Affinage

PCDH9

Protocadherin-9 · UniProt Q9HC56

Length
1237 aa
Mass
136.1 kDa
Annotated
2026-06-10
25 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCDH9 is a calcium-dependent protocadherin cell-adhesion molecule predominantly expressed in brain that organizes excitatory synapses and supports long-term recognition memory (PMID:9787079, PMID:25802080, PMID:39557582). At glutamatergic synapses in hippocampal CA1, PCDH9 constrains synaptic architecture: its loss produces oversized presynaptic terminals and postsynaptic densities, dysregulates the SHANK2/CORTACTIN pathway, and increases miniature excitatory postsynaptic currents while reducing network activity (PMID:39557582). PCDH9 also functions as a signaling receptor that is processed by regulated proteolysis—neuronal activity drives MMP-dependent cleavage of PCDH9, releasing a C-terminal/intracellular fragment that translocates to the nucleus and promotes dendritic growth, spine density, and synaptic strengthening (PMID:41685090). In cancer, PCDH9 acts as a tumor suppressor; re-expression induces apoptosis, G0/G1 arrest, and reduced proliferation and invasion across glioma and hepatocellular carcinoma models (PMID:24214103, PMID:28791409). Its nuclear intracellular domain interacts with DNMT1 to stimulate methylation of the CDH2 (N-cadherin) promoter, silencing CDH2 and suppressing migration and metastasis (PMID:38357662). PCDH9 abundance is controlled by E3 ubiquitin ligases COP1/RFWD2 and RNF145, which drive its polyubiquitination and proteasomal degradation (PMID:35084653, PMID:41613811), while its expression is suppressed post-transcriptionally by multiple miRNAs and epigenetically by promoter methylation (PMID:28055966, PMID:31632082, PMID:36387162, PMID:28791409).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1998 Medium

    Established PCDH9 as a member of the protocadherin family of calcium-dependent cell-cell adhesion proteins with brain-predominant, developmentally regulated expression, framing it as a candidate neural recognition molecule.

    Evidence Gene isolation, genomic organization, and tissue/developmental expression profiling

    PMID:9787079

    Open questions at the time
    • No functional or mechanistic role demonstrated
    • Adhesion partners and homophilic/heterophilic specificity unaddressed
  2. 2013 Medium

    Identified a tumor-suppressor function by showing that restoring PCDH9 in glioma cells halts proliferation and invasion, opening a cancer biology axis distinct from its neural role.

    Evidence Lentiviral PCDH9 re-expression in U87/U251 glioma lines with viability, apoptosis, cell cycle, invasion, and marker Western blots

    PMID:24214103

    Open questions at the time
    • Molecular mechanism of growth suppression not defined
    • Bax/Bcl-2/cyclin D1 changes correlative, not causally dissected
  3. 2015 High

    Demonstrated in vivo that PCDH9 is required for long-term social and object recognition memory and sensory cortex development, establishing its physiological neural function.

    Evidence Pcdh9 knockout mice from QTL mapping with behavioral testing and brain morphology analysis

    PMID:25802080

    Open questions at the time
    • Synaptic/cellular mechanism underlying behavioral deficits not resolved at this stage
    • Molecular pathways downstream of PCDH9 unidentified
  4. 2017 Medium

    Showed that PCDH9 is silenced in cancers by two converging regulatory routes—miRNA targeting and promoter methylation—explaining how its tumor-suppressor function is lost.

    Evidence miR-215-5p dual promoter/3'UTR luciferase reporters in glioma; quantitative methylation and 5-azacytidine rescue in hepatocellular carcinoma with functional assays

    PMID:28055966 PMID:28791409

    Open questions at the time
    • Mechanism of dual promoter+3'UTR miRNA targeting unusual and not structurally explained
    • Tumor-suppressor effector pathway still undefined
  5. 2019 Medium

    Extended the miRNA-suppression model to ovarian cancer, reinforcing post-transcriptional control of PCDH9 as a recurring oncogenic strategy.

    Evidence miR-200a-3p 3'UTR luciferase reporter, expression assays, and PCDH9-restoration rescue in ovarian cancer cells

    PMID:31632082

    Open questions at the time
    • Single lab, single cancer type
    • Downstream effectors of PCDH9 in ovarian cancer not defined
  6. 2022 High

    Identified the first post-translational regulator of PCDH9 stability, COP1, defining ubiquitin-proteasome control of PCDH9 protein levels in glioma.

