Non-receptor tyrosine kinases

Besides the cytokine receptors that lack intrinsic kinase activity but have associated JAK kinases, STAT proteins can be activated by a variety of G-protein coupled receptors and growth factor receptors with intrinsic tyrosine kinase activity (for example EGF, PDGF, CSF-1, and angiotensin receptor). Increasing evidence suggests a critical role for STAT family members in oncogenesis and aberrant cell proliferation. Constitutively activated STATs have been found in many transformed cell lines and a wide variety of human tumor entities. Numerous non-receptor tyrosine kinases and viral oncoproteins, such as v-Src, v-Abl, v-Sis, and v-Eyk, have been identified to induce DNA-binding activity of STAT proteins. 

Tyrosine kinase inhibitors interfere with the function of tyrosine kinases that catalyze the transfer of the y-phosphate group of ATP to tyrosine residues of protein substrates. Tyrosine kinases can be subdivided into two large families, receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (NRTKs see corresponding chapter). The human genome... 

PKA and PKC are, however, not the only kinases to regulate TRPVl. The Ca /calmodulin-dependent kinase II (CaMKII) sensitizes TRPVl by phosphorylation [57, 58], as does phophatidylinositol 3-kinase (PI3K) via its downstream target AKT [59]. This latter finding links TRPVl to the ERK (extracellular signal-regulated protein kinase) pathway. The non-receptor tyrosine kinase Src likewise potentiates capsaicin-induced currents [60]. 

Many non-receptor tyrosine kinases have been identified as products of retrovirally encoded oncogenes. Non-receptor tyrosine kinases can be divided into two groups transmembrane and cytosolic families. The c-src tyrosine kinase is the prototype of the cytosolic tyrosine kinases. Regions within these non-receptor tyrosine kinases share homology with the Src kinase, known as Src homology 2 and 3 (SH2 and SH3) domains, and mediate protein-protein interactions between the receptor tyrosine kinases and the intracellular targets (reviewed in Cantley et al., 1991 Pawson and Gish, 1992 Mayer and Baltimore, 1993). 

SH2 and SH3 domains refer to src homology 2 and 3, a non-receptor tyrosine kinase where these domains were identified originally. They bind to phos-phorylated tyrosine and pro line rich epitopes, respectively, with specificities each in respect to the neighboring amino acids. Grb2 is an adapter molecule par excellence having both SH2 and SH3 domains (see also the respective article in this volume). 

Increased p42/p44 MAPK Increased c-jun and c-fos Increased non-receptor tyrosine kinase activity-increased phospholipase C Increased p38 MAPK Reduced cAMP Increased NO and NOS... 

S IP-dependent activation of the non-receptor tyrosine kinase Pyk2 was dissociated from p42/p44 MAPK in aortic smooth muscle cells (Guo et al,... 

Several of the new Bcr-Abl kinase inhibitors reported subsequent to imatinib also inhibit Src, a non-receptor tyrosine kinase. In 2000, il was re-porled lhat the known Src inhibitor PD180970 (12) also inhibited Abl kinase [73] (Scheme 5). This property was soon found to be shared by several other pyrido[2,3-d]pyrimidine Src inhibitors including PD173955 (13) [74] (Scheme 5). A crystal structure of PD 173955 demonstrated that this compound could bind to both the active and inactive form of Abl [37]. While the conformation of active Src kinase is similar to that of active Abl, the conformations of the inactive kinases are quite different. Unlike PD 173955, imatinib only binds the inactive form of Abl. The inability of imatinib to inhibit Src is... 

Firmbach-Kraft I, Byers M, Shows T, Dalla-Favera R, Krolewski JJ. Tyk2, prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene 1990 5 1329-1336. 

Collagen signals through the same pathway as that of immune receptors. It induces phosphorylation on tyrosine on Fc receptor y-chain (FcRy), the non-receptor tyrosine kinase Syk and phospholipase Cy2 (PLCy2) . 

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