Insulin receptor for

Various hormonal agents (eg, glucocorticoids) lower the affinity of insulin receptors for insulin growth hormone in excess increases this affinity slightly. Aberrant serine and threonine phosphorylation of the insulin receptor subunits or IRS molecules may result in insulin resistance and functional receptor down-regulation. 

Receptors that are a transmembrane protein with a ligand-binding site on the extracellular side and a catalytic domain on the cytosolic side. In the insulin receptor, for example, the catalyst is a protein tyrosine kinase, which is stimulated by insulin binding to the extracellular domain of the receptor. 

A number of hormone and growth factor receptors are distinctive in that they contain an intrinsic enzymatic activity and a single membrane-spanning domain. An example of this this class of receptors is the insulin receptor, for which no second messengers have yet been detected. 

Metabolic Functions. Chromium (ITT) potentiates the action of insulin and may be considered a cofactor for insulin (137,138). In in vitro tests of epididymal fat tissue of chromium-deficient rats, Cr(III) increases the uptake of glucose only in the presence of insulin (137). The interaction of Cr(III) and insulin also is demonstrated by experimental results indicating an effect of Cr(III) in translocation of sugars into ceUs at the first step of sugar metaboHsm. Chromium is thought to form a complex with insulin and insulin receptors (136). 

Insulin Receptor. Figure 1 Structure and function of the insulin receptor. Binding of insulin to the a-subunits (yellow) leads to activation of the intracellular tyrosine kinase ((3-subunit) by autophosphorylation. The insulin receptor substrates (IRS) bind via a phospho-tyrosine binding domain to phosphorylated tyrosine residues in the juxtamembrane domain of the (3-subunit. The receptor tyrosine kinase then phosphorylates specific tyrosine motifs (YMxM) within the IRS. These tyrosine phosphorylated motifs serve as docking sites for some adaptor proteins with SRC homology 2 (SH2) domains like the regulatory subunit of PI 3-kinase. 

Thirty years ago, receptors for polypeptide hormones such as insulin and GH were identified as binding activity in cells, membranes, or solubihzed membrane proteins using radiolabeled proteins... 

All RTKs contain between one and three tyrosines in the kinase activation loop, which is composed of subdomains VII and VIII of the protein kinase catalytic core. Phosphorylation of these tyrosines has been shown to be critical for stimulation of catalytic activity and biological function for a number of RTKs, including insulin receptor, FGF receptor, VEGF receptor, PDGF receptor, Met (hepatocyte growth factor receptor), and TrkA (NGF receptor). A major exception is the EGF receptor, for which autophosphorylation of a conserved tyrosine in the activation loop does not seem to be involved in signaling. Substitution of tyrosine with phenylalanine has no effect on RTK activity or downstream signals. 

The catalytic pi 10 subunit has four isoforms, all of which contain a kinase domain and a Ras interaction site. In addition, the a, (3, and y isoforms possess an interaction site for the p85 subunit. The class I enzymes can be further subdivided class IA enzymes interact through their SH2 domains with phosphotyrosines present on either protein tyrosine kinases or to docking proteins such as insulin-receptor substrates (IRSs GAB-1) or linkers for activation of T cells (LATs in the case of T cells). 

Bohni R, Riesgo-Escovar J, Oldham S et al 1999 Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS 1-4. Cell 97 865—875 Chen C, Jack J, GarofaloRS 1996 The Drosophila insulin receptor is required for normal growth. Endocrinology 137 846—856... 

---