Protein tyrosine kinases inactivation

Stein, R. A. and Staros, J. V. (1996). Thermal inactivation of the protein tyrosine kinase of the epidermal growth factor. Biochemistry 35,9197-9203. 

Binding of phosphotyrosine 527 to the SH2 domain induces conformational strains in the SH3 and kinase domains, distorting the kinase active site so it is catalytically inactive. The kinase activity of cellular Src proteins is normally activated by removing the phosphate on tyrosine 527. (b) Domain structure of c-Src and v-Sre. Phosphorylation of tyrosine 527 by Csk, another cellular tyrosine kinase, inactivates the Src kinase activity. The transforming v-Src oncoprotein encoded by Rous sarcoma virus is missing the C-terminal 18 amino acids including tyrosine 527 and thus is constitutively active. [Part (a) from F. Sicheri et al.,... 

Genistein, which is isolated from soy, inactivates Bcl-2 by phosphorylation, delays the G2/M phase of die cell cycle, and induces apoptosis of hiunan breast adenocarcinoma MCF-7 cells and it is also an inhibitor of protein tyrosine kinase and topoisomerase II (42). The natural estrogen metabolite 2-methoxyestradiol (2ME) is anti- angiogenic in vivo, can phosphorylate Bcl-2 and its mechanism of action is independent of die signaling enemies JNK/SAPK (41). The dolastatins are natural peptides, which inhibit microtubule assembly and induce apoptosis and phosphorylate Bcl-2 in small cell lung cancer (SCLC) (43). Beta-Lapachone,... 

Src tyrosine kinase contains both an SH2 and an SH3 domain linked to a tyrosine kinase unit with a structure similar to other protein kinases. The phosphorylated form of the kinase is inactivated by binding of a phosphoty-rosine in the C-terminal tail to its own SH2 domain. In addition the linker region between the SH2 domain and the kinase is bound in a polyproline II conformation to the SH3 domain. These interactions lock regions of the active site into a nonproductive conformation. Dephosphorylation or mutation of the C-terminal tyrosine abolishes this autoinactivation. 

Intracellular and extracellular ROS activate tyrosine and serine-threonine kinases (i.e., the MAPK family members). Following TNF-a, TGF-f5 or EGF stimulation, intracellular ROS are generated which stimulate various signaling pathways [73], Tyrosine kinase receptors (e.g., EGF, PDGF and TGF-a) may be activated by ROS directly via protein sulfhydryl group modifications, or inhibition of phosphotyrosine phosphatases (PTPases) and subsequent receptor activation. The latter is possible as PTPases contain a redox-sensitive cysteine at their active site [78], and oxidation of protein sulfhydryl groups results in the inactivation of PTPases. 

There are numerous data that peroxynitrite is involved in cell death and tissue injuries in many clinical conditions. An important mechanism underlying peroxynitrite toxicity is the reaction of tyrosine nitration. Tyrosine nitration inactivates certain enzymes, as was postulated for prostacyclin (PGI2) synthase (M14), cytochrome P450 2B1 (RIO), tyrosine hydroxylase (A 14), and MnSOD (Yl). Moreover, nitration blocks tyrosine phosphorylation, and thus interferes with the tyrosine kinase signaling pathways (K18). The peroxynitrite treatment of rat liver epithelial cells stimulates mitogen-activated protein kinases p38 MAPK, JNK1/2, and ERK1/2 the mechanism of this effect awaits elucidation (S9). 

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