Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic.
Vesicular traffic of the glucose transporter GLUT4 occurs in response to insulin, muscle contraction, and metabolic stimuli that lead to changes in the energy status of the cell. These stimuli are associated with linked kinase cascades that lead to changes in glucose uptake that meet the energy challenges imposed on the highly regulated cell types in insulin-responsive tissues. The need to mechanistically link these kinase-associated stimuli to identifiable intermediates in vesicular traffic has long been known but has been difficult to fulfill. The Rab-GTPase-activating proteins AS160 and TBC1D1 have now emerged as strong candidates to fill this void. Here we review the initial discovery of these proteins as phosphorylated substrates for Akt and the more recent emerging data that indicate that these proteins are substrates for additional kinases that are downstream of contraction and energy status signaling. The mechanism of coupling these phosphorylated proteins to vesicle traffic appears to be dependent on linking to small GTPase of the Rab family. We examine the current state of a hypothesis that suggests that phosphorylation of the Rab-GTPase-activating proteins leads to increased GTP loading of Rab proteins on GLUT4 vesicles and subsequently to increased interaction with Rab effectors that control GLUT4 vesicle translocation.
Sakamoto
Kei
K
MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow St., Dundee, DD1 5EH, UK. k.sakamoto@dundee.ac.uk
Holman
Geoffrey D
GD
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; C526441:TBC1D1 protein, human; C518767:TBC1D4 protein, human; D051057:Proto-Oncogene Proteins c-akt