IRSProteins and Insulin Signaling

Insulin and IGF1 receptors, like the receptors for other growth factors and cytokines, are composed of an extracellular ligand-binding domain that controls the conformation and activity of the intracellular tyrosine kinase [9,10]. Unlike most receptor tyrosine kinases that are activated upon ligand-induced dimerization, insulin and IGF1 receptors exist as inactive covalent dimers composed of two extracellular a-subunits and two transmembrane P-subunits. Insulin and IGF1 bind between the two a-subunits, thus inducing a conformation change that promotes tyrosine autophosphorylation on the cytoplasmic side of the adjacent P-subunits [11,12]. Autophosphorylation occurs in three distinct regions of the P-subunits, including the regulatory loop, the juxtamem-brane region, and the C-terminus. Phosphorylation of three tyrosine residues in the regulatory loop activates the tyrosine kinase by opening the catalytic domain to facilitate entry of adenosine triphosphate (ATP) and peptide substrates; autophosphorylation of the NPEY motif in the juxtamem-brane region creates a binding site for IRS-proteins and other substrates that have similar phosphotyrosine binding (PTB) domains. The role of phosphorylation in the C terminus is poorly understood.

The mammalian insulin receptor is biologically inactive without its substrates, suggesting that most signals are generated through complexes that are assembled around tyrosyl-phosphorylated scaffolds, including IRS1 and its homologs; Shc, APS, and SH2B [13]; and Gab1/2, Dock1/2, and cbl [14-20]. Although the role of each of these substrates merits attention, work with transgenic mice reveals that many insulin responses, especially those that are associated with somatic growth and carbohydrate metabolism are mediated largely through IRS1 and IRS2 [21]. IRS-proteins are composed of multiple interaction domains and phosphorylation motifs [22]. At least three IRS-proteins occur in mice and people, including IRS1 and IRS2, which are widely expressed, and IRS4, which is limited to the thymus, brain, kidney, and P-cells [23]. Rodents also express IRS3, which is largely restricted to adipose tissue and displays activity similar to

IRS1; however, an IRS3 ortholog might not occur in people [24]. Disruption of the genes for IRS3 or IRS4 in mice is uninformative [25,26]. By contrast, mice lacking IRS1 are small and those without IRS2 are infertile and develop diabetes [5,27]. The Drosophila genome contains a single IRS-protein called Chico that promotes growth and regulates metabolism in flies (Fig. 1) [28], while a functional IRS-protein is not expressed in Caenorhabditis elegans. However, the insulin and IGF receptor orthologs in flies and worms contain a significant C-terminal extension that is absent from mammalian orthologs and contains potential tyrosine phosphorylation sites that can recruit PI 3-kinase without IRS-proteins [29].

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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