Receptor tyrosine kinases phosphorylation, regulation

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]. 

Fig. 11. Modes of action of fluorine on osteoblastic cells, (a) Tyrosine phosphatase hypothesis in osteoblastic cells, fluoride ion directly inhibits tyrosine phosphatase. Inhibition of this enzyme enhances the tyrosine phosphorylation of signalling molecules induced by receptor tyrosine kinase, which leads to activation of the extracellular signal-regulated kinase (ERK) through the Ras pathway and enhanced cell proliferation, (b) G-protein hypothesis in osteoblast-like cells, fluoride ions form a complex with aluminum, probably fluoroaluminate, which interacts with guanosine 5 -diphosphate (GDP) to form guanosine 5 -triphosphate (GTP)-like molecule. Activation of the G, protein stimulates the tyrosine phosphorylation of signalling molecules by a yet unknown tyrosine kinase (Tyr Kin) and activation of the ERK kinase through the Ras pathway leads to enhanced cell proliferation. (Reproduced by permission of Elsevier from Ref. [175] ...

Fig. 9.11. Model of regulation and activation of Raf kinase. The active Ras.GTP complex binds and activates Raf kinase, which passes the signal on to the MAP kinase pathway. Various proteins including the 14-3-3 proteins and the molecular chaperons hsp 90 and p50 are thought to be involved in the regulation of the Raf kinase signahng function. In addition, Raf kinase is regulated by phosphorylation. Tyr phosphorylation (possibly via Src kinase) and Ser phosphorylation via protein kinase C have a stimulatory effect. In contrast, Ser phosphorylation via protein kinase A has an inhibitory effect. RTK receptor tyrosine kinase.

Fig. 10.2. Components and activation of the ERK pathway. Ordering and specificity of protein kinases in the ERK pathway. ExtraceUular signals are registered via receptor tyrosine kinases and passed on to the Ras protein. Ras GTP activates protein kinases belonging to the group of MAPKK kinases (Raf kinases and MEEKs). The MAPKK kinases phosphorylate the downstream group of protein kinases, the MAPKKs at two Ser residues. The MAPKKs phosphorylate the MAPKs (ERKl and ERK2) at a Tyr and a Thr residue, and thus are classified as dual specificity kinases. MAPK mitogenic activated protein kinase ERK extracellularly regulated kinase MEK MAP/ERK kinase MAPKK MAPK kinase MAPKKK MAPKK kinase MEKK MEK kinase.

We have proposed a mechanism by which lL-1 exerts its deleterious effects on islet function and viability (Fig. 11 Corbett et al., 1992). In this proposed mechanism, lL-1 is released by macrophages during the initial stages of islet infiltration. IL-1 binds to a specific IL-1 receptors on the /3 cell activating a tyrosine kinase. Tyrosine kinase phosphorylation stimulates second messengers to induce the expression of c-/os, c-jun, the activation of NF-xB, and possibly other early transcriptional regulators. These early-immediate transcriptional response elements may activate or stimulate the expression of inducible nitric oxide... 

Cytokine receptors, like receptor tyrosine kinases, have extracellular and intracellular domains and form dimers. However, after activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules (JAK) are activated, resulting in phosphorylation of signal transducers and activation of transcription (STAT) molecules. STAT dimers then travel to the nucleus, where they regulate transcription. 

Fig. 6-24 Schematic representation of the epidermal growth factor (EGF) receptor. The receptor is an integral membrane protein with a single transmembrane domain. The ligand binding site is in the extracellular domain and there is a tyrosine kinase domain near the C terminus in the cytoplasm, (a) At rest the receptor exists as single subunits. (b) Upon binding EGF, the receptor forms dimers stabilized by noncovalent associations. After dimerization the activated tyrosine kinase phosphorylates tyrosine residues in the cytoplasmic domain prior to the recruitment of further proteins to bind to the receptor. The formation of a protein assembly on the cytoplasmic domain is necessary for activation of enzymes that regulate cell metabolism and gene transcription.

Receptor tyrosine kinases (RTKs) are activated (phosphorylated) by inhibition of a negatively regulating phosphatase upon treatment with UV (A, B, or C), hydrogen peroxide, or iodoacetamide. The phosphatase activity, (i.e., dephosphorylation and inactivation of RTKs) is restored upon the addition of thiol-regenerating agents, if not inhibited irreversibly by iodoacetamide [20]. H2O2 not only inactivates membrane-bound phosphatases but also diminishes cytosolic general protein tyrosine phosphatase activity in mouse fibroblasts [21]. Further, the activation of JNK by sodium arsenite, which is reactive towards thiols (especially vicinal dithiols), is by inactivation of a JNK phosphatase [22]. 

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