Abstract
The full program for expression of insulin’s action is contained in a locus on the cell surface, the insulin receptor (1,2). During the last decade, a general scheme of the receptor’s structure has been developed (3–8). Recently, our concept of the receptor’s structure has been refined by data obtained from cloning the receptor and other techniques (9–14). The picture that has emerged is that the predominant form of the receptor on the cell surface is that of a disulfide-linked heterotetrameric glycoprotein consisting of two distinct subunits, alpha and beta. Studies employing photoaffinity labeling techniques, as well as studies in which insulin is bound to and then affinity crosslinked to the receptor have shown that the alpha subunit contains the ligand binding region and hence must have a significant extracellular domain. In support of this, analysis of the sequence derived from the recent cloning of the receptor predicts that the alpha subunit lacks a significant hydrophobic region, suggesting that the alpha subunit is entirely extracellular. The beta subunit has a short extracellular domain, a hydrophobic membrane spanning region and an intracytoplasmic domain (13,14). As detailed below, this intracytoplasmic domain contains a tyrosine specific protein kinase activity (15–18). Upon binding of insulin to its receptor this kinase is somehow activated. Data are accumulating to suggest that activation of this kinase initiates a cascade of events leading to insulin’s bioeffects. Thus the alpha and beta subunits of the insulin receptor subserve distinct but interdependent functions in the pathway leading from insulin binding to insulin action.
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References
P. Freychet, J. Roth, and D. M. Neville, Insulin receptors in the liver: specific binding of 125I-insuin to the plasma membrane and its relation to insulin bioactivity, Proc. Natl. Acad. Sci. USA 68:1833–1837 (1971).
C. R. Kahn, K. L. Baird, J. S. Flier, C. Grunfeld, J. T. Harmon, L. C. Harrison, F. A. Karlsson, M. Kasuga, G. L. King, U. Lang, J. M. Podskalney, and E. Van Obberghen, Insulin receptor antibodies and the mechanism of insulin action, Rec. Progr. Horm. Res. 37:477–538 (1981).
P. Cuatrecasas, Interaction of concanavalin A and wheat germ agglutinin with the insulin receptor of fat cells and liver, J. Biol. Chem. 248:3528–3534 (1973).
J. Massague, P. Pilch, and M. P. Czech, Electrophoretic resolution of three major insulin receptor structures with unique subunit stoichio-metries. Proc. Natl. Acad. Sci. USA 77:7137–7141 (1980).
J. Massague, P. Pilch, and M. P. Czech, A unique proteolytic cleavage site on the B-subunit of the insulin receptor. J. Biol. Chem. 256:3182–3190 (1981).
J. A. Hedo, M. Kasuga, E. Van Obberghen, J. Roth, and C. R. Kahn, Direct demonstration of glycosylation of insulin receptor subunits by biosynthetic labeling: evidence for heterogeneity, Proc. Natl. Acad. Sci. USA 78:4791–4795 (1981).
P. F. Pilch, and M. P. Czech, Interaction of cross-linking agents with the insulin effector systems of isolated fat cells, J. Biol. Chem. 254:3375–3381 (1979).
C. C. Yip, C. W. T. Yeung, M. L. Moule, Photoaffinity labeling of insulin receptor proteins of liver plasma membrane proteins, Biochemistry 19:70–76 (1980).
M. Kasuga, J. A. Hedo, K. M. Yamada, and C. R. Kahn, The structure of the insulin receptor and its subunits: evidence for multiple non-reduced forms and a 210K possible proreceptor, J. Biol. Chem. 257:10392–10399 (1982).
Y. Fujita-Yamaguchi, S. Choi, Y. Sakamoto, and K. Itakura, Purification of the insulin receptor with full binding activity, J. Biol. Chem. 258:5045–5049 (1983).
S. Jacobs, E. Hazum, and P. Cuatrecasas, Digestion of insulin receptors with proteolytic and glycosidic enzymes — effects on purified and membrane-associated receptor subunits, Biochem. Biophys. Res. Commun. 94:1066–1073 (1980).
V. L. Herzberg, F. Grigorescu, A. S. B. Edge, R. Spiro, and C. R. Kahn, Characterization of insulin receptor carbohydrate by comparison of chemical and enzymatic deglycosylation, Biochem. Biophys. Res. Commun. 129:789–795 (1985).