    Evidence Yeast two-hybrid, reciprocal Co-IP, K48-linked ubiquitination assays, proteasome inhibition, and inverse correlation in human glioma tissue

    PMID:35084653

    Open questions at the time
    • Ubiquitination site(s) on PCDH9 not mapped
    • Whether cleavage and degradation are coupled not addressed
  7. 2024 High

    Defined the nuclear effector mechanism of PCDH9: a cleaved intracellular domain binds and activates DNMT1 to methylate and silence the CDH2 promoter, providing a molecular basis for metastasis suppression.

    Evidence Co-IP, nuclear fractionation, DNMT1 activity and promoter bisulfite assays, migration and in vivo metastasis models in gastric cancer

    PMID:38357662

    Open questions at the time
    • Protease generating the cancer-context ICD not identified
    • Generality of CDH2 silencing across tumor types untested
  8. 2024 High

    Resolved the synaptic mechanism behind PCDH9's memory role, localizing it to glutamatergic synapses and showing it constrains synapse size and excitatory transmission via the SHANK2/CORTACTIN pathway.

    Evidence Pcdh9 KO mice with EM ultrastructure, snRNA-seq, mEPSC and network recordings, and biochemical localization in hippocampal CA1

    PMID:39557582

    Open questions at the time
    • Direct biochemical link between PCDH9 and SHANK2/CORTACTIN not established
    • Trans-synaptic adhesion partners unidentified
  9. 2026 Medium

    Connected synaptic activity to nuclear signaling by showing neuronal-activity-driven MMP cleavage of PCDH9 releases a CTF that promotes dendritic and spine remodeling, unifying adhesion and intracellular signaling functions.

    Evidence Biochemical fractionation, MMP inhibitor treatment, immunohistochemistry, CTF overexpression with morphology and electrophysiology in neurons

    PMID:41685090

    Open questions at the time
    • Specific MMP and cleavage site not identified
    • Nuclear targets of the neuronal CTF not defined
    • Relationship to the DNMT1-binding cancer ICD unclear
  10. 2026 Medium

    Identified a second E3 ligase, RNF145, that degrades PCDH9, linking its loss to hepatocellular carcinoma migration and invasion and broadening proteasomal control of PCDH9 across cancers.

    Evidence Co-IP, ubiquitination assays, and transwell/wound-healing assays with RNF145 knockdown in HCC cells

    PMID:41613811

    Open questions at the time
    • Ubiquitin linkage type not specified
    • Whether COP1 and RNF145 act redundantly or in distinct contexts unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown which protease(s) generate the nuclear fragment in neurons versus cancer cells and whether the activity-dependent CTF and the DNMT1-binding tumor-suppressor ICD are the same proteolytic product acting through a shared nuclear program.
  • Cleavage protease identity and site uncharacterized in both contexts
  • Trans-synaptic adhesion partner(s) of full-length PCDH9 not identified
  • No structural model of the ICD-DNMT1 interaction

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 2 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005634 nucleus 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-112316 Neuronal System 2 R-HSA-1643685 Disease 2 R-HSA-4839726 Chromatin organization 1
Partners

