DEPDC7

DEPDC7 is a cytosolic DEP- and RhoGAP-domain-containing protein that functions as a context-specific regulator of NF-κB signaling and as a tumor suppressor (PMID:25541973, PMID:29344171, PMID:27016254). In the CBM-NF-κB pathway, DEPDC7 binds the CARMA2 and CARMA3 scaffolds, and its overexpression activates NF-κB while its knockdown selectively impairs NF-κB activation downstream of G protein-coupled receptor stimuli (CARMA2/3-dependent) but not CARMA1-dependent stimuli, placing it specifically in the CARMA2/3 branch of CBM signaling (PMID:25541973). In hepatocellular carcinoma, DEPDC7 acts as a tumor suppressor: gain-of-function inhibits proliferation, cell cycle entry, and motility/invasion, whereas loss-of-function promotes these phenotypes (PMID:29344171, PMID:27016254). Mechanistically, DEPDC7 directly interacts with the JAK1 kinase domain and suppresses JAK1/STAT3 signaling, thereby inhibiting epithelial-mesenchymal transition (raising E-cadherin while reducing N-cadherin and vimentin) and promoting cell cycle arrest and apoptosis (PMID:41930189).

1. 2014 Medium

   Established DEPDC7's first molecular role by placing it within the CBM-NF-κB signaling module, answering whether this DEP-domain protein had a defined pathway function.

   Evidence Co-immunoprecipitation with CARMA2/CARMA3, subcellular localization, and shRNA knockdown with NF-κB reporter assays across distinct receptor stimuli in cell lines

   PMID:25541973

   Open questions at the time

   • Reciprocal binding and the structural basis of the CARMA2/3 interaction not resolved
   • Whether DEPDC7's RhoGAP domain contributes catalytically to NF-κB activation is untested
   • Single-lab study without independent replication
2. 2017 Medium

   Defined DEPDC7 as a tumor suppressor in hepatocellular carcinoma through bidirectional functional perturbation, addressing whether its expression causally affects cancer cell behavior.

   Evidence Overexpression and shRNA knockdown in hepatoma cell lines with proliferation, cell cycle, migration, and invasion assays

   PMID:27016254 PMID:29344171

   Open questions at the time

   • No mechanistic pathway placement linking DEPDC7 to the observed phenotypes
   • No in vivo tumor model
   • Relationship to its earlier NF-κB role left unexplored
3. 2026 Medium

   Provided the mechanistic basis for DEPDC7's tumor-suppressive phenotype by identifying JAK1 as a direct binding partner and JAK1/STAT3 suppression as the operative pathway.

   Evidence Co-immunoprecipitation and molecular docking against the JAK1 kinase domain, RNA-seq pathway analysis, and functional assays in Huh-7 cells with EMT marker western blots and electron microscopy

   PMID:41930189

   Open questions at the time

   • Direct JAK1 binding supported by Co-IP plus docking but not by structural or reconstitution methods
   • Whether DEPDC7 acts through its RhoGAP or DEP domain to inhibit JAK1 is unknown
   • Not independently replicated; nuclear localization role uncharacterized

• How DEPDC7's two reported activities — CARMA2/3-dependent NF-κB activation and JAK1/STAT3 suppression — are reconciled within a single protein, and the catalytic role of its RhoGAP domain, remain unresolved.
• No structural characterization of DEP or RhoGAP domain function
• GAP substrate (if any) not identified
• Cell-type context determining NF-κB versus JAK1/STAT3 output is undefined