Subcellular compartmentalization and trafficking of the insulin-responsiveglucose transporter, GLUT4

Insulin increases glucose transport into cells of target tissues, primarily striated muscle and adipose. This is accomplished via the insulin-dependen t translocation of the facilitative glucose transporter 4 (GLUT4) from intr acellular storage sites to the plasma membrane. Insulin binds to the cell-s urface insulin receptor and activates its intrinsic tyrosine kinase activit y. The subsequent activation of phosphatidylinositol 3-kinase (PI 3-K) is w ell 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) (PKC lambda/zeta) appear to function downstream of PI 3-K, but how these e ffectors influence GLUT4 translocation remains unknown. In addition, emergi ng evidence suggests that a second signaling cascade that functions indepen dently of the PI 3-K pathway is also required for the insulin-dependent tra nslocation of GLUT4. This second pathway involves the Rho-family GTP bindin g protein TC10, which functions within the specialized environment of lipid raft microdomains at the plasma membrane. Future work is necessary to iden tify the downstream effectors that link TC10, PKB, and PKC lambda/zeta to G LUT4 translocation. Progress in this area will come from a better understan ding of the compartmentalization of GLUT4 within the cell and of the mechan isms responsible for targeting the transporter to specialized insulin-respo nsive storage compartments. Furthermore, an understanding of how GLUT4 is r etained within and released from these compartments will facilitate the ide ntification of downstream signaling molecules that function proximal to the GLUT4 storage sites. (C) 2001 Academic Press.