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 PCDH9 is a member of the protocadherin subfamily of calcium-dependent cell-cell adhesion and recognition proteins. It is predominantly expressed in brain but also in a broader variety of tissues, with developmentally regulated expression patterns. Gene isolation, genomic organization analysis, expression profiling Genomics Medium 9787079
2013 Restoration of PCDH9 expression in glioma cell lines (U87 and U251) reduced tumor cell viability, induced apoptosis, caused G0/G1 cell cycle arrest, and suppressed colony formation and invasion. Molecularly, PCDH9 restoration upregulated Bax protein and downregulated Bcl-2 and cyclin D1. Lentiviral PCDH9 re-expression in glioma cell lines, cell viability assays, apoptosis assays, cell cycle analysis, invasion assays, Western blot Journal of molecular neuroscience : MN Medium 24214103
2015 Pcdh9 knockout mice exhibit specific long-term social and object recognition deficits, early touch-evoked biting, rotarod performance deficits, and sensory gating deficits. Structural changes were observed in deep layers of sensory cortices, where Pcdh9 is selectively expressed, implicating PCDH9 in sensory cortex development and long-term memory functions. Chromosome substitution strain QTL mapping, Pcdh9 knockout mouse generation, behavioral testing, gene expression analysis, brain morphology analysis Biological psychiatry High 25802080
2017 miR-215-5p suppresses PCDH9 expression in glioma by targeting both the promoter and 3'UTR of PCDH9 simultaneously (dual inhibition), leading to increased glioma cell proliferation, clone formation, migration, and reduced apoptosis. Luciferase reporter assays (promoter and 3'UTR), qRT-PCR, Western blot, cell proliferation, migration, and apoptosis assays in glioma cell lines Oncotarget Medium 28055966
2017 PCDH9 promoter methylation leads to transcriptional silencing in hepatocellular carcinoma (HCC), and treatment with DNA demethylation agent 5-azacytidine restores PCDH9 expression. Restored PCDH9 expression inhibits HCC cell proliferation and xenograft tumor formation by inducing G0/G1 cell cycle arrest. Quantitative methylation analysis, 5-azacytidine treatment, PCDH9 re-expression, cell proliferation assays, xenograft tumor formation, cell cycle analysis Molecular medicine reports Medium 28791409
2019 miR-200a-3p directly binds the 3'-UTR of PCDH9 mRNA and decreases PCDH9 expression in ovarian cancer cells, thereby promoting ovarian cancer cell proliferation, colony formation, and invasion. Restoring PCDH9 expression inhibits the pro-proliferative effect of miR-200a-3p. Luciferase reporter assay (3'UTR), qRT-PCR, Western blot, cell proliferation, colony formation, invasion assays, rescue experiments OncoTargets and therapy Medium 31632082
2022 COP1 (RFWD2), a RING-finger E3 ubiquitin ligase, physically interacts with PCDH9 and promotes its Lys48-linked polyubiquitination and proteasomal degradation in glioma cells. COP1 protein levels are inversely correlated with PCDH9 protein levels in human glioma tissues. Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assays, proteasome inhibitor experiments, Western blot, human glioma tissue analysis Molecular neurobiology High 35084653
2022 PCDH9 overexpression in melanoma inhibits cell proliferation and migration, downregulates RAC1, MMP2, and MMP9, and upregulates Pyk2 and Cyclin D1. The circ_0084043/miR-134-5p axis indirectly regulates PCDH9: circ_0084043 sponges miR-134-5p, thereby relieving miR-134-5p-mediated suppression of PCDH9. PCDH9 overexpression also inhibits melanoma tumor growth in vivo. Lentiviral overexpression/knockdown of PCDH9, proliferation/invasion/apoptosis assays, qRT-PCR, Western blot, in vivo xenograft, ceRNA luciferase reporter assays Frontiers in oncology Medium 36387162
2024 PCDH9 is cleaved in gastric cancer cells, generating an intracellular domain (ICD) that translocates to the nucleus. In the nucleus, the PCDH9 ICD interacts with DNA methyltransferase 1 (DNMT1) and increases DNMT1 activity, which leads to increased DNA methylation at the CDH2 (N-cadherin) promoter, downregulating CDH2 expression and thereby dampening gastric cancer cell migration and in vivo metastasis. Co-immunoprecipitation, nuclear fractionation, DNMT1 activity assays, DNA methylation analysis (promoter bisulfite), cell migration assays, in vivo metastasis models, correlation with patient tissue data iScience High 38357662
2024 PCDH9 primarily localizes at glutamatergic synapses in the mouse hippocampus CA1 region, with expression peaking in the first week after birth. Pcdh9 KO neurons exhibit oversized presynaptic terminals and postsynaptic densities, widespread upregulation of synaptic genes (by snRNA-seq), dysregulation of the SHANK2/CORTACTIN pathway, increased miniature excitatory postsynaptic currents (mEPSC), and reduced network activity in CA1. Pcdh9 KO mice, electron microscopy (ultrastructural), single-nucleus RNA-seq, electrophysiology (mEPSC recordings), biochemical fractionation/localization, network activity recordings The Journal of neuroscience High 39557582
2026 Neuronal activity triggers Matrix Metalloprotease (MMP)-dependent cleavage of PCDH9, generating a C-terminal fragment (CTF) that translocates to the nucleus. Overexpression of the PCDH9 CTF promotes dendritic growth, increases spine density, and strengthens excitatory synaptic transmission, identifying PCDH9 CTF as an activity-dependent signaling molecule linking synaptic activity to structural and functional remodeling. Biochemical fractionation, immunohistochemistry, MMP inhibitor treatment, neuronal cultures, CTF overexpression, dendritic morphology analysis, spine density quantification, electrophysiology Frontiers in cellular neuroscience Medium 41685090
2026 RNF145, an E3 ubiquitin ligase, physically interacts with PCDH9 and promotes its ubiquitination and subsequent proteasomal degradation, thereby facilitating hepatocellular carcinoma cell migration and invasion. Knockdown of RNF145 abolishes migratory and invasive capacities of HCC cells. Co-immunoprecipitation, Western blot, ubiquitination assays, transwell migration/invasion assays, wound-healing assay, RNF145 knockdown Oncology research Medium 41613811

