Protein tyrosine kinases classes

The catalytic pi 10 subunit has four isoforms, all of which contain a kinase domain and a Ras interaction site. In addition, the a, (3, and y isoforms possess an interaction site for the p85 subunit. The class I enzymes can be further subdivided class IA enzymes interact through their SH2 domains with phosphotyrosines present on either protein tyrosine kinases or to docking proteins such as insulin-receptor substrates (IRSs GAB-1) or linkers for activation of T cells (LATs in the case of T cells). 

Protein kinases differ in their cellular and subcellular distribution, substrate specificity and regulation. These properties determine the functional roles played by the very large number of protein kinases that have been found in mammalian tissues, most of which are known to be expressed in neurons [3]. The major classes of protein serine-threonine kinase in the brain, listed in Table 23-1, are covered in this chapter. The major classes of protein tyrosine kinases in the brain are discussed in Chapter 24. 

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. " " ... 

Wilks AF, Harpur AG, Kurban RR, Ralph SJ, Zurcher G, Ziemiecki A. Two novel protein tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol Cell Biol 1991 11 2057-2065. 

Many members of this class of receptors have an enzymatic activity known as a protein tyrosine kinase within their cytoplasmic segment. This kinase phosphorylates tyrosine residues in the receptors themselves (autophosphory lation), and in other proteins to initiate biochemical cascades. Phosphorylatipn of tyrosine can be reversed by protein tyrosine phosphatases, which are also present in all cells (Shenolikar and Naim, 1990). Tyrosine phosphatases form a diverse family of proteins, some of which are cytosolic while others are transmembrane molecules analogous to receptors. Some members of the transmembrane class may be involved in the mechanism of bacterial and viral infections (Tonks, 1991). Thus, kinases and phosphatases together act as on-off switches in the a ctivation of receptors and other proteins. 

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.

We turn now to a second important class of cell-surface receptors, the cytokine receptors, whose cytosolic domains are closely associated with a member of a family of cytosolic protein tyrosine kinases, the JAK kinases. A third class of receptors, the receptor tyrosine kinases (RTKs), contain intrinsic protein tyrosine kinase activity in their cytosolic domains. The mechanisms by which cytokine receptors and receptor tyrosine kinases become activated by ligands are very similar, and there is considerable overlap in the intracellular signal-transduction pathways triggered by activation of receptors in both classes. In this section, we first describe some similarities in signaling from these two receptor classes. We then discuss the JAK-STAT pathway, which is initiated mainly by activation of cytokine receptors. 

Two receptor classes, cytokine receptors and receptor tyrosine kinases, transduce signals via their associated or intrinsic protein tyrosine kinases. Ligand binding triggers formation of functional dimeric receptors and phosphorylation of the activation lip in the kinases, enhancing their catalytic activity (see Figure 14-5). 

Klages, S. Adam, D. Class, K. Fargnoli, J. Bolen, J.B. Penhallow, R.C. Ctk a protein-tyrosine kinase related to Csk that defines an enzyme family. Proc. Natl. Acad. Sci. USA, 91, 2597-2601 (1994)... 

Runting, A.S. Stacker, S.A. Wilks, A.F. Tie2, a putative protein tyrosine kinase from a new class of cell surface receptor. Growth Factors, 9, 99-105 (1993)... 

Most signaling pathways include steps in which protein kinases are activated. There are three major classes of protein kinases (1) Protein tyrosine kinases catalyze the transfer of the y-phosphate of ATP onto tyrosine residues in their substrate proteins (2) Protein serine/threonine kinases similarly transfer the y-phosphate of ATP onto serine or threonine residues and (3) Mixed-function protein kinases catalyze the transfer of the y-phosphate of ATP onto tyrosine, serine, or threonine residues. 

There are two main classes of protein tyrosine kinases (PTKs) as cell surface receptors involved in signal transduction. Phosphorylation on Tyr represents an authentic physiological process. While phosphorylation in nontransformed cells occurs mostly on Ser and Thr, phosphorylation in transformed cells includes Ser, Thr and Tyr residues. Thus Tyr phosphorylation is intimately linked to cell proliferation/transformation. Tyrosine phosphorylation is not limited to the actions of the transforming viruses or growth factors. It regulates a number of important signaling processes including ... 

Quinazolinones are an important class of fused heterocycles that have been reported with remarkable activities in biology and pharmacology such as anticancer, antiinflammatory, anticonvulsant, antibacterial, antidiabetic, hypolipidemic, and protein tyrosine kinase inhibitors. Alper and Zheng reported a palladium-catalyzed cyclocarbonylation of o-iodoanilines with imidoyl chlorides to produce quinazolin-4(3H)-ones in 2008. A wide variety of substituted quinazolin-4(3H)-ones were prepared in 63-91% yields (Scheme 3.27a). The reaction is believed to proceed via in situ formation of an amidine, followed by oxidative addition, CO insertion, and intramolecular cyclization to give the substituted quinazolin-4(3H)-ones. Later on, a procedure was established based on generating the amidine in situ by a copper-catalyzed reaction of terminal allq nes, sulfonyl azide and o-iodo-anilines. The desired quinazolinones can be produced by carbonylation with Pd(OAc)2-DPPB-NEt3-THF as the reaction system. In the same year, Alper s group developed a procedure for 2,3-dihydro-4(lH)-quinazolinone preparation. The reaction started with the reaction of 2-iodoanilines and N-toluenesulfonyl aldimines followed by palladium-catalyzed intramolecular... 

This protocol is particularly useful in the synthesis of the class of polychlorinated marine natural product known as chlorosulfolipids, which are believed to be responsible for seafood poisoning. ° With this protocol, Vanderwal et al. succeeded in the enantioselective total synthesis of maUiamensilipin A 11, a protein tyrosine kinase inhibitor isolated from alga Poterioochromonas malhamen-sis The enantioselective synthesis of (+)-danicalipin A 14, another chlorosulfolipid isolated from the alga Ochro-monas danica by Umezawa et al. also used this strategy as a key step (Scheme 42.5). 

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