Insulin receptor tyrosine specific protein kinase

It is not clear whether V(V) or V(IV) (or both) is the active insulin-mimetic redox state of vanadium. In the body, endogenous reducing agents such as glutathione and ascorbic acid may inhibit the oxidation of V(IV). The mechanism of action of insulin mimetics is unclear. Insulin receptors are membrane-spanning tyrosine-specific protein kinases activated by insulin on the extracellular side to catalyze intracellular protein tyrosine phosphorylation. Vanadates can act as phosphate analogs, and there is evidence for potent inhibition of phosphotyrosine phosphatases (526). Peroxovanadate complexes, for example, can induce autophosphorylation at tyrosine residues and inhibit the insulin-receptor-associated phosphotyrosine phosphatase, and these in turn activate insulin-receptor kinase. 

The Insulin Receptor Is a Tyrosine-Specific Protein Kinase... 

Insulin receptors (IRs) are membrane-spanning tyrosine-specific protein kinases early in the insulin signaling cascade, insulin, by binding on the... 

Fig. 8.7. Structure of the catalytic domain of the insulin receptor. The crystal structure of the tyrosine kinase domain of the insulin receptor (Hubbard et al., 1994) has a two-lobe structure that is very similar to the structure of the Ser/Thr-specific protein kinases. Structural elements of catalytic and regulatory importance are shown. The P loop mediates binding of the phosphate residue of ATP the catalytic loop contains a catalytically essential Asp and Asn residue, found in equivalent positions as conserved residues in many Ser/Thr-specific and Tyr-specific protein kinases. Access to the active center is blocked by a regulatory loop containing three Tyr residues (Tyrll58, Tyrll62 and Tyrll63). Tyrll62 undergoes autophosphorylation in the course of activation of the insulin receptor. MOLSKRIPT representation according to Kraulis, (1991).

The core of all eukaryotic Ser/Thr- and Tyr-specific protein kinases adopt a common fold illustrated in Fig. 7.3 for the tyrosine kinase domain of the insulin receptor. The structure comprises two lobes that are conneded by a hinge region. The N-terminal lobe contains five / -structures and one a-helix, named C-helix. In contrast, the larger C-terminal lobe is mostly a-helical. It comprises a four-helix bundle, additional a-he-lices, and two short yS-strands. ATP and 1 or 2 metal ions are bound at the interface of the two lobes, while the binding site for the peptide substrate is located mostly in the C-terminal lobe. The following structural elements have been found to be critical for catalysis and for protein kinase control ... 

The insulin receptor is a transmembrane receptor tyrosine kinase located in the plasma membrane of insulin-sensitive cells (e.g., adipocytes, myocytes, hepatocytes). It mediates the effect of insulin on specific cellular responses (e.g., glucose transport, glycogen synthesis, lipid synthesis, protein synthesis). 

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. 

Figure 11.2 Structure of the insulin receptor (a). Binding of insulin promotes autophosphorylation of the (3-subunits, where each (3-subunit phosphorylates the other (3-subunit. Phosphate groups are attached to three specific tyrosine residues (tyrosines 1158, 1162 and 1163), as indicated in (b). Activation of the (3-subunit s tyrosine kinase activity in turn results in the phosphorylation of various intracellular (protein) substrates which trigger the mitogen-activated protein kinase and/or the phosphoinositide (PI-3) kinase pathway responsible for inducing insulin s mitogenic and metabolic effects. The underlying molecular events occurring in these pathways are complex (e.g. refer to Combettes-Souverain, M. and Issad, T. 1998. Molecular basis of insulin action. Diabetes and Metabolism, 24, 477-489)...

Typically of receptor tyrosine kinases, binding of insulin to the extracellular domains of the IR causes autophosphorylation of specific tyrosine residues within the intracellular region of the [3 units. Some RTKs, as described above and as illustrated by JAKs described above and also shown in Figure 4.20, would at this point recruit adaptor proteins to bind directly to the phosphorylated intracellular... 

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