Affinage

PCDH7

Protocadherin-7 · UniProt O60245

Length
1069 aa
Mass
116.1 kDa
Annotated
2026-04-29
20 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1998 Medium

    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

    PMID:9615233

    Open questions at the time
    • No functional data; adhesive or signaling activity uncharacterized
    • Isoform-specific functions not addressed
  2. 2011 High

    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

    PMID:21824415

    Open questions at the time
    • Downstream functional consequence of PCDH7 derepression in MeCP2-deficient neurons unknown
    • Whether PCDH7 upregulation contributes to Rett-associated phenotypes untested
  3. 2018 High

    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

    PMID:30409919

    Open questions at the time
    • Molecular mechanism by which PCDH7 activates ERK not defined
    • Whether PCDH7 directly engages RAS-RAF complexes unknown
  4. 2019 Medium

    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

    PMID:31872382

    Open questions at the time
    • Functional consequence of PCDH7 re-expression in AIPC not tested
    • Whether AR directly recruits DNMT1 to the PCDH7 locus unclear
  5. 2020 Medium

    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

    PMID:32457908

    Open questions at the time
    • Interaction domain on PCDH7 not mapped
    • No structural or biophysical confirmation of the PP1α interaction
    • Single-lab finding without independent replication
  6. 2020 Medium

    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

    PMID:32616769

    Open questions at the time
    • cis vs. trans interaction mode not determined
    • Whether PCDH7 directly modulates NMDAR gating or acts indirectly via spine remodeling unclear
  7. 2020 Medium

    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

    PMID:32330872

    Open questions at the time
    • Relative contribution of the feedback loop vs. direct PCDH7-ERK coupling not quantified
    • Generalizability beyond colon cancer untested
  8. 2023 Medium

    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

    PMID:36936789

    Open questions at the time
    • Downstream effectors of Pcdh7 in neural differentiation not identified
    • Whether mammalian neurogenesis similarly depends on PCDH7 unknown
  9. 2024 Medium

    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

    PMID:39425457

    Open questions at the time
    • Mechanism connecting PCDH7 to lipogenic enzyme expression not defined
    • Whether fatty acid synthesis is the primary anoikis-resistance mechanism unclear
  10. 2025 Medium

    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

    PMID:41271034

    Open questions at the time
    • Binding interface between PCDH7 and ZEB1 not mapped
    • Whether the PCDH7-ZEB1 interaction occurs at the membrane or in the cytoplasm unresolved
  11. 2025 Medium

    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

    PMID:40870033

    Open questions at the time
    • Mechanism underlying seizure phenotype (circuit vs. synaptic) not identified
    • Behavioral and cognitive phenotyping beyond seizure threshold not reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 1
Partners
GRIN1HIF1AMECP2PPP1CATRIM26ZEB1

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. cDNA cloning, Northern blot, Southern blot, chromosomal localization Genomics Medium 9615233
2011 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. ChIP-on-BAC array, chromatin immunoprecipitation (ChIP), promoter-reporter assay, siRNA knockdown, Mecp2-null mouse brain analysis BMC neuroscience High 21824415
2018 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. Transgenic gain-of-function mouse model, CRISPR/Cas9 somatic loss-of-function in vivo, immunohistochemistry for p-ERK1/2 Molecular cancer research : MCR High 30409919
2020 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. Co-immunoprecipitation, overexpression/knockdown functional assays, western blot for pMLC2, actomyosin contractility measurements, anchorage-independent growth assay Frontiers in cell and developmental biology Medium 32457908
2020 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. 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 Scientific reports Medium 32616769
2020 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. Luciferase reporter assay, ChIP for EZH2 and H3K27me3, co-immunoprecipitation, RNA pulldown, ERK inhibitor treatment, siRNA knockdown, xenograft and liver metastasis models Molecular therapy. Nucleic acids Medium 32330872
2019 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. ChIP-seq for AR binding, bisulfite sequencing/BSAS for methylation, DNMT1 overexpression, DNA methyltransferase inhibitor treatment, RT-PCR, western blot Genes & genomics Medium 31872382
2022 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. siRNA knockdown, MEK inhibitor treatment, western blot, MTT and colony formation assays, in vivo nude mouse xenograft, ferroptosis and autophagy assays Biochemistry and cell biology Medium 35926236
2023 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. Zebrafish genetic knockdown/knockout, in situ hybridization, immunostaining, cell proliferation and differentiation assays iScience Medium 36936789
2024 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. Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, western blot for FASN/ACC1, triglyceride content measurement, Caspase3 activity assay, in vivo nude mouse xenograft Journal of biochemical and molecular toxicology Medium 39425457
2025 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. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, siRNA knockdown, in vitro and in vivo functional assays, western blot Biochemical pharmacology Medium 41271034
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, suggesting a dosage-sensitive role in epileptogenesis. CRISPR-generated null allele, brain histology, cortical layer analysis, seizure susceptibility assay (PTZ or equivalent) Genes Medium 40870033

Source papers

Stage 0 corpus · 20 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
2018 Modulation of Mutant Kras -Driven Lung Tumorigenesis In Vivo by Gain or Loss of PCDH7 Function. Molecular cancer research : MCR 24 30409919
2020 PCDH7 interacts with GluN1 and regulates dendritic spine morphology and synaptic function. Scientific reports 23 32616769
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 16 35926236
2021 The Clinical Significance and Biological Function of PCDH7 in Cervical Cancer. Cancer management and research 12 34012292
2023 PCDH7 as the key gene related to the co-occurrence of sarcopenia and osteoporosis. Frontiers in genetics 9 37476411
2023 Integrative analysis illustrates the role of PCDH7 in lung cancer development, cisplatin resistance, and immunotherapy resistance: an underlying target. Frontiers in pharmacology 9 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 7 39425457
2023 Concurrent glomerular PCDH7 deposits in PLA2R-associated membranous nephropathy. CEN case reports 5 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
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