RANK/TNFRSF11A ELISA Kit, Human

When RANK on osteoclasts is activated it sends signals into the cells through adapter proteins. RANK contains 383 amino acids in its intracellular domain (residues 234–616), which contain three putative binding domains (termed I, II, and III) for tumor necrosis factor receptor associated factors (TRAFs). These TRAF binding domains were shown to be functionally important for the RANK dependent induction of NF- κB and JNK activities. However, interaction with TRAFs is necessary for NFκB activation but not essential for activation of the JNK pathway. RANKL also activates the anti-apoptotic Akt through a signaling complex involving c-Src and TRAF6. c-Src and TRAF6 interact with each other and with RANK after receptor engagement and a deficiency in c-Src or addition of Src family kinase inhibitors blocks TRANCE mediated Akt activation in osteoclasts. TRAF6, in turn, increases the kinase activity of c-Src leading to tyrosine phosphorylation of downstream signaling molecules such as c-Cbl. Moreover, RANK can recruit TRAF6, Cbl family scaffolding proteins, and the phospholipid kinase PI3-K in a ligand and Src dependent manner. RANKL mediated Akt activation is defective in cbl-b-/- dendritic cells. Thus, Cbl family proteins are not only negative regulators of signaling, but also the positive modulators of TNFR superfamily signalling.³