Subcellular compartmentalization and trafficking of the insulin-responsive glucose transporter, GLUT4.
Insulin increases glucose transport into cells of target tissues, primarily striated muscle and adipose. This is accomplished via the insulin-dependent translocation of the facilitative glucose transporter 4 (GLUT4) from intracellular storage sites to the plasma membrane. Insulin binds to the cell-surface insulin receptor and activates its intrinsic tyrosine kinase activity. The subsequent activation of phosphatidylinositol 3-kinase (PI 3-K) is well known to be necessary for the recruitment of GLUT4 to the cell surface. Both protein kinase B (PKB) and the atypical protein kinase C(lambda/zeta) (PKClambda/zeta) appear to function downstream of PI 3-K, but how these effectors influence GLUT4 translocation remains unknown. In addition, emerging evidence suggests that a second signaling cascade that functions independently of the PI 3-K pathway is also required for the insulin-dependent translocation of GLUT4. This second pathway involves the Rho-family GTP binding protein TC10, which functions within the specialized environment of lipid raft microdomains at the plasma membrane. Future work is necessary to identify the downstream effectors that link TC10, PKB, and PKClambda/zeta to GLUT4 translocation. Progress in this area will come from a better understanding of the compartmentalization of GLUT4 within the cell and of the mechanisms responsible for targeting the transporter to specialized insulin-responsive storage compartments. Furthermore, an understanding of how GLUT4 is retained within and released from these compartments will facilitate the identification of downstream signaling molecules that function proximal to the GLUT4 storage sites.
Watson
R T
RT
Department of Physiology and Biophysics, University of Iowa, Iowa, Iowa City 52242, USA.
Pessin
J E
JE
D017667:Adipocytes / Q000378:metabolism; D020816:Amino Acid Motifs; D002451:Cell Compartmentation; D051275:Glucose Transporter Type 4; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008954:Models, Biological; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020033:Protein Isoforms; D021381:Protein Transport / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms; C495692:SLC2A4 protein, human; D019869:Phosphatidylinositol 3-Kinases; C503256:RHOQ protein, human; D020741:rho GTP-Binding Proteins