YWHAE dimer binds phosphorylated DENND1 proteins

Stable Identifier
R-HSA-8933452
Type
Reaction
Species
Homo sapiens
Compartment
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Summation

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).

Literature References
PubMed ID Title Journal Year
22762500 TBC1D13 is a RAB35 specific GAP that plays an important role in GLUT4 trafficking in adipocytes

Davey, JR, Humphrey, SJ, Junutula, JR, Mishra, AK, Lambright, DG, James, DE, Stöckli, J

Traffic 2012
26055712 Phosphorylation-dependent Regulation of Connecdenn/DENND1 Guanine Nucleotide Exchange Factors

Kulasekaran, G, Nossova, N, Marat, AL, Lund, I, Cremer, C, Ioannou, MS, McPherson, PS

J. Biol. Chem. 2015
23684622 Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2

Humphrey, SJ, Yang, G, Yang, P, Fazakerley, DJ, Stöckli, J, Yang, JY, James, DE

Cell Metab. 2013
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