The Insulin Receptor Tyrosine Kinase

Rothenberg, Paul; White, Morris F.; Kahn, C. Ronald

doi:10.1007/978-3-642-74098-5_11

Cited by 19 publications

(7 citation statements)

References 201 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although many purified proteins and synthetic peptides can be phosphorylated in vitro by isolated insulin receptors ( 11 ), these reactions do not occur in vivo, and thus their physiological significance is uncertain. In most cells, insulin stimulates tyrosine phosphorylation of a cytoplasmic protein with a relative molecular mass between 165 and 185 kD, collectively called ppl 85 (12)(13)(14)(15)(16)(17)(18)(19).…”

mentioning

confidence: 99%

Regulation of insulin receptor substrate-1 in liver and muscle of animal models of insulin resistance.

Saad¹,

Araki²,

Miralpeix³

et al. 1992

J. Clin. Invest.

296

189

View full text Add to dashboard Cite

IntroductionInsulin rapidly stimulates tyrosine phosphorylation ofa protein of -185 kD in most cell types. This protein, termed insulin receptor substrate-I (IRS-1), has been implicated in insulin signal transmission based on studies with insulin receptor mutants. In the present study we have examined the levels of IRS-1 and the phosphorylation state ofinsulin receptor and IRS-1 in liver and muscle after insulin stimulation in vivo in two rat models of insulin resistance, i.e., insulinopenic diabetes and fasting, and a mouse model of non-insulin-dependent diabetes mellitus (ob/ob) by immunoblotting with anti-peptide antibodies to IRS-1 and anti-phosphotyrosine antibodies. As previously described, there was an increase in insulin binding and a parallel increase in insulin-stimulated receptor phosphorylation in muscle of fasting and streptozotocin-induced (STZ) diabetic rats. There was also a modest increase in overall receptor phosphorylation in liver in these two models, but when normalized for the increase in binding, receptor phosphorylation was decreased, in liver and muscle of STZ diabetes and in liver of 72 h fasted rats. In the hyperinsulinemic ob/ob mouse there was a decrease in insulin binding and receptor phosphorylation in both liver and muscle. The tyrosyl phosphorylation of IRS-1 after insulin stimulation reflected an amplification of the receptor phosphorylation in liver and muscle of hypoinsulinemic animals (fasting and STZ diabetes) with a twofold increase, and showed a significant reduction ('-50%) in liver and muscle of ob/ob mouse. By contrast, the levels of IRS-1 protein showed a tissue specific regulation with a decreased level in muscle and an increased level in liver in hypoinsulinemic states of insulin resistance, and decreased levels in liver in the hyperinsulinemic ob/ob mouse. These data indicate that: (a) IRS-1 protein levels are differentially regulated in liver and muscle; (b) insulin levels may play a role in this differential regulation of IRS-1; (c) IRS-1 phosphorylation depends more on insulin receptor kinase activity than IRS-1 protein levels; and (d) Insulin resistance is characteristic of many disease states including non-insulin-dependent diabetes mellitus (NIDDM),' uncontrolled insulin-dependent diabetes, obesity, and prolonged fasting (1-4). Although various defects in insulin action have been reported in these conditions, the exact mechanisms involved in the insulin resistance have not been adequately defined. Insulin initiates its metabolic and growth-promoting effects by binding to the a subunit of its tetrameric receptor (5), thereby activating the kinase in the ,B subunit, which in turn catalyzes the intramolecular autophosphorylation of specific tyrosine residues of the 13 subunit, further enhancing the tyrosine kinase activity of the receptor toward other protein substrates (5-7). Considerable evidence demonstrates that insulin receptor tyrosine kinase activity is essential for many, if not all, of the biological effects of insulin ( 8-10).Although many ...

show abstract

mentioning

confidence: 99%

Regulation of insulin receptor substrate-1 in liver and muscle of animal models of insulin resistance.