A. Ullrich, J. R. Bell, E. Y. Chen, R. Herrera, L. M. Petruzelli, T. J. Dull, A. Gray, L. Coussens, Y.-C. Liao, M. Tsubokawa, A. Mason, P. H. Seeburg, C. Grunfeld, O. M. Rosen, and J. Ramachandran, Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes, Nature 313:756–761 (1985).
Y. Ebina, L. Ellis, K. Jarnagin, M. Edery, L. Graf, E. Clauser, J.-H. Ou, F. Marsiarz, Y. Kan, I. D. Goldfine, R. A. Roth, and W. J. Rutter, The human insulin receptor cDNA: the structural basis for hormone activated transmembrane signalling. Cell 40:747–758 (1985).
M. Kasuga, F. A. Karlsson, and C. R. Kahn, Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor, Science 215:185–187 (1982).
R. A. Roth, and D. J. Cassell, Insulin receptor: evidence that it is a protein kinase, Science 219:299–301 (1983).
M. A. Shia, and P. Pilch, The β-subunit of the insulin receptor is an insulin-activated protein kinase. Biochemistry 22:717–723 (1983).
L. Petruzelli, R. Herrera, and O. M. Rosen, Insulin receptor is an insulin dependent tyrosine protein kinase: copurification of insulin binding and protein kinase activity to homogeneity from human placenta. Proc. Natl. Acad. Sci. USA 81:3327–3331 (1984).
J. A. Hedo, and P. Gorden, Biosynthesis of the insulin receptor, Horm. Metabol. Res. 17:487–490 (1985).
J. A. Hedo, E. Collier, and A. Watkinson, Myristyl and palmityl acyla-tion of the insulin receptor, J. Biol. Chem. 262:954–957 (1987).
M. K. Kamps, J. E. Buss, and B. M. Sefton, Rous sarcoma virus transforming protein lacking myristic acid phosphorylates known polypeptide substrates without inducing transformation, Cell 45:105–112 (1985).
A. I. Magee, and M. J. Schlesinger, Fatty acid acylation of eucaryotic cell membrane proteins, Biochim. Biophys. Acta 694:279–289 (1982).
J. A. Hedo, C. R. Kahn, M. Hayashi, K. M. Yamada, and M. Kasuga, Biosynthesis and glycosylation of the insulin receptor. Evidence for a single polypeptide precursor of the two major subunits, J. Biol. Chem. 258:10020–10026 (1983).
J. A. Hedo, and I. A. Simpson, Biosynthesis of the insulin receptor in rat adipose cells, intracellular processing of the Mr-190,000 pro-receptor, Biochem. J. 232:71–78 (1985).
J. Forsayeth, B. Maddux, and I. D. Goldfine, Biosynthesis and processing of the human insulin receptor, Diabetes 35:837–846 (1986).
G. V. Ronnett, V. P. Knutsen, R. A. Kohanski, T. L. Simpson, and M. D. Lane, Role of glycosylation in the processing of newly translated insulin proreceptor in 3T3–L1 adipocytes, J. Biol. Chem. 259:4566–4575 (1984).
S. Jacobs, F. C. Kull, and P. Cuatrecasas, Monensin blocks the maturation of receptors for insulin and somatomedin C.: identification of receptor precursors, Proc. Natl. Acad. Sci. USA 80:1228–1231 (1983).
V. Duronio, S. Jacobs, and P. Cuatrecasas, Complete glycosylation of the insulin and insulin-like growth factor I receptors is not necessary for their biosynthesis and function. Use of swainsonine as an inhibitor in IM-9 cells, J. Biol. Chem. 261:970–975 (1986).
H. Schachter, Glycoproteins: their structure, biosynthesis and possible clinical implications, Clin. Biochem. 17:3–14 (1983).
N. Sharon, Progress in glycoprotein research, Trends Biochem. Sci. 9:198–202 (1984).
R. W. Rees-Jones, J. A. Hedo, Y. Zick, and J. Roth, Insulin stimulated phosphorylation of the insulin receptor precursor, Biochem. Biophys. Res. Commun. 116–417–422 (1983).
M. Muggeo, P. DeMeyts, and J. Roth, The insulin receptor of vertebrates is functionally more conserved during evolution than the hormone itself, Endocrinology 104 :1393–1402 (1979).
W. Kemmler, R. Renner, A. Zynamon, and K. D. Hepp, Interactions between insulins and liver membrane receptors of guinea pig, calf and chicken. Exclusion of a species specific insulin receptor. Biochim. Biophys. Acta, 543:349–356 (1978).
