Meta-Biol

• Pathways

In response to insulin signaling, active AKT phosphorylates the C-terminal region of RAB35 GEFs DENND1A and DENND1B at at least 2 sites in the C-terminal region. This relieves an autoinhibitory conformation of the GEFs, allowing full GEF activity and promoting RAB35 binding. The open conformation of DENN1D proteins is stabilized subsequent to AKT-mediated phosphorylation by binding of a dimer of the 14-3-3 protein YWHAE. Abrogation of AKT phosphorylation disrupts both 14-3-3 and RAB35 binding to DENND1 proteins (Kulasekaran et al, 2015). Active RAB35 is needed for the insulin-dependent translocation of GLUT4 to the plasma membrane (Davey et al, 2012; Humphrey et al, 2013).