Tyrosine-kinase activity

Inhibition of hematopoietic growth factors Imatinib (Glivec ) is applied to treat chronic myeloid leukemia in Philadelphia-chromosome positive patients. In these patients, translocation of parts of chromosomes 9 and 22 results in the expression of a fusion protein with increased tyrosine kinase activity, called Bcr-Abl. Imatinib is a small Mw inhibitor selective for the tyrosine kinase activity of Bcr-Abl. Thereby, it inhibits the Bcr-Abl induced cell cycle progression and the uncontrolled proliferation of tumor cells. 

Activation of the tyrosine kinase activity of the INSR is essential for the receptor function. The tyrosine kinase domain of the INSR is localized in the... 

Concanavalin A is a plant lectin from the jack bean (Canavalia ensiformis) which binds with high affinity to mannose residues of glycoproteins. Concanavalin A is known to stimulate the tyrosine kinase activity of the INSR (3-subunit with consecutive activation of kinases downstream the insulin receptor (IRS, PI 3-kinase). It is believed that Concanavalin A stimulates the activation and autophosphorylation of the INSR kinase through aggregation of the receptor, although the precise mechanism of action is unclear. 

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. 

Molecnles that Interfere with Receptor Tyrosine Kinase Activity... 

Besides cytoplasmic protein kinases, membrane receptors can exert protein kinase activity. These so-called receptor tyrosine kinases (RTK) contain a ligandbinding extracellular domain, a transmembrane motif, and an intracellular catalytic domain with specificity for tyrosine residues. Upon ligand binding and subsequent receptor oligomerization, the tyrosine residues of the intracellular domain become phosphory-lated by the intrinsic tyrosine kinase activity of the receptor [3, 4]. The phosphotyrosine residues ftmction as docking sites for other proteins that will transmit the signal received by the RTK. 

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]. 

Single protein kinases such as PKA, PKC, and Ca +-calmodulin (CaM)-kinases, which result in the phosphorylation of serine and threonine residues in target proteins, play a very important role in hormone action. The discovery that the EGF receptor contains an intrinsic tyrosine kinase activity that is activated by the binding of the hgand EGF was an important breakthrough. The insuhn and IGF-I receptors also contain intrinsic... 

Tyrosine kinase activation can also initiate a phosphorylation and dephosphorylation cascade that involves the action of several other protein kinases and the counter-... 

Gao and Yamaguchi, 1999c Gao and Yamaguchi, 2000 Kajiya et al., 2000 Yamagishi et at., 2001 Bone marrow cells or isolated osteoclasts Suppression of osteoclast formation by genistein is partly due to Ca signalling mechanism and partly due to inhibition of tyrosine kinase activity. 

LiNASSiER c, PIERRE M, LE PECQ J B and PIERRE J (1990) Mechanism of action in NIH-3T3 cells of genistein, an inhibitor of EGF receptor tyrosine kinase activity. Biochem Pharmacol. 39 (1) 187-93. 

Barlic J, Andrews JD, Kelvin AA, et al. Regulation of tyrosine kinase activation and granule release through beta-arrestin by CXCRI. Nat Immunol 2000 1(3) 227-233. 

The role of tyrosine kinase signaling in actin cytoskeleton regulation is well established (166-171), and certain steps in the activation pathways of both Rac 1 and RhoA, two molecules known to modulate actin function, may also require tyrosine kinase activity (172,173). In fact, two recent reports have also indicated... 

Suter DM, Forscher P. Transmission of growth cone traction force through apCAM-cytoskeletal linkages is regulated by Src family tyrosine kinase activity. J Cell Biol 2001 155(3) 427-438. 

Kosako, H Gotoh, Y Matsuda, S Ishikawa, M and Nishida, E. (1992). Xenopus MAP kinase activator is a serine/threonine/tyrosine kinase activated by threonine phosphorylation. EMBO J. 11 2903-2908. 

Ullrich, A., and Schlessinger, J. (1990). Signal transduction by receptors with tyrosine kinase activity. Cell 61 203-212. 

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... 

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