C. C. Yip, M. L. Moule, and C. W. T. Yeung, Characterization of insulin receptor subunits in brain and other tissues by photoaffinity labeling, Biochem. Biophys. Res. Commun. 96:1671–1678 (1981).
K. A. Heidenreich, N. R. Zahnheiser, P. Berhanu, D. Brandenberg, and J. Olefsky, Structural differences between insulin receptors in the brain and peripheral target tissues, J. Biol. Chem. 258:8527–8530 (1983).
S. A. Hendricks, C-D. Agardh, S. I. Taylor, and J. Roth, Unique features of the insulin receptor of rat brain, J. Neurochem. 43:1302–1309 (1984).
J. Sheraer, and D. LeRoith, The interaction of brain insulin receptors with wheat germ agglutinin, Neuropeptides 9:1–8 (1987).
T. Ciaraldi, R. Robbins, J. W. Leidy, P. Thamm, and P. Berhanu, Insulin receptors on cultures hypothalamic cells: functional and structural differences from receptors on peripheral target cells, Endocrinology 116:2179–2185 (1985).
K. A. Heidenreich, and D. Brandenburg, Oligosaccharide heterogeneity of insulin receptors. Comparison of N-linked glycosylation of insulin receptors in adipocytes and brain, Endocrinology 118:1835–1842 (1986).
L. Bassas, F. de Pablo, M. A. Lesniak, and J. Roth, The insulin receptors of chick embryo show tissue specific structural differences which parallel those of the insulin-like growth factor I receptors, Endocrinology (in press).
J. Simon, and D. LeRoith, Insulin receptors of chicken liver and brain: characterization of alpha and beta subunit properties, Eur. J. Biochem. 158:125–132 (1986).
J. Shemer, J. Penhos, and D. LeRoith, Insulin receptors in lizard brain and liver: structural and functional studies of the alpha and beta subunits demonstrate evolutionary conservation. Diabetologia 29:321–329 (1986).
C. Hart, J. Shemer, J. C. Penhos, M. A. Lesniak, J. Roth, and D. LeRoith, Frog brain and liver show evolutionary conservation of tissue specific differences among insulin receptors, Gen. and Comp. Endocrin. (in press).
W. Lowe, and D. LeRoith, Insulin receptors from guinea pig liver and brain: structural and functional studies, Endocrinology 118:1669–1677 (1986).
S. Gammeltoft, M. Fehlmann, and E. Van Obberghen, Insulin receptors in the mammalian central nervous system: binding characteristics and subunit structure. Biochimie 67:1147–1153 (1985).
W. L. Lowe, F. T. Boyd, D. W. Clarke, M. K. Raizada, C. Hart, and D. LeRoith, Development of brain insulin receptors: structural and functional studies of insulin receptors from whole brain and primary cell cultures, Endocrinology 119:25–35 (1986).
R. J. Comi, G. Grunberger, and P. Gorden, Relationship of insulin binding and insulin-stimulated tyrosine kinase activity is altered in type II diabetes, J. Clin. Invest. 79:453–462 (1987).
F. Wold, Fatty acylation of proteins (Keep fit with fat?), Trends Biochem. Sci. 11:58–59 (1986).
E. Van Obberghen, B. Rossi, A. Kowalski, H. Gazzano, and G. Ponzio, Receptor-mediated phosphorylation of the hepatic insulin receptor: evidence that the Mr 95,000 receptor subunit is its own kinase, Proc. Natl. Acad. Sci. USA 80:945–949 (1983).
Y. Zick, J. Whittaker, and J. Roth, Insulin stimulated phosphorylation of its own receptor. Activation of a tyrosine-specific protein kinase that is tightly associated with the receptor, J. Biol. Chem. 258:3431–3434 (1983).
M. Kasuga, Y. Fujita-Yamaguchi, D. L. Blithe, M. F. White, and C. R. Kahn, Characterization of the insulin receptor kinase purified from human placental membranes, J. Biol. Chem. 258:10973–10980 (1983).
R. A. Nemenoff, Y. C. Kwok, G. I. Shulman, P. J. Blackshear, R. Osathamondh, and J. Avruch, Insulin-stimulated tyrosine protein kinase. Characterization and relation to the insulin receptor. J. Biol. Chem. 259:5058–5065 (1984).
