Signal transduction pathways---kinase inhibition

As in all eukaryotic cells, protein kinases play an important role in the life cycle of the kinetoplastids and, as such, are attractive targets. Recent efforts, predominantly through genetic (RNAi) means, have validated a number of kinases as essential for survival of T. brucei, but few have been explored with chemical probes [33-35]. 

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CBj and CB receptors share some common signal transduction pathways. Both inhibit adenylate cyclase via G-proteins (Gj family) and stimulate mitogen-activated protein kinase. Activation of CBj receptors, unlike that of CB receptors, has been shown to affect ion chaimels (Mackie and Hille, 1992 Mackie et al., 1995). 

Sorafenib is a multitargeted cancer therapy that inhibits VEGFR, PDGFR, KIT, fetal liver tyrosine kinase 3 (FLT-3), and the serine/threonine kinase RAF. RAF kinase is a key downstream effector of Ras in the MAPK/Ras signal-transduction pathway that has been linked to various cancers. Sorafenib is both a tyrosine kinase inhibitor and serine/threonine signal-transduction inhibitor. Sorafenib has been approved in renal cancer. 

Phosphorylation of H3 is not limited to mitosis and also occurs in G1 phase of the cell cycle. Activation of the Ras-Raf-MEK-ERK signal transduction pathway and/or of the p38 stress kinase pathway when cells are treated with epidermal growth factor (EGF), 12-G-tetradecanoylphorbol-13-acetate (TPA), anesomycin, okadiac acid, and stresses such as UV irradiation induces the rapid phosphorylation of H3 at Ser-10 and/or Ser-28 [68-72] (Figs. 5 and 6). Inhibition of the MEK1,2 activity with PD98059 prevents the activation of ERK and TPA-induced H3... 

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