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Characterization of two novel protocadherins (PCDH8 and PCDH9) localized on human chromosome 13 and mouse chromosome 14. Genomics 68 9787079
2018 Lnc-PCDH9-13:1 Is a Hypersensitive and Specific Biomarker for Early Hepatocellular Carcinoma. EBioMedicine 47 30045829
2017 The Gene Encoding Protocadherin 9 (PCDH9), a Novel Risk Factor for Major Depressive Disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 45 28990594
2019 MiR-200a-3p promoted the malignant behaviors of ovarian cancer cells through regulating PCDH9. OncoTargets and therapy 43 31632082
2015 Genetic Mapping in Mice Reveals the Involvement of Pcdh9 in Long-Term Social and Object Recognition and Sensorimotor Development. Biological psychiatry 38 25802080
2017 Dual inhibition of PCDH9 expression by miR-215-5p up-regulation in gliomas. Oncotarget 29 28055966
2017 PCDH9 acts as a tumor suppressor inducing tumor cell arrest at G0/G1 phase and is frequently methylated in hepatocellular carcinoma. Molecular medicine reports 25 28791409
2013 Characterizing the role of PCDH9 in the regulation of glioma cell apoptosis and invasion. Journal of molecular neuroscience : MN 25 24214103
2019 Semaphorin 3A (SEMA3A), protocadherin 9 (PCdh9), and S100 calcium binding protein A3 (S100A3) as potential biomarkers of carcinogenesis and chemoresistance of different neoplasms, including ovarian cancer - review of literature. Ginekologia polska 17 31059116
2022 The Chemopreventive Role of β-Elemene in Cholangiocarcinoma by Restoring PCDH9 Expression. Frontiers in oncology 13 35903688
2024 Expression of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) Candidate Genes EDA2R, PCDH9, and TRAF7 in Normal Human Kidney Development and CAKUT. Genes 12 38927638
2024 Nuclear translocation of cleaved PCDH9 impairs gastric cancer metastasis by downregulating CDH2 expression. iScience 11 38357662
2009 Pure monosomy and pure trisomy of 13q21.2-31.1 consequent to a familial insertional translocation: exclusion of PCDH9 as the responsible gene for autosomal dominant auditory neuropathy (AUNA1). American journal of medical genetics. Part A 11 19353688
2022 Circ_0084043-miR-134-5p axis regulates PCDH9 to suppress melanoma. Frontiers in oncology 10 36387162
2024 Disruption of the Autism-Associated Pcdh9 Gene Leads to Transcriptional Alterations, Synapse Overgrowth, and Defective Network Activity in the CA1. The Journal of neuroscience : the official journal of the Society for Neuroscience 8 39557582
2022 COP1 Acts as a Ubiquitin Ligase for PCDH9 Ubiquitination and Degradation in Human Glioma. Molecular neurobiology 7 35084653
2022 PCDH9 suppresses melanoma proliferation and cell migration. Frontiers in oncology 7 36452505
2024 Influence of PCDH9 (rs9540720) and narcissistic personality traits on the incidence of major depressive disorder in Chinese first-year university students: findings from a 2-year cohort study. Frontiers in genetics 5 38384361
2025 Spatial and Temporal Expression Patterns of EDA2R, PCDH9, and TRAF7 in Yotari (Dab1) Mice: Implicationsfor Understanding CAKUT Pathogenesis. International journal of molecular sciences 4 40650197
2024 Unraveling the Role of PCDH9 in Breast Cancer and Identifying Therapeutic Strategies for PCDH9-Deficient Tumors. Breast cancer (Dove Medical Press) 3 39279908
2025 The lncRNA MIR22HG suppresses prostate cancer cell proliferation, migration, and epithelial-mesenchymal transition via the miR-4428/PCDH9 axis. Translational cancer research 1 40530115
2026 RNF145 Promotes Hepatocellular Carcinoma Metastasis through Ubiquitination and Degradation of PCDH9. Oncology research 0 41613811
2026 Neuronal activity drives PCDH9 cleavage and nuclear translocation to coordinate structural and functional remodeling. Frontiers in cellular neuroscience 0 41685090
2025 The Interaction Between Family Functioning and the PCDH9 rs9540720 Polymorphism on Major Depressive Disorder in Chinese Freshmen. Psychology research and behavior management 0 40060108
2025 The dual role of PCDH9 in tumors, neurological and developmental diseases. Medical oncology (Northwood, London, England) 0 40986169

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