Signaling Mechanisms That Regulate Glucose Transport

Abstract

phosphotyrosine-binding Pleckstrin homology Src homology 2 phosphatidylinositol insulin-like growth factor platelet-derived growth factor 5′-AMP-activated protein kinase. Insulin, the major hormonal regulator of glucose transport in humans, has served as a prototypic molecule for understanding cell signaling pathways since its discovery in 1922. It was among the first proteins for which primary amino acid sequence and three-dimensional structure were determined. The insulin receptor was likewise among the first peptide receptors to be identified by ligand binding, and its subunit structure was deduced in the earliest days of modern receptor biology (1Massague J. Pilch P.F. Czech M.P. Proc. Natl. Acad. Sci. U. S. A. 1980; 77: 7137-7141Crossref PubMed Scopus (161) Google Scholar). The structure of its tyrosine kinase domain was the first of the tyrosine kinases to be solved by x-ray crystallography (2Hubbard S.R. EMBO J. 1997; 16: 5572-5581Crossref PubMed Scopus (769) Google Scholar). Further, much is now known about downstream insulin receptor signaling components (3Avruch J. Mol. Cell. Biochem. 1998; 182: 31-48Crossref PubMed Scopus (319) Google Scholar). Despite these advances, our understanding of how insulin and the related proteins, insulin-like growth factors I and II, stimulate glucose transport (via the translocation of glucose transporter proteins from intracellular to plasma membranes) is fragmentary. One reason for this is that the major target for insulin signaling to glucose transport is a complex membrane trafficking pathway that is likely to contain many unknown components. As summarized in the preceding introductory comments (4Olefsky J.M. J. Biol. Chem. 1999; 274: 1863Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar) and detailed in the companion minireviews to be published subsequently (5Pessin J.E. Thurmond D.C. Elmendorf J.S. Coker K.J. Okada S. J. Biol. Chem. 1999; 274: 2593-2596Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar, 6Charron M.J. Katz E.B. Olson A.L. J. Biol. Chem. 1999; 274: 3253-3256Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar), glucose uptake via the GLUT4 isoform of mammalian hexose transporters accounts for most of the stimulatory effect of insulin on this process in muscle and fat cells. GLUT4 rapidly recycles through the plasma membrane/endosomal membrane system in the presence of insulin. However, in the basal state this transporter protein is directed to and retained within specific intracellular membranes through the action of distinct elements within the GLUT4 structure (7Corvera S. Czech M.P. Cell. Dev. Biol. 1996; 7: 249-257Crossref Scopus (5) Google Scholar). Insulin causes movement of GLUT4 out of this sequestered localization, leading to an increase in its steady state concentration on the cell surface membrane where it can catalyze glucose uptake. However, to accomplish this, insulin signaling is likely to regulate GLUT4 trafficking at multiple steps, consistent with data showing insulin also enhances cell surface display of proteins such as transferrin receptor and GLUT1 that recycle to a large extent independently of GLUT4. To further complicate our understanding of this system, different signaling elements may be required to modulate each of these different putative regulated steps in the GLUT4 trafficking pathway. Substrate phosphorylation by the insulin receptor tyrosine kinase appears to involve the binding of phosphorylated receptor tyrosine 960 to phosphotyrosine-binding (PTB)1 domains of substrate proteins (8White M.F. Mol. Cell. Biochem. 1998; 182: 3-11Crossref PubMed Scopus (622) Google Scholar). Adjacent Pleckstrin homology (PH) domains on some substrate proteins also appear critical for receptor binding and phosphorylation. Tyrosine kinase signaling is often initiated by the recruitment of signaling proteins through their Src homology 2 (SH2) or PTB domains to phosphotyrosine sites. In the case of insulin receptor, tyrosine phosphorylation of four related substrate (IRS) proteins (8White M.F. Mol. Cell. Biochem. 1998; 182: 3-11Crossref PubMed Scopus (622) Google Scholar) and Gab-1 (9Rocci S. Tartare-Deckert S. Murdaca J. Wong A.J. Van Obberghen E. Mol. Endocrinol. 1998; 12: 914-923Crossref PubMed Scopus (65) Google Scholar) causes many candidate signaling proteins to be recruited, including: 1) the p110-type phosphatidylinositol 3-kinase (PI 3-kinase) through the SH2 domains of p85 regulatory subunits; 2) Grb2 and the protein tyrosine phosphatase SH-PTP2, which appear to be necessary for p21ras activation (10Pawson T. Nature. 1995; 373: 573-580Crossref PubMed Scopus (2211) Google Scholar); 3) the tyrosine kinase Fyn, which in turn may also activate the PI 3-kinase and p21raspathways; and 4) Rho-associated protein serine/threonine kinase ROKα (11Farah S. Agazie Y. Ohan N. Ngsee J.K. Liu X.J. J. Biol. Chem. 1998; 273: 4740-4746Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scho