YWHAE dimer binds phosphorylated DENND1 proteins

RAB35 GEFs DENND1A and DENND1B are phosphorylated by AKT in response to insulin signaling at at least 2 sites in the C-terminal region. This phosphorylation relieves an autoinhibitory conformation of the GEF that sterically blocks the N-terminal DENN domain, obstructing RAB35 binding and full GEF activity. Subsequent to AKT-dependent phosphorylation, DENN1D proteins are bound by a 14-3-3 dimer, which is thought to stabilize the open conformation of the GEF, promoting full GEF activity and RAB35 binding (Kulasekaran et al, 2015). Active RAB35 contributes to GLUT4 translocation to the plamsa membrane in response to insulin signaling, among other cellular roles (Kulasekaran et al, 2015; Davey et al, 2012; Humphrey et al, 2013).

RAB35 GEFs的DENND1A和DENND1B在胰岛素信号通路刺激下，至少在C端区域的两处位点被AKT磷酸化。此种磷酸化作用缓解了GEF的自身抑制构象，该构象通过空间位阻作用阻止了N端DENN结构域的结合，从而阻碍了RAB35的结合及GEF的完全活性。在AKT依赖性磷酸化之后，DENN1D蛋白被14-3-3二聚体结合，据推测这有助于稳定GEF的开放构象，进而促进GEF的完全活性和RAB35的结合（Kulasekaran等，2015）。活性RAB35在胰岛素信号通路刺激下，参与GLUT4向质膜转位，以及其他细胞功能（Kulasekaran等，2015；Davey等，2012；Humphrey等，2013）。