Saad¹,

Araki²,

Miralpeix³

et al. 1992

J. Clin. Invest.

296

189

View full text Add to dashboard Cite

show abstract

“…[1][2][3]. This protein has been extensively studied and it is known that it exists as a disulfide-linked heterotetrameric membrane glycoprotein consisting of two extracellular a (135 kDa) and two transmembrane j3 (95 kDa) subunits.…”

mentioning

confidence: 99%

A region of the insulin receptor important for ligand binding (residues 450-601) is recognized by patients' autoimmune antibodies and inhibitory monoclonal antibodies.

Zhang

Roth

1991

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Chimeric receptors containing different portions of the homologous human insulin receptor, insulin-like growth factor I receptor, and insulin receptor-related receptor were utilized to identify the epitopes recognized by various anti-insulin receptor antibodies. The antibodies studied included 12 monoclonal antibodies to the extracellular domain of the human insulin receptor as well as 15 patients' sera with autoimmune anti-insulin receptor antibodies. AR of the patients' sera and all 8 monoclonal antibodies that inhibit inslin binding were found to recognize an epitope contained within residues 450-601 of the a subunit of the receptor. In contrast, 2 monoclonal antibodies that do not inhibit insulin binding were found to recognize the cysteine-rich region of the a subunit. Chimeric insulin receptors that had residues 450-601 replaced with the homologous residues of the insulin-like growth factor I receptor exhibited a decreased ability to bind insulin. In contrast, insulin-like growth factor I receptors that have had the comparable region replaced with that of the insulin receptor showed no decrease in their ability to bind ligand. These results indicate that residues 450-601 of the insulin receptor are important for insulin binding and include the major site for recognition by inhibitory monoclonal antibodies and patients' autoimmune anti-receptor antibodies.Insulin elicits its diverse biological responses by binding to a specific receptor (for reviews, see refs. 1-3). This protein has been extensively studied and it is known that it exists as a disulfide-linked heterotetrameric membrane glycoprotein consisting of two extracellular a (135 kDa) and two transmembrane j3 (95 kDa) subunits. Insulin primarily interacts with the a subunit since this subunit is predominantly labeled when 125I-labeled insulin (125I-insulin) is cross-linked to the receptor (4-6). Recently a fragment of this subunit that was linked to insulin has been isolated and identified as containing residues 205-316 of the receptor (7, 8). These residues are within a region of the a subunit that is particularly high in cysteines (9, 10) and is encoded by exon 3 of the insulin receptor (IR) gene (11). These results have led to the proposal that this cysteine-rich region is responsible for high-affinity binding of insulin (7,8).However, lipking of a biotinylated insulin to the receptor was shown to label a fragment (residues 21-120) at the amino terminus of the receptor (12). Moreover, mutant forms ofthe receptor with changes in either residue 15 or 89 in the amino terminus exhibited a decreased ability to bind insulin (13,14). In complementary studies, chimeric receptors have been constructed between the human IR and either the homologous insulin-like growth factor I receptor (IGF-IR) or the insulin receptor-related receptor (IRR) (15-18). These studies have indicated that the cysteine-rich region of the IGF-IR can confer high-affinity binding of IGF-I and IGF-Il to the IR (16-18). However, these studies indicated that the IRspecific residu...

show abstract

“…Several studies subsequently established that (a) the insulin receptor is an insulin-sensitive tyrosine kinase with its domain located in the l3-subunit of the receptor, and (b) the kinase is stimulated as a result of hormonal binding to the a-subunit of the receptor followed by auto phosphorylation of at least three specific tyrosine residues in the l3-subunit. The characteristics of the insulin receptor and its tyrosine kinase have been extensively reviewed by Kahn et al (52), Rothenberg et al (96), and Roth (95). In addition, Taylor et al (120) and Makino et al (74) reviewed the physiological and clinical effects of receptor mutations.…”

Section: Introductionmentioning

confidence: 97%