C. F. Burant, M. K. Teutelaar, G. E. Landreth, and M. G. Buse, Phosphorylation of insulin receptors solubilized from rat skeletal muscle, Diabetes 33:704–708 (1984).
M. R. Hammerman, and J. R. Gavin III, Insulin stimulated phosphorylation and insulin binding in canine renal basolateral membranes, Am. J. Physiol. 247:F408-F417 (1984).
L. Petruzelli, R. Herrera, R. Garcia-Arenas, and O. Rosen, Acquisition of insulin-dependent tyrosine kinase activity during Drosophila embryo-genesis, J. Biol. Chem. 260:16072–16075 (1985).
R. W. Rees-Jones, M. Quarum, S. A. Hendricks, and J. Roth, The insulin receptor of rat brain is coupled to tyrosine kinase activity, J. Biol. Chem. 259:3470–3474 (1984).
T. Hunter, and J. A. Cooper, Protein-tyrosine kinases, Annu. Rev. Bio-chem. 54:897–930 (1985).
E. G. Krebs, Historical perspective on protein phosphorylation and a classification system for protein kinases, Phil. Trans. R. Soc. Lond. 303:3–11 (1983).
M. A. Shia, J. B. Rubin, and P. F. Pilch, The insulin receptor protein kinase. Physicochemical requirements for activity, J. Biol. Chem. 258:14450–14455 (1983).
M. F. White, H. U. Häring, M. Kasuga, and C. R. Kahn, Kinetic properties and sites of autophosphorylation of the partially purified insulin receptor from hepatoma cells, J. Biol. Chem. 259:255–264 (1984).
Y. Zick, R. W. Rees-Jones, and J. Roth, Insulin-induced phosphorylation of the insulin receptor: a very early event at the target cell, in “Proceeding of the 11th Congress of the International Diabetes Federation,” Excerpta Medica, Amsterdam (1983), pp. 161–170.
Y. Zick, M. Kasuga, C. R. Kahn, and J. Roth, Characterization of insulin-mediated phosphorylation of the insulin receptor in a cell free system, J. Biol. Chem. 258:75–80 (1983).
D. T. Pang, B. R. Sharma, J. A. Shafer, M. F. White, and C. R. Kahn, Predominance of tyrosine phosphorylation of insulin receptors during the initial response of intact cells to insulin, J. Biol. Chem. 260:7131–7136 (1985).
H. H. Klein, G. R. Freidenberg, M. Kladde, and J. M. Olefsky, Insulin activation of insulin receptor tyrosine kinase activity in intact rat adipocytes: an in vitro system to measure histone kinase activity of insulin receptors activated in vitro, J. Biol. Chem. 261:4691–4697 (1986).
O. M. Rosen, R. Herrera, Y. Oluwe, L. Petruzelli, and M. H. Cobb, Phosphorylation activates the insulin receptor tyrosine kinase, Proc. Natl. Acad. Sci. USA 80:3237–3240 (1983).
K.-T. Yu, and M. P. Czech, Tyrosine phosphorylation of the insulin receptor subunit activates the receptor-associated tyrosine kinase activity. J. Biol. Chem. 259:5277–5286 (1984).
M. Kasuga, Y. Fujita-Yamaguchi, D. L. Blithe, M. F. White, and C. R. Kahn, Characterization of the insulin receptor kinase purified from human placental membranes, J. Biol. Chem. 258:10973–10980 (1983).
L. A. Stadtmauer, and O. M. Rosen, Phosphorylation of exogenous substrates by the insulin receptor-associated protein kinase, J. Biol. Chem. 258:6682–6685 (1983).
E. M. Sale, M. F. White, and C. R. Kahn, Phosphorylation of glycolytic and gluconeogenic enzymes by the insulin receptor kinase, J. Cellular Biochem. 29:15–26 (1986).
Y. Zick, G. Grunberger, R. W. Rees-Jones, and R. J. Comi, Use of tyrosine containing polymers to characterize the substrate specificity of insulin and other hormone-stimulated tyrosine kinases, Eur. J. Biochem. 148:177–182 (1985).
S. Braun, W. E. Raymond, and E. Rucker, Synthetic tyrosine polymers as substrates and inhibitors of tyrosine-specific protein kinases, J. Biol. Chem. 259:2051–2054 (1984).
M. F. White, S. Takayama, and C. R. Kahn, Differences in the sites of phosphorylation of the insulin receptor in vivo and in vitro, J. Biol. Chem. 260:9470–9478 (1985).
J. Shemer, N. Perrotti, J. Roth, and D. LeRoith, Characterization of an endogenous substrate related to insulin and insulin growth factor I receptor in lizard brain, J. Biol. Chem. 262:3434–3439 (1987).
R. W. Rees-Jones, and S. I. Taylor, An endogenous substrate for the insulin receptor-associated tyrosine kinase, J. Biol. Chem. 260:4461–4467 (1985).
M. F. White, E. W. Stegmann, T. J. Dull, A. Ullrich, and C. R. Kahn, Characterization of an endogenous substrate of the insulin receptor in cultured cells, J. Biol. Chem. 262:9769–9777 (1987).
M. Bernier, D. M. Laird, and M. D. Lane, Insulin-activated tyrosine phosphorylation of a 15-kilodalton protein in intact 3T3-L1 adipocytes, Proc. Natl. Acad. Sci. USA 84:1844–1848 (1987).
H. U. Häring, M. F. White, F. Machico, B. Ermel, E. Schleicher, and B. Obermeir, Insulin rapidly stimulates phosphorylation of a 46-kDa membrane protein on tyrosine residues as well as phosphorylation of several soluble proteins in intact fat cells, Proc. Natl. Acad. Sci. USA 84:113–117 (1987).
D. O. Morgan, L. Ho, L. J. Korn, and R. A. Roth, Insulin action is blocked by a monoclonal antibody that inhibits the insulin receptor kinase, Proc. Natl. Acad. Sci. USA 83:328–332 (1986).
C. K. Chou, T. J. Dull, D. S. Russell, R. Gherzi, D. Lebwohl, A. Ullrich, and O. M. Rose, Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin, J. Biol. Chem. 262:1842–1847 (1987).
Y. Ebina, E. Araki, M. Taira, F. Shimada, M. Mori, C. C. Craik, K. Siddle, S. B. Pierce, R. A. Roth, and W. J. Rutter, Replacement of lysine residue 1030 in the putative ATP-binding region of the insulin receptor abolishes insulin- and antibody-stimulated glucose uptake and receptor kinase activity, Proc. Natl. Acad. Sci. USA 84:704–708 (1987).
I. A. Simpson, and J. Hedo, Insulin receptor phosphorylation may not be a prerequisite for acute insulin action, Science 223:1301–1304 (1984).
Y. Zick, R. W. Rees-Jones, S. I. Taylor, P. Gorden, and J. Roth, The role of antireceptor antibodies in stimulating phosphorylation of the insulin receptor, J. Biol. Chem. 259:4396–4400 (1984).
J. R. Forsayeth, J. F. Caro, M. K. Sinka, B. A. Maddux, and I. D. Goldfine, Monoclonal antibodies to the human insulin receptor that activate glucose transport but not insulin receptor kinase activity, Proc. Natl. Acad. Sci. USA 84:3448–3451 (1987).
M. Okamoto, M. F. White, R. Maron, and C. R. Kahn, Autophosphorylation and kinase activity of insulin receptor in diabetic rats, Am. J. Physiol. 251 (Endocrinol. Metab.):E542-E550 (1986).
J. M. Amatruda, and A. M. Roncone, Normal hepatic insulin receptor autophosphorylation in non-ketotic diabetes mellitus, Biochem. Biophys. Res. Commun. 129:163–170 (1985).
G. Grunberger, Y. Zick, and P. Gorden, Defect in phosphorylation of insulin receptors in cells from an insulin resistant patient with normal insulin binding, Science 223:932–934 (1984).
F. Grigorescu, J. S. Flier, and C. R. Kahn, Defect in receptor phosphorylation in erythrocytes and fibroblasts associated with severe insulin resistance, J. Biol. Chem. 259:15003–15006 (1984).
R. J. Comi, G. Grunberger, and P. Gorden, Relationship of insulin binding and insulin stimulated tyrosine kinase activity is altered in type II diabetes, J. Clin. Invest. 79:453–462 (1987).
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Hart, C.B., Roth, J., Lesniak, M.A. (1988). Post-Translational Modifications of the Insulin Receptor. In: Zappia, V., Galletti, P., Porta, R., Wold, F. (eds) Advances in Post-Translational Modifications of Proteins and Aging. Advances in Experimental Medicine and Biology, vol 231. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-9042-8_41
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