadherin couples to MEK/ERK was not biochemically defined
    • Direct upstream effector not identified
  4. 2019 Medium

    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

    PMID:31872382

    Open questions at the time
    • Tumor-suppressive vs oncogenic role context not reconciled with lung cancer data
    • Single cell-line system
  5. 2020 Medium

    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

    PMID:32457908

    Open questions at the time
    • Direct interaction not validated by reciprocal/structural approaches
    • Single lab
  6. 2020 Medium

    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

    PMID:32616769

    Open questions at the time
    • Whether interaction is direct in vivo not confirmed
    • Link to behavioral/circuit phenotype not established
  7. 2020 Medium

    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

    PMID:32330872

    Open questions at the time
    • Molecular link from PCDH7 to ERK activation not biochemically defined
    • Generality beyond colon cancer untested
  8. 2022 Medium

    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

    PMID:35926236

    Open questions at the time
    • No direct biochemical interaction confirming the signaling link
    • Mechanism of ferroptosis/autophagy coupling not resolved
  9. 2023 Medium

    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

    PMID:36936789

    Open questions at the time
    • Mechanism of Pcdh7–Dopey2 mutual repression unknown
    • Conservation to mammalian neurogenesis not demonstrated
  10. 2024 Medium

    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

    PMID:39425457

    Open questions at the time
    • How PCDH7 mechanistically upregulates FASN/ACC1 not defined
    • Single tumor type
  11. 2025 Medium

    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

    PMID:41271034

    Open questions at the time
    • Structural basis of PCDH7–ZEB1 interaction unknown
    • How a transmembrane protein shields a nuclear factor not spatially resolved
  12. 2025 High

    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

    PMID:42234744

    Open questions at the time
    • Epitope and ligand-blocking mechanism not fully mapped
    • Combination/biomarker context for clinical use undefined
  13. 2025 Medium

    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

    PMID:40870033

    Open questions at the time
    • Cellular basis of altered seizure latency not identified
    • Possible redundancy with other protocadherins untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 1
Partners
GRIN1PPP1CATRIM26ZEB1

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. cDNA cloning, Northern blot, Southern blot, chromosomal localization Genomics Medium 9615233
2011 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. Chromatin immunoprecipitation (ChIP-on-BAC array), promoter-reporter assay, siRNA knockdown, qRT-PCR in cell lines and mouse brain BMC neuroscience Medium 21824415
2020 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. Co-immunoprecipitation (direct interaction with PP1α), overexpression and siRNA knockdown assays, western blot for pMLC2, cell-in-cell formation assays Frontiers in cell and developmental biology Medium 32457908
2020 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. Unbiased transmembrane protein screen (~1,500 proteins) using purified GluN1-NTD as bait, primary neuron and brain-slice culture overexpression/knockdown, electrophysiology Scientific reports Medium 32616769
2018 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. 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 Molecular cancer research : MCR High 30409919
2020 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. 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 Molecular therapy. Nucleic acids Medium 32330872
2022 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. 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 Biochemistry and cell biology Medium 35926236
2019 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. ChIP-seq (AR binding), bisulfite sequencing/bisulfite amplicon sequencing (methylation), DNMT1 overexpression, DNMT inhibitor treatment, CCK-8, transwell, flow cytometry Genes & genomics Medium 31872382
2024 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. 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 of biochemical and molecular toxicology Medium 39425457
2025 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. Co-immunoprecipitation (PCDH7–ZEB1 interaction), ubiquitination assay, siRNA knockdown, overexpression, western blot (ZEB1, E-cadherin, EMT markers), in vivo xenograft and metastasis model Biochemical pharmacology Medium 41271034
2023 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. Zebrafish CRISPR/morpholino mutant analysis, in situ hybridization, immunostaining of neural markers, genetic epistasis (Dopey2/Pcdh7 double mutants) iScience Medium 36936789
2025 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. 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 Science advances High 42234744
2025 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. CRISPR-generated null allele, brain morphology and histology, cortical layer analysis, seizure susceptibility assay Genes Medium 40870033

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Cloning, expression analysis, and chromosomal localization of BH-protocadherin (PCDH7), a novel member of the cadherin superfamily. Genomics 71 9615233
2011 The protocadherins, PCDHB1 and PCDH7, are regulated by MeCP2 in neuronal cells and brain tissues: implication for pathogenesis of Rett syndrome. BMC neuroscience 57 21824415
2018 AQP8 inhibits colorectal cancer growth and metastasis by down-regulating PI3K/AKT signaling and PCDH7 expression. American journal of cancer research 42 29511597
2020 PCDH7 Inhibits the Formation of Homotypic Cell-in-Cell Structure. Frontiers in cell and developmental biology 35 32457908
2013 Hypermethylation of the polycomb group target gene PCDH7 in bladder tumors from patients of all ages. The Journal of urology 26 23369722
2020 PCDH7 interacts with GluN1 and regulates dendritic spine morphology and synaptic function. Scientific reports 25 32616769
2018 Modulation of Mutant Kras -Driven Lung Tumorigenesis In Vivo by Gain or Loss of PCDH7 Function. Molecular cancer research : MCR 24 30409919
2022 Circular RNA circDVL1 inhibits clear cell renal cell carcinoma progression through the miR-412-3p/PCDH7 axis. International journal of biological sciences 18 35280687
2022 PCDH7 knockdown potentiates colon cancer cells to chemotherapy via inducing ferroptosis and changes in autophagy through restraining MEK1/2/ERK/c-Fos axis. Biochemistry and cell biology = Biochimie et biologie cellulaire 17 35926236
2021 The Clinical Significance and Biological Function of PCDH7 in Cervical Cancer. Cancer management and research 13 34012292
2023 PCDH7 as the key gene related to the co-occurrence of sarcopenia and osteoporosis. Frontiers in genetics 10 37476411
2023 Integrative analysis illustrates the role of PCDH7 in lung cancer development, cisplatin resistance, and immunotherapy resistance: an underlying target. Frontiers in pharmacology 10 37538171
2020 Recurrence-Associated Long Non-coding RNA LNAPPCC Facilitates Colon Cancer Progression via Forming a Positive Feedback Loop with PCDH7. Molecular therapy. Nucleic acids 9 32330872
2024 HIF1A/PCDH7 axis mediates fatty acid synthesis and metabolism to inhibit lung adenocarcinoma anoikis. Journal of biochemical and molecular toxicology 8 39425457
2023 Concurrent glomerular PCDH7 deposits in PLA2R-associated membranous nephropathy. CEN case reports 6 38145434
2019 Effect of aberrantly methylated androgen receptor target gene PCDH7 on the development of androgen-independent prostate cancer cells. Genes & genomics 4 31872382
2023 Dopey2 and Pcdh7 orchestrate the development of embryonic neural stem cells/ progenitors in zebrafish. iScience 3 36936789
2025 Identification of cold tumor induction-related markers in pancreatic cancer and the clinical implication of PCDH7. Journal of cancer research and clinical oncology 2 39856454
2026 Monoclonal antibodies targeting PCDH7 inhibit tumor growth and enhance immune responses in KRAS-mutant non-small cell lung cancer. Science advances 0 42234744
2025 Epilepsy Associated Gene, Pcdh7, Is Dispensable for Brain Development in Mice. Genes 0 40870033
2025 PCDH7 promotes EMT and chemoresistance by stabilizing ZEB1 via inhibition of TRIM26-mediated ubiquitination in lung adenocarcinoma. Biochemical pharmacology 0 41271034

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