Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators

Abstract : AS160 and TBC1D1 are related RabGAPs implicated in regulating the trafficking of GLUT4 storage vesicles to the cell surface. All animal species examined contain TBC1D1, whereas AS160 evolved with the vertebrates. TBC1D1 has two clusters of phosphorylated residues, either side of the second PTB domain. Each cluster contains a 14-3-3-binding site. When AMPK is activated in HEK293 cells, 14-3-3s bind primarily to phosphoSer237 in TBC1D1; whereas 14-3-3 binding depends primarily on phosphoThr596 in cells stimulated with insulin-like growth factor 1 (IGF1), epidermal growth factor (EGF) and phorbol ester (PMA); and both phosphoSer237 and phosphoThr596 contribute to 14-3-3 binding in cells stimulated with forskolin. In HEK293 cells, LY294002 inhibits phosphorylation of Thr596 of TBC1D1, and promotes phosphorylation of AMPK and Ser237 of TBC1D1. In vitro phosphorylation experiments indicated regulatory interactions amongst phosphorylated sites, for example phosphorylation of Ser235 prevents subsequent phosphorylation of Ser237. In rat L6 myotubes, endogenous TBC1D1 is strongly phosphorylated on Ser237 and binds to 14-3-3s in response to the AMPK activators AICAR, phenformin and A-769662, whereas insulin promotes phosphorylation of Thr596 but not 14-3-3 binding. In contrast, AS160 is phosphorylated on its 14-3-3-binding sites (Ser341 and Thr642) and binds to 14-3-3s in response to insulin, but not A-769662, in L6 cells. These findings suggest that TBC1D1 and AS160 may have complementary roles in regulating vesicle trafficking in response to insulin and AMPK-activating stimuli in skeletal muscle.
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Shuai Chen, Jane Murphy, Rachel Toth, David G Campbell, Nick A Morrice, et al.. Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. Biochemical Journal, Portland Press, 2007, 409 (2), pp.449-459. ⟨10.1042/BJ20071114⟩. ⟨hal-00478871⟩

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