Signaling pathways protein tyrosine kinases

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. 

Downstream in the pathway of rescue, PKB effects a number of phosphorylations that prevent apoptosis (Figure 8.17) (see Section 8.2 3.2). It is of interest to note that both growth factor receptors, such as TrkA, and adhesion molecules generate rescue signals through activation of protein tyrosine kinases, and apparently cells require both attachment to extracellular matrix and the presence of a particular growth factor in order not to die. 

Comparison of Signal-Transduction Pathways Downstream of a Protein Tyrosine Kinase Receptor in Species of Three Separate Phyla... 

Photoaffinity Labeling of Receptor Protein Tyrosine Kinases (PTK) and Biomolecular Targets Involved in the Signaling Pathways... 

The coupling of superantigen—major histocompatibility complex class II to T-cell receptor swifdy results in cell-signaling cascades. ° These staphylococcal toxins can increase levels of phosphatidyl inositol from quiescent T cells, such as other mitogens, as well as elicit intracellular Ca movement that activates the protein kinase C (PKC) pathway important for interleukin-2 (IL-2) expression. " IL-2 is intimately linked to T-cell proliferation. In addition to the PKC pathway, the protein tyrosine kinase (PTK) pathway is also activated by superantigens, leading to elevated expression of various proinflammatory cytokines. Staphylococcal superantigens also potently activate transcriptional factors NF-/IB (nuclear factor kappa B) and AP-1 (activator protein-1), which subsequently elicit the synthesis of proinflammatory cytokines. " " ... 

Src is the prototype of the superfamily of protein tyrosine kinases and was one of the first protein kinases to be characterized by various genetic, cellular, and structure-function studies to help imderstand its role in signal transduction pathways as well as in disease processes, including cancer, osteoporosis, and both tumor- and inflammation-mediated bone loss [28-38]. In fact, studies on Src provided some of the first evidence correlating protein kinase activity and substrate protein phosphorylation in the regulation of signal transduction pathways relative to normal cellular activity as well as mahgnant transformations. Src family kinases include Fyn, Yes, Yrk, Blk, Fgr, Hck, Lyn,... 

The main function of lipidation is to promote membrane association of signaling proteins. Lipid anchors target proteins to the membrane, as is the case for the cytoplasmic protein tyrosine kinases, so that they can participate in membrane-associated signaling pathways. Furthermore, protein lipidation is thought to mediate protein-protein association and/or stabilize protein conformations (review Casey, 1995). 

Fig. 5.5. General functions of transmembrane receptors. Extracellular signals convert the transmembrane receptor from the inactive form R to the active form R. The activated receptor transmits the signal to effector proteins next in the reaction sequence. Important effector reactions are the activation of heterotrimeric G-proteins, of protein tyrosine kinases and of protein tyrosine phosphatases. The tyrosine kinases and tyrosine phosphatases may be an intrinsic part of the receptor or they may be associated with the receptor. The activated receptor may also include adaptor proteins in the signaling pathway or it may induce opening of ion channels.

Parson, IT, and Parson, S.J. Src family protein tyrosine kinases cooperating with growth factor and adhesion signaling pathways (1997) Curr. Op. Cell Biol. 9, 187-192... 

Leptin makes the cells of liver and muscle more sensitive to insulin. One hypothesis to explain this effect suggests cross-talk between the protein tyrosine kinases activated by leptin and those activated by insulin (Fig. 23-35) common second messengers in the two signaling pathways allow leptin to trigger some of the same downstream events that are triggered by insulin, through insulin receptor substrate-2 (IRS-2) and phos-phoinositide 3-kinase (PI-3K) (Chapter 12). 

As work with vanadium compounds and diabetes in cell system has continued, it has become clear that there are also insulin-independent mechanisms at work. One insulin-independent signal transduction pathway appears to be involved in glycogen metabolism reactions in rat adipocytes [137] that also involve PI-3K. A major difference was that only vanadate promoted glycogenesis through the activation of a cytosolic protein tyrosine kinase, which was mediated in an insulin receptor-independent manner. 

Vanadate stimulates protein kinases in the cytosol, as demonstrated in adipose cells and extracts. The activation of a membrane and cytosolic protein tyrosine kinase have been demonstrated in adipocytes, and the membranous enzyme has been postulated to be a way to involve PI-3K actions without activation of insulin receptor substrate-1 (IRS-1) in the insulin signal transduction pathway [140], It is always difficult to determine if protein kinase activation is direct or the result of stimulation of a protein phosphatase. The fact that kinase stimulation was seen in isolated extracts after cell disintegration in this adipocyte cell system supports the idea that vanadium addition to cells could directly stimulate kinases via an as-yet-undetermined mechanism. In other experiments with 3T3-L1 adipocytes bis(acetylacetonato)oxovana-dium (IV) BMOV and bis(l-N-oxide-pyridine-2thiolato)oxovanadium (TV) caused increased tyrosine phosphorylation of both the insulin receptor and IRS-1 in a synergistic way with insulin, as measured by antibodies to phosphotyrosine residues [141]. 

Fig. 11.1 Activation of MAPK pathway by Angll and ET-1 in VSMC. Stimulation of Angll and ET-1 receptors through Gq/n activation enhances the activity of PLCp. Activated PLC 3 converts PIP2 to IP3 and diacylglycerol (DAG). IP3 elevates the concentration of intracellular calcium and DAG activates PKC. PKC and/or Ca2+/calmodulin (CaM)-dependent protein kinases (CaMK) activate nonreceptor (NR) and/or receptor (R) protein tyrosine kinases. Activation of these components signals the stimulation of Ras/Raf/MEK/ERKl/2 and p70 s6k. ERK1/2 and p70 s6k are translocated to nucleus and regulate nuclear events by activating transcription factors through phosphorylation.

Slevin, M. et al., Angiogenic oligosaccharides of hyaluronan induce protein tyrosine kinase activity in endothelial cells and activate a cytoplasmic signal transduction pathway resulting in proliferation,... 

A more detailed picture of the folding of the SH3 (Src homology 3) domain of the Fyn protein kinase has been obtained by relaxation dispersion experiments.93 9 SFI3 domains bind proline-rich sequences and are key components of proteins involved in protein tyrosine kinase signalling pathways. The folding of the SFI3 domain of the Fyn protein kinase has been extensively characterized by stopped-flow and NMR experiments. CPMG relaxation dispersion analysis revealed that the Fyn SH3 domain is essentially a three-state folder with an intermediate state. 

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