Receptor protein phosphotyrosine phosphatase

Receptor Serine/Threonine Receptor Protein Kinase = Receptor Protein Phosphotyrosine Phosphatase = Receptor Tyrosine Kinase = Signal Transducer and Activator of Transcription = Transforming Growth Factor P = Tetradecanoylphorbolacetate = Tetradecanoylphorbolacetate Response Element = Change in Permeability of PM to specific solutes = Change in Transmembrane Potential. 

It is not clear whether V(V) or V(IV) (or both) is the active insulin-mimetic redox state of vanadium. In the body, endogenous reducing agents such as glutathione and ascorbic acid may inhibit the oxidation of V(IV). The mechanism of action of insulin mimetics is unclear. Insulin receptors are membrane-spanning tyrosine-specific protein kinases activated by insulin on the extracellular side to catalyze intracellular protein tyrosine phosphorylation. Vanadates can act as phosphate analogs, and there is evidence for potent inhibition of phosphotyrosine phosphatases (526). Peroxovanadate complexes, for example, can induce autophosphorylation at tyrosine residues and inhibit the insulin-receptor-associated phosphotyrosine phosphatase, and these in turn activate insulin-receptor kinase. 

As outlined above, protein phosphorylation is a key process involved in many signal transduction pathways and reversal of this process is catalyzed by a multiplicity of phosphoprotein phosphatases (PPs). Major PPs catalyzing dephosphorylation of phosphoserine or phosphothreonine residues on proteins include PP1 (inhibited by phosphorylated inhibitor protein I-1 and by okadaic acid and microsystins), PP2 (also inhibited by okadaic acid and microcystins), PP2B or calcineurin (CaM-activated and having a CaM-like regulatory subunit) and PP2C (Mg2+-dependent) [18]. These PPs have been found in all eukaryotes so far examined [18, 19]. In addition, a variety of protein phosphotyrosine phosphatases can reverse the consequences of RTK or JAK/STAT receptor activation [20]. 

Phosphotyrosine phosphatases are integrated just like tyrosine Idnases into signalling pathways. They interact with receptors and have recognition motifs that direct diem to their targets. 5 Protein phosphotyrosine phosphatases downregulate tyrosine phosphorylation and play a role in cellular regulation as important as that of 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. 

The insulin receptor substrate IRS couples the insulin receptor to sequential effector molecules (review Ogawa et al., 1998). On binding of insulin to the insulin receptor, the tyrosine kinase activity of the receptor is stimulated. The IRS protein is phosphory-lated at several Tyr residues, which then serve as attachment points for sequential effector molecules as e.g. the Grb2-mSos complex, the P13-kinase and the protein tyrosine phosphatase SHP-2. The IRS protein also has a phosphotyrosine binding domain and a PH domain. Both modules are required for signal transduction in vivo. It is assumed that the PTB domain binds to autophosphorylation sites of the insulin receptor and that the PH domain is involved in membrane association of IRS. 

Because the primary eveuts between insulin binding to its receptor and glucose transport are signal transduction events, a role for chromodulin in these events has been probed. Chromoduhn activates the tyrosine kinase activity of insulin-activated insulin receptor and activates a membrane phosphotyrosine phosphatase in adipocyte membranes. The addition of bovine liver chromodulin to rat adipocytic membranes in the presence of insuhn results in a concentration-dependent eightfold stimulation of insulin-dependent protein tyrosine kinase activity (while no activation... 

The above may be of pathophysiological relevance as a decreased basal and insulin-stimulated glycogen phosphatase activity and phosphorylase phosphatase activity (Type-1 protein phosphatase, PP-1) in the skeletal muscle of insulin-resistant individuals has been found (Freymond era/., 1988 Kida era/., 1990, 1992 Damsbo et al., 1991). Other studies suggest increased phosphotyrosine phosphatase activity in patients with NIDDM who show decreased autoactivation of the insulin receptor kinase (McGuire et al., 1991). 

Agazie YM, Hayman MJ (2003) Development of an efficient substrate-trapping mutant of Src homology phosphotyrosine phosphatase 2