A positive regulatory role for Cbl family proteins in tumor necrosis factor-related activation-induced cytokine (TRANCE) and CD40L-mediated Akt activation

Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE) is a TNF family member essential for osteoclast differentiation, and it induces the activation and survival of osteoclasts and mature dendritic cells. We recently demonstrated that TRANCE activates Akt via a mechanism involving TRANCE receptor (TRANCE-R)/RANK, TRAF6, and c-Src. Here, we show that TRANCE-R and CD40 recruit TRAF6, Cbl family-scaffolding proteins, and the phospholipid kinase phosphatidylinositol 3-kinase in a ligand-dependent manner. The recruitment of Cbl-b and c-Cbl to TRANCE-R, is dependent upon the activity of Src-family kinases. TRANCE and CD40L-mediated Akt activation is defective in Cbl-b -/- dendritic cells, and CD40L-mediated Akt activation is defective in c-Cbl -/- B cells. These findings implicate Cbl family proteins as not only negative regulators of signaling but as positive modulators of TNF receptor superfamily signaling as well.