Kinase, kinases pathway

Besides direct apoptosis effectors, there are a number of other diugs which influence the above explained apoptosis pathways more indirectly. This class of diugs includes molecules which inhibit survival pathways like e.g. the Ras/Raf kinase pathway, the NF-kB pathway and many others. Also inhibitors of survival cytokines which are sometimes produced by cancer cells in an autocrine fashion can render cells susceptible to apoptosis and, hence, effective cancer therapy. These include, but are not limited to, ligands for dependence receptors and cytokines like e.g. interleukin-4. 

Anthrax toxin Lethal factor Lethal factor MEKs Endoprotease Increase in intracellular cAMP Inhibition of MAP-kinase pathways Calmodulin dependent adenylylcyclase... 

In general terms, cross talk refers to the interaction between signalling pathways, e.g. between pathways involving heterotrimeric GTP-binding proteins and tyrosine kinase pathways. 

Functionally, the Dl-like receptors (Dl, D5) are coupled to the G protein Gas and thus can stimulate adenylyl cyclase. The D2-like receptors (D2, D3, and D4) couple to pertussis toxin sensitive G proteins (Gai/0), and consequently inhibit adenylyl cyclase activity. While the Dl-like receptors almost exclusively signal through Gas-mediated activation of adenylyl cyclase, the D2-like receptors have been reported to modulate the activity of a plethora of signaling molecules and pathways. Many of these actions are mediated through the G(3y subunit. Some of these molecules and pathways include the calcium channels, potassium channels, sodium-hydrogen exchanger, arachidonic acid release, and mitogen-activated protein kinase pathways. 

Adaptor protein, containing one SH2 and two SH3 domains, which assembles signaling complexes at receptors. Particularly important for activation of the Ras-MAP kinase pathway. 

Stimulation of the insulin receptor results in the activation of two major pathways [3] (i) the mitogen-activated protein (MAP) kinase cascade (discussed in chapter MAP kinase cascade) and (ii) the phospha-tidylinositol 3-kinase (PI 3-kinase) pathway which has been extensively studied in the context of the metabolic responses to insulin (summarized in Table 1 and Fig. 2). 

Pearson G, Robinson F, Gibson TB et al (2001) Mitogen-activated protein (MAP) kinase pathways regulation and physiological functions. Endocrine Rev 22 153-183... 

PARs are coupled to multiple G-proteins and mediate a number of well-defined cellular responses via classical second messenger and kinase pathways. PARs are differentially expressed in cells of the vasculature as well in the brain, lung, gastrointestinal tract, skin as well as other highly vascularised tissues and evidence suggests distinct physiological functions and roles in disease states [2]. 

In chronic myelogenous leukemia (CML) as well as in a subset of acute lymphoblastic leukemia (ALL) Bcr-Abl, a fusion protein of c-Abl and the breakpoint cluster region (bcr), is expressed in the cytosol of leukemic cells. This fusion protein forms homo-oligomeric complexes that display elevated kinase activity and is the causative molecular abnormality in CML and certain ALL. The transforming effect of Bcr-Abl is mediated by numerous downstream signaling pathways, including protein kinase C (PKC), Ras-Raf-ERK MAPK, JAK-STAT (see below), and PI3-kinase pathways. 

In addition to Lyn, a second Src family kinase, Fyn, associates with the FceRI P chain and is activated after FceRI aggregation [26]. Fyn phosphorylates the adaptor Gab2 to activate the phosphatidyUnositol-3-OH kinase (PI3K) pathway the SH2 domain-... 

Yang L, Williams DE, Kim J, Demirjian L, Qasimi R 53 Ruschmann J, Cao LP, Ma K, Chung SW, Duronio V, Andersen RJ, Krystal G, Mui AL Small-molecule agonists of SHIPl inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells. Blood 2007 110 1942-1949. 

Figure 38-7. Activation of elF-4E by insulin and formation of the cap binding elF-4F complex. The 4F-cap mRNA complex is depicted as in Figure 38-6. The 4F complex consists of elF-4E (4E), elF-4A, and elF-4G. 4E is inactive when bound by one ofa family of binding proteins (4E-BPs). Insulin and mitogenic factors (eg, IGF-1, PDGF, interleukin-2, and angiotensin II) activate a serine protein kinase in the mTOR pathway, and this results in the phosphorylation of 4E-BP. Phosphorylated 4E-BP dissociates from 4E, and the latter is then able to form the 4F complex and bind to the mRNA cap. These growth peptides also phosphorylate 4E itself by activating a component of the MAP kinase pathway. Phosphorylated 4E binds much more avidly to the cap than does nonphosphorylated 4E.

Shikonm stimulates glucose uptake in 3T3-L1 adipocytes via an insulin-independent tyrosine kinase pathway. Biochem. Biophys Res Commun. 292 (3) 642-51. 

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]. 

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