Insulin receptor tyrosine kinase domain

PHOSPHORYLA TWN chronic myelongenous leukemia-associated KIO BCR-ABL Drosophila Kr protein hepatitis B virus core and precore antigens human c-fos protein human c-myc protein human EGF receptor human epidermal growth factor receptor (tyrosine kinase domain) human immunodeficiency virus p24 human immunodeficiency virus tat protein human insulin receptor 6-subunit human insulin receptor - tyrosine kinase domain... 

Figure 14.21 The modular structure of Insulin receptor substrates IRS-1 and IRS-2 This schematic view represents the amino acid sequence common to IRS-1 and lRS-2. Each protein contains a pleckstrin homology domain (which binds phosphoinositide lipids), a phospbotyrosine-binding domain, and four sequences that approximate Tyr-X-X-Met (YXXM). The latter are phosphorylated by the insulin receptor tyrosine kinase.

Inhibition of EGF-R tyrosine kinase by hypericin 1 was shown to be irreversible, non-competitive and time as well as temperature dependent. The IC50 increased from 0.75 pM in the dark to 44 nM with light illumination for 30 min. This effect was presumably due to a type I photosensitization mechanism since exclusion of oxygen did not alter the inhibition curve. Some Ser/Thr protein kinases (e.g., protein kinase A, casein kinase 1 and 2) and the enzyme 5 -nucleotidase were not inhibited even at concentrations > 100 pM [144]. However, the same authors recently reported that hypericin 1 in addition to protein kinase C also caused the light-dependent inhibition of certain other Ser/Thr kinases (e.g. protein kinase CK-2, mitogen-activated kinase) and the insulin receptor tyrosine kinase, while it was ineffective towards the cytosolic tyrosine kinases Lyn, Fgr, TPK-IIB and CSK. These results suggest that distantly related protein kinases could still share common reactive domains for the interaction with hypericin 1 [156]. In contrast to the above mentioned studies, Richter and Davies [157] observed no inhibition of EGF-induced tyrosine phosphorylation of the EGF-R in HN5 squamous carcinoma... 

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. 

The cytoplasmic domain of the P-subunit displays three distinct sub-domains (a) the juxtam-embrane domain , implicated in recognition/binding of intracellular substrate molecules (b) the tyrosine kinase domain, which (upon receptor activation) displays tyrosine kinase activity (c) the C-terminal domain, whose exact function is less clear, although site-directed mutagenesis studies implicate it promoting insulin s mitogenic effects. 

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... 

The insulin receptor (top) is a dimer with subunits that have activatable tyrosine kinase domains in the interior of the cell (see p. 224). Binding of the hormone increases the tyrosine kinase activity of the receptor, which then phosphorylates itself and other proteins (receptor substrates) at various tyrosine residues. Adaptor proteins, which conduct the signal further, bind to the phosphotyrosine residues. 

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).

Hubbard, S.R., Wei, L., EUis, L. and Hendrickson, W.A. Crystal structnre of the tyrosine kinase domain of the human insulin receptor (1994) Natnre 372, 746-754... 

I Insulin binding activates I receptor tyrosine kinase activity in the intracellular domain of the 3 subunit of the insulin receptor. 

Using directed mutation of the cloned receptor gene, Lys 1018 in the ATP-binding part of the tyrosine kinase domain was replaced by alanine. This caused a loss both of kinase activity and of biologic response to insulin.362 Thus, both the tyrosine kinase activity and autophosphorylation appear essential. If so, aggregation of two or more receptors may increase the extent of autophosphorylation and initiate a response. 

The EGF receptor, for example, shows striking similarity to the insulin receptor in overall organization and amino acid sequence however, instead of separate a and /3 chains, the EGF receptor is composed of a single polypeptide that appears to be a composite of the a and /3 chains of the insulin receptor. As is true with the insulin receptor, the intracellular domain of the EGF receptor has tyrosine kinase activity. 

Insulin-llke factor Regulates metabolism and longevity in Caenorhabditis elagans Insulin-like receptors, DAF-2 in Caenorhabditis elegans and Drosophila Tyrosine kinase domains... 

Homologues of the mammalian insulin receptor, IR, are the DAF-2 receptor in Caenorhabditis elegans and the IR-like receptor in Drosophila. TTie DAF-2 receptor shares 35% of its amino-acid sequence with the human insulin receptor and 34% with the insulin-like growth factor receptor-1. The tyrosine kinase domain of the DAF-2 receptor is 70% similar and 50% identical to the tyrosine kinase domain of the human insulin receptor. A ligand for DAF-2 has not yet been identified, but an insulin-like peptide is anticipated. Since a t5T>ical insulin receptor substrate, like lRS-1 or IRS-2, has not been found in C. elegans, it is assumed that a COOH-terminal extension of the DAF-2 receptor serves as a built-in receptor substrate, which when phosphorylated, helps to recruit signalling proteins. 

The insulin receptor is the prototype of a t3rrosine kinase receptor with a constimtive, oligomeric structure (Chapter 1). The receptor has been cloned and characterized in detail, notably by Axel Ullrich, R. C. Kahn and colleagues, see Chapter 1.29 Binding of insulin stimulates the intrinsic receptor tyrosine kinase. A crystal structure of the tyrosine kinase domain of the insulin receptor was solved. This leads to phosphorylation of tyrosine residues and to the recruitment and subsequent phosphorylation of substrates. 

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