Phosphorylation protein tyrosine kinase

Hanks, S.K. Calab, M.B. Harper, M.C. Patel, S.K. Focal adhesion protein-tyrosine kinase phosphorylated in response to cell attachment to fibronec-tin. Proc. Natl. Acad. Sci. USA, 89, 8487-8491 (1992)... 

The photo-Arbuzov rearrangement of allyl-, benzyl- and naphtylmethyl-phosphites (Scheme 13), first developed by Bentrude et al. [20], found applications in the preparation of phosphonates (70-90%) [38]. Arylphosphonates have been shown to act as protein tyrosine kinase inhibitors [39] or non-hy-drolyzable analogs of phosphorylated tyrosine residues [40]. 

Like all immunoreceptor family members, FceRI lacks intrinsic tyrosine kinase activity. IgE and antigen-induced crosshnking of FceRI initiates a complex series of phosphate transfer events via the activation of non-receptor Src, Syk and Tec family protein tyrosine kinases (fig. 1). The Src family kinase Lyn, which associates with the FceRI p subunit in mast cells, transphosphorylates neighboring FceRI ITAMs after receptor aggregation [7, 26]. Once phosphorylated, the p chain ITAM binds to the SH2 domain of additional Lyn molecules, while the phosphorylated y chain ITAM recruits Syk to the receptor complex, where it is activated by both autophosphorylation and phosphorylation by Lyn [2, 7,15, 26]. 

In spite of having no intrinsic catalytic domains, activation of T lymphocytes commences with tyrosine phosphorylations, activation of PLC-v with production of IP3 and DAG, and elevation of cytosolic free Ca2+. Thus, the consequences of receptor ligation are not dissimilar from those induced by the receptors for EGF or PDGF. An early study trying to explain the induction of tyrosine kinase activity resulted in the discovery of the nonreceptor protein tyrosine kinase Lck (p56lck), a T-cell-specific member of the Src family. Lck is associated with the cytosolic tail of CD4 (in helper T cells) or CD8 (in cytotoxic T cells) (Figure 8.14). As mentioned, the extracellular domains of these... 

Downstream in the pathway of rescue, PKB effects a number of phosphorylations that prevent apoptosis (Figure 8.17) (see Section 8.2 3.2). It is of interest to note that both growth factor receptors, such as TrkA, and adhesion molecules generate rescue signals through activation of protein tyrosine kinases, and apparently cells require both attachment to extracellular matrix and the presence of a particular growth factor in order not to die. 

In B lymphocytes, coupling of the antigen receptors to Erk MAPkinase is protein tyrosine kinase (PTK)-dependent (Pao et al, 1997). Following ligation of the BCR (Fig. 19.2) the PTK, Lyn, tyrosine phosphorylates the immunoreceptor tyrosine-based activation motifs (ITAMs) on the accessory transducing molecules Ig-a and Ig-(3, leading to the recruitment... 

Tyrosine kinases phosphorylate protein tyrosine residues using ATP. Phospholipase C cleaves PIP2 into IP3 and PAG. 

A further consideration is that receptors which primarily activate one pathway may, on occasion, activate a second pathway (Fig. 10-10). An example is the ability of GPCRs, such as a2-adrenergic receptors or mAChRs, to activate the MAPK cascade. Activation of adenylyl cyclase-linked receptors results in the release of G protein Py subunits, which, probably via an intermediary protein tyrosine kinase (PTK-X), stimulates phosphorylation of the adaptor protein SHC [36]. This in turn recruits the Grb2-SOS complex and activates the MAPK pathway. 

Activation of PI-PLC-linked receptors, such as the mAChR, results in increased PKC activity. Since the addition of phorbol esters, which are PKC agonists (see Ch. 20), results in phosphorylation of Raf, this mechanism may provide an explanation for the ability of PI-PLC-coupled receptors to activate MAPK. A recently discovered protein tyrosine kinase PYK2, which is enriched in the CNS, is also activated by PKC. Like PTK-X, PYK2 phosphorylates SHC and recruits the Grb2-SOS complex, which results in activation of the MAPK cascade. PYK2 is also activated by... 

The functioning of G proteins may be influenced by phosphorylation. G proteins, as well as their associated receptors and RGS proteins, have been reported to undergo phosphorylation by a host of protein serine/ threonine kinases and protein tyrosine kinases. While the ramifications of receptor phosphorylation are becoming increasingly well understood (see Chs 23 and 24), the effect of phosphorylation of G proteins and RGS proteins, and its role in the regulation of physiological processes, have been more difficult to establish with certainty. This remains an important area of future investigation. 

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). 

Since then, a plethora of tyrosine-phosphorylated proteins has been discovered. Originally, tyrosine phosphorylation was believed to be involved primarily in regulating cell proliferation, since many oncogene products and growth factor receptors are protein tyrosine kinases (PTKs). However, it has become clear that tyrosine phosphorylation is involved in regulating a variety of cellular processes. In fact, the nervous system contains a large variety of PTKs and protein tyrosine phosphatases (PTPs), and some of these are exclusively expressed in neuronal tissues. Figure 24-1 shows the... 

FIGURE 24-2 Tyrosine phosphorylation and dephosphorylation. Protein tyrosine kinases (PTK) catalyze the transfer of the y-phosphate group from ATP to the hydroxyl group of tyrosine residues, whereas protein tyrosine phosphatases (PTP) remove the phosphate group from phosphotyro-sine. R, protein. 

CaMK kinases are Ca2+/calmodulin regulated kinases, while CMGC Pks collect cyclic-dependent, mitogene-activated peptide (MAP) kinases, GSK3 and Clk kinases, that phosphorylate substrates in proline-rich domains. The last group are PTKs (protein tyrosine kinases), which include both receptor and non-receptor kinases, which phosphorylates tyrosine residues (this will be discussed in Sect. 4.3). 

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