Kinases, cell proliferation

EGFR Receptor tyrosine kinase Inhibition of cell proliferation and colony formation decrease of in vivo tumorigenicity... 

The anthrax toxin is a tripartite toxin and consists ofthe binding component protective antigen (PA), the lethal factor (LF), which is a metalloprotease, and the edema factor (EF), which is a calmodulin-dependent adenylyl-cyclase. Both enzyme components are translocated via PA into target cells. PA is activated by furin-induced cleavage and forms heptamers, which are similar to the binding components of C2 toxin and iota toxin. In the low pH compartment of endosomes, the heptamers form pores to allow translocation of LF and EF. LF cleaves six of the seven MEKs (MAPK-kinases) thereby inhibiting these enzymes. The functional consequence is the blockade of the MAPK pathways that control cell proliferation, differentiation, inflammation, stress response, and survival. Whether this is the reason for the LT-induced cell death of macrophages is not clear [1]. 

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. 

Phosphorylation is the reversible process of introducing a phosphate group onto a protein. Phosphorylation occurs on the hydroxyamino acids serine and threonine or on tyrosine residues targeted by Ser/Thr kinases and tyrosine kinases respectively. Dephosphorylation is catalyzed by phosphatases. Phosphorylation is a key mechanism for rapid posttranslational modulation of protein function. It is widely exploited in cellular processes to control various aspects of cell signaling, cell proliferation, cell differentiation, cell survival, cell metabolism, cell motility, and gene transcription. 

TASINATO A D, BOISCOBOINIK D, BARTOLI G M, MARONi p and Azzi A (1995) d-a-tocopherol inhibition of vascular smooth muscle cell proliferation occurs at physiological concentrations, correlates with protein kinase C inhibition, and is independent of its ntioydd ait xo eriie% Proceedings National Academy Sciences USA 92, 12190-4. 

ATLURU s, ATLURU D (1991) Evidence that genistein, a protein-tyrosine kinase inhibitor, inhibits CD28 monoclonal antibody stimulated human T-cell proliferation. Transplantation. 51 448-50. 

Gleevec ) is a tyrosine kinase inhibitor used as first-line therapy in the majority of patients with CML. As a potent tyrosine kinase inhibitor, imatinib inhibits phosphorylation of various proteins involved in cell proliferation. Imatinib works by binding to the ATP-binding pocket of BCR-ABL.7 The drug induces complete hematologic responses in more than 95% of patients and complete cytogenetic responses in about 80% of patients in chronic phase.8 Most patients have traces of the disease when measured by RT-PCR and are not cured of their disease. 

Chandrasekar B, Bysani S, Mummidi S. CXCL16 signals via Gi, phosphatidylino-sitol 3-kinase, Akt, I kappa B kinase, and nuclear factor-kappa B and induces cell-cell adhesion and aortic smooth muscle cell proliferation. J Biol Chem 2004 279(5) 3188-3196. 

Sulpice E, Bryckaert M, Lacour J, Confreres JO, Tobelem G. Platelet factor 4 inhibits FGF2-induced endothelial cell proliferation via the extracellular signal-regulated kinase pathway but not by the phosphatidylinositol 3-kinase pathway. Blood 2002 100(9) 3087-3094. 

Receptor tyrosine kinases are critical components of signaling pathways that control cell proliferation and differentiation. Enhanced RTK activity due to activating mutations or overexpression has been implicated in human cancers. Thus, selective inhibitors of RTKs have considerable value. Although a number of compounds have been identified as effective inhibitors of RTKs,... 

The nonreceptor PTKs are a large group of signaling proteins that have diverse roles in the control of cell proliferation, differentiation, and death. Some are widely expressed others are restricted to particular tissues. Their early classification was dominated by the discovery of pp60src, to the extent that the major group of kinases were simply known as the Src family. There are at least ten known subfamilies of nonreceptor PTKs. 

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