CPNE3

CPNE3 is a calcium-dependent phospholipid-binding protein that functions as a pro-tumorigenic signaling adaptor, driving cell migration, invasion, and proliferation across multiple cancer types (PMID:23713811, PMID:41190648). Its central mechanism is an interaction with the scaffold protein RACK1—mapped to the CPNE3 VWFA domain—that engages receptor tyrosine kinase signaling: CPNE3 associates with phosphorylated ErbB2 and RACK1 to activate focal adhesion kinase (FAK) (PMID:30519322), and the same VWFA-mediated RACK1 interaction activates MET (c-MET) signaling to promote NSCLC proliferation and migration (PMID:41190648). CPNE3 additionally activates PI3K/AKT signaling to promote proliferation and suppress apoptosis (PMID:35003348), and in colorectal cancer binds KIF4 to drive PI3K/AKT/mTOR activation and suppress autophagy (PMID:41816564). Beyond kinase pathways, CPNE3 participates in a positive feedback loop with the Hippo effector YAP1, being a YAP1/TEAD transcriptional target that in turn binds cytoplasmic YAP1 and blocks its β-TRCP–mediated ubiquitination and degradation (PMID:38493426). CPNE3 also suppresses EMT through regulation of SQSTM1/p62, with p62 acting downstream of CPNE3 to restrain migration (PMID:39844538). Outside cancer, CPNE3 maintains glucose-stimulated insulin secretion in pancreatic β-cells by sustaining expression of GLUT2, NeuroD1, INSR, and insulin (PMID:34667273), and protects cardiomyocytes from ischemia/reperfusion injury via RACK1 (PMID:34970351).

1. 2013 Medium

   Established CPNE3 as a functional driver of cancer cell motility rather than a bystander, by showing loss- and gain-of-function effects on migration, invasion, and in vivo metastasis.

   Evidence siRNA knockdown and overexpression in NSCLC cell lines with in vitro migration/invasion assays and a mouse metastasis model

   PMID:23713811

   Open questions at the time

   • No molecular partner or signaling pathway identified
   • Mechanism of how CPNE3 promotes motility unresolved
2. 2018 Medium

   Connected CPNE3's motility phenotype to a defined signaling axis by identifying RACK1 and phospho-ErbB2 as binding partners and placing CPNE3 upstream of RACK1/FAK.

   Evidence Co-immunoprecipitation and RACK1 siRNA epistasis (knockdown rescues CPNE3-overexpression phenotype) with FAK pathway western blots in NSCLC

   PMID:30519322

   Open questions at the time

   • Binding interface on CPNE3 not mapped
   • Direct vs indirect ErbB2 interaction unclear
3. 2021 Medium

   Extended the migration/invasion and FAK-pathway role of CPNE3 beyond lung cancer to glioblastoma, and additionally implicated PI3K/AKT in CPNE3-driven proliferation and apoptosis suppression.

   Evidence siRNA knockdown (FAK markers) plus overexpression with xenograft, GSEA, and pharmacological PI3K/AKT rescue (LY294002) in GBM cells

   PMID:33725213 PMID:35003348

   Open questions at the time

   • No direct binding partner demonstrated for the FAK arm in GBM
   • How CPNE3 engages PI3K/AKT mechanistically unresolved
4. 2021 Medium

   Revealed non-cancer physiological roles, showing CPNE3 is required for glucose-stimulated insulin secretion and for cardioprotection, broadening its functional repertoire.

   Evidence Cpne3 silencing in INS-1 β-cells (GSIS, glucose uptake, downstream regulator markers) and RACK1-dependent overexpression in hypoxia/reoxygenation H9c2 cells plus a rat I/R model

   PMID:34667273 PMID:34970351

   Open questions at the time

   • Direct molecular targets in β-cells beyond expression changes unknown
   • Whether cardioprotection uses the same RACK1/kinase axis as cancer unclear
5. 2024 Medium

   Embedded CPNE3 in a self-reinforcing transcriptional circuit by showing it is both a YAP1/TEAD target and a stabilizer of YAP1 protein against β-TRCP-mediated degradation.

   Evidence ChIP/luciferase reporter, CPNE3–YAP1 co-IP, and ubiquitination assays with proliferation/invasion readouts in gastric cancer

   PMID:38493426

   Open questions at the time

   • Structural basis of CPNE3–YAP1 binding not defined
   • How cytoplasmic CPNE3 shields YAP1 from β-TRCP mechanistically unresolved
6. 2025 Medium

   Resolved the structural basis of the RACK1 interaction (VWFA domain) and identified MET as an additional effector, while a parallel arm linked CPNE3 to EMT suppression via SQSTM1/p62.

   Evidence Domain-mapping co-IP, MET inhibitor and RACK1 siRNA epistasis, plus SILAC proteomics and p62 knockdown rescue in NSCLC/LUAD cells with xenografts

   PMID:39844538 PMID:41190648 PMID:41313527

   Open questions at the time

   • Context-dependence of EMT-promoting vs EMT-suppressing effects across studies unreconciled
   • Whether RACK1 bridges CPNE3 to both FAK and MET via the same interface unclear
7. 2026 Medium

   Identified KIF4 as a direct CPNE3 partner linking it to PI3K/AKT/mTOR activation and autophagy suppression in colorectal cancer.

   Evidence Co-immunoprecipitation, immunofluorescence, and KIF4 knockdown rescue of CPNE3-overexpression phenotype with autophagy and PI3K/AKT/mTOR marker western blots

   PMID:41816564

   Open questions at the time

   • Direct biochemical KIF4 binding interface not mapped
   • Mechanistic link between KIF4 and PI3K/AKT/mTOR unresolved

• It remains unknown how CPNE3's calcium/phospholipid-binding biochemistry mechanistically governs its diverse partner engagements (RACK1, YAP1, KIF4) and whether membrane recruitment integrates these arms into a unified function.
• No structural model of CPNE3 with any partner
• Role of calcium/lipid binding in partner selection untested
• Reciprocal/context-dependent EMT effects not reconciled