Receptors with Kinase Activity

Another protein hormone, epidermal growth factor, is bound to the extracellular domain of its receptor. A mutated form of the receptor, which lacks the hormone-binding domain, results in the kinase activity being permanently on. This leads to cancer because the cell is signaled to grow at all times—the hallmark of cancer. 

This part is a tyrosine-specific protein kinase 

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Molecnles that Interfere with Receptor Tyrosine Kinase Activity... 

Inhibitors of receptor tyrosine kinases are finding increased use in neoplastic disorders in which excessive growth factor signaling is often involved. Some of these inhibitors are monoclonal antibodies (eg, trastuzumab, cetuximab), which bind to the extracellular domain of a particular receptor and interfere with binding of growth factor. Other inhibitors are membrane-permeant "small molecule" chemicals (eg, gefitinib, erlotinib), which inhibit the receptor s kinase activity in the cytoplasm. 

The insulin receptor is the prototype for a number of receptor enzymes with a similar structure and receptor Tyr kinase activity. The receptors for epidermal growth factor and platelet-derived growth factor, for example, have structural and sequence similarities to the insulin receptor, and both have a protein Tyr kinase activity that phosphorylates IRS-1. Many of these receptors dimerize after binding ligand the insulin receptor is already a dimer before insulin binds. The binding of adaptor proteins such as Grb2 to (P) Tyr residues is a common mechanism for promoting protein-protein interactions, a subject to which we return in Section 12.5. 

Tyrosyl phosphorylation of the solubilized insulin receptor also appears to affect its functioning per se, in that autophosphorylation leads to an increase in the receptor tyrosyl kinase activity expressed towards exogenous substrates [68]. As autophosphorylation occurs at multiple sites on the j8 subunit it will be necessary to determine which of these sites are of regulatory significance. Such studies require that results obtained using solubilized receptor preparations be compared with those using intact cells where tyrosyl phosphorylation of the receptor appears to be very small in comparison with the phosphorylation of the receptor on serine residues [69]. 

In Xenopus o(x es (126,134), treatment with metformin has been shown to increase insulin receptor tyrosine kinase activity associated with activation of phospholipase C and increased levels of IPg and intracellular Ca. Thus metformin, through increasing receptor tyrosine kinase activity, may facilitate IRS protein phosphorylation and activation of phosphatidylinositol-3-kinase, leading to increased glucose uptake. 

One Ca + receptor with enzymatic activity is protein kinase C. Its activity is markedly increased in the presence of Ca ", and it has a high calcium-binding constant (see Table 3.2) in the presence of diacylglycerol or phorbol esters. ... 

Proteins in complex with activated receptors are often phosphorylated by the associated kinase(s), leading to modulation of enzymatic activity or, in the case of adaptor proteins such as She, IRS-1/-2, and Gab-l/-2, binding of other proteins to the phosphorylated site(s). Because these proteins are substrates of receptor-associated kinase activity, they are commonly assumed to leave the receptor complex after phosphorylation in some models... 

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