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).
Nossova, N, Kulasekaran, G, Lund, I, Cremer, C, Marat, AL, Ioannou, MS, McPherson, PS
Stöckli, J, James, DE, Davey, JR, Lambright, DG, Mishra, AK, Junutula, JR, Humphrey, SJ
James, DE, Yang, G, Stöckli, J, Fazakerley, DJ, Yang, P, Yang, JY, Humphrey, SJ
protein serine/threonine kinase activity of p-T,p-S-AKT [cytosol]
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