Protein tyrosine kinases signaling complexes

MAPK kinase (MAPKK). MAPK kinase itself is activated by phosphorylation by still another protein kinase, termed MAPK kinase kinase (MAPKKK). MAPK kinase kinase is activated upon interaction with a member of the Ras superfamily of small G proteins, which are bound to the plasma membrane (see Ch. 19). The exact mechanism of activation remains unknown, but it is believed that Ras and related proteins, in the activated GTP-bound form, can bind MAPK kinase kinase and thereby draw the kinase to the plasmalemma, where it is activated by as yet unknown factors, perhaps even an additional kinase, MAPK kinase kinase kinase (MAPKKKK). The mechanism governing the activation of Ras and related proteins by extracellular signals is quite complex and involves numerous Tinker proteins, for example She, Grb and Sos, that couple Ras to a variety of plasmalemma-associated growth factor-protein tyrosine kinase receptors (see Chs 20,24 and 27). 

The coupling of superantigen—major histocompatibility complex class II to T-cell receptor swifdy results in cell-signaling cascades. ° These staphylococcal toxins can increase levels of phosphatidyl inositol from quiescent T cells, such as other mitogens, as well as elicit intracellular Ca movement that activates the protein kinase C (PKC) pathway important for interleukin-2 (IL-2) expression. " IL-2 is intimately linked to T-cell proliferation. In addition to the PKC pathway, the protein tyrosine kinase (PTK) pathway is also activated by superantigens, leading to elevated expression of various proinflammatory cytokines. Staphylococcal superantigens also potently activate transcriptional factors NF-/IB (nuclear factor kappa B) and AP-1 (activator protein-1), which subsequently elicit the synthesis of proinflammatory cytokines. " " ... 

Figure 33.30. T-Cell Activatiou. The interaction between the T-cell receptor and a class I MHC-peptide complex results in the binding of CDS to the MHC protein, the recruitment of the protein tyrosine kinase Lck, and the phosphorylation of tyrosine residues in the ITAM sequences of the CD3 chains. After phosphorylation, the ITAM regions serve as docking sites for the protein kinase ZAP-70, which phosphorylates protein targets to transmit the signal.

An early step in T-cell activation is stimulation of tyrosine kinase activity [172]. Interestingly, protein tyrosine kinases co-immunoprecipitate with antibodies against GPI-anchored proteins [173,174] and co-localize with GPI-anchored proteins in large non-covalent complexes [175]. These studies suggest that protein tyrosine kinases are part of the signal transduction mechanism by which GPI-anchored proteins mediate T-cell activation. 

Fry, M.J. Panayotou, G. Booker, G.W. Waterfield, M.D. New insights into protein-tyrosine kinase receptor signaling complexes. Protein Sci., 2, 1785-1797 (1993)... 

The disturbances in protein phosphorylation patterns in Cr(VI) treated cells are considered among the possible reasons for Cr(VI) toxicity and carcinogenicity (295, 626). The question then arises, as to whether the proposed beneficial action of Cr(III) in activation of insulin receptor tyrosine kinase (496,497) is, in fact, a sign of Cr(III) toxicity (5). Unpredictable changes in the concentrations of phosphorylated proteins in the presence of excess Cr(III) may lead to abnormalities in the cell signaling pathways and ultimately to cancer (5). An answer to this dilemma may lie in selectivity studies (which are yet to be performed) of different types of Cr(III) complexes toward various kinases or phosphatases. Clearly, the Cr(III) complexes of potential use as anti-diabetics should be highly selective in the activation of protein tyrosine kinase of the p-subunit of the insulin receptor (496, 497). On the other hand, the potential ability of some Cr(III) complexes to selectively activate non-insulin dependent protein kinases may lead to beneficial effects, such as stimulation of immune responses or antitumor activity (627, 628). 

A family of receptors are known to induce response similar to those of the receptor tyrosine kinases yet possess not intrinsic catalytic activity. Instead they recrait catalytic subunits from within the cell in the form of one or more nomeceptor protein tyrosine kinases (nrPTKs). These proteins exist within the cytosol as soluble components or they may be membrane-associated. Recmitment of mPTKs and the consequent tyrosine phosphorylations are usually the first steps in the assembly of a substantial signaling complex consisting of a dozen or more proteins that bind and interact with each other (Hunter, 1996). 

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