DEPDC7

DEPDC7 is a DEP-domain-containing cytoplasmic and nuclear protein that functions as a tumor suppressor in hepatocellular carcinoma by restraining cell proliferation, cell cycle progression, migration, invasion, and epithelial–mesenchymal transition (PMID:29344171, PMID:27016254, PMID:41930189). It physically interacts with CARMA2 and CARMA3, components of the CBM signaling complex, and its expression is required for NF-κB activation downstream of G protein-coupled receptor stimulation (PMID:25541973). DEPDC7 also directly binds the JAK1 kinase domain, and its overexpression suppresses JAK1/STAT3 signaling, promotes apoptosis, and reverses EMT marker expression in hepatoma cells (PMID:41930189).

1. 2014 Medium

   The molecular partners and signaling output of DEPDC7 were unknown; co-immunoprecipitation revealed that DEPDC7 physically binds CARMA2 and CARMA3 and is required for NF-κB activation downstream of GPCRs, establishing it as a component of CBM-dependent innate signaling.

   Evidence Co-immunoprecipitation, shRNA knockdown with NF-κB reporter assay, subcellular localization imaging in HEK293T and related cell lines

   PMID:25541973

   Open questions at the time

   • No reciprocal validation in an independent lab
   • Whether DEPDC7 acts catalytically (e.g., via its RhoGAP-like domain) or as a scaffold for CBM assembly is unresolved
   • Physiological GPCR ligands and tissue contexts for this NF-κB role are not defined
2. 2016 Medium

   Whether DEPDC7 influences cancer cell behavior was untested; knockdown in hepatoma cells increased migration and invasion, providing the first evidence for a tumor-suppressive role.

   Evidence Lentiviral shRNA knockdown in HepG2 cells; Matrigel migration and invasion assays

   PMID:27016254

   Open questions at the time

   • Single cell line and single lab; awaits independent confirmation
   • Downstream effectors mediating the anti-migratory effect are not identified
3. 2017 Medium

   Bidirectional gain- and loss-of-function experiments extended the tumor-suppressive phenotype to proliferation and cell cycle control, consolidating DEPDC7 as a negative regulator of hepatoma cell growth and motility.

   Evidence Overexpression and shRNA knockdown in SK-Hep-1, Huh-7, and HepG2 hepatoma lines; proliferation, cell cycle, migration, and invasion assays

   PMID:29344171

   Open questions at the time

   • No in vivo tumor model
   • Mechanism connecting DEPDC7 to cell cycle arrest not molecularly defined
4. 2026 Medium

   The signaling pathway through which DEPDC7 suppresses hepatoma growth was identified: DEPDC7 directly binds the JAK1 kinase domain to suppress JAK1/STAT3 signaling and EMT, linking its tumor-suppressive activity to a defined kinase target.

   Evidence Co-immunoprecipitation, molecular docking, RNA-seq, overexpression in Huh-7 cells with western blot for JAK1/STAT3 and EMT markers

   PMID:41930189

   Open questions at the time

   • JAK1 interaction demonstrated by Co-IP and docking but not by orthogonal methods (e.g., in vitro pulldown with purified proteins)
   • Whether DEPDC7 inhibits JAK1 catalytic activity directly or promotes its degradation is unresolved
   • Relationship between the CARMA/NF-κB axis and the JAK1/STAT3 axis of DEPDC7 function is not integrated

• It remains unknown whether DEPDC7's DEP or RhoGAP-like domains possess intrinsic enzymatic activity, how the NF-κB–promoting and JAK1/STAT3–suppressing functions are coordinated, and whether DEPDC7 acts as a tumor suppressor in vivo.
• No in vivo genetic model (knockout mouse or xenograft rescue)
• No biochemical characterization of DEP or RhoGAP domain catalytic activity
• No structural data for DEPDC7 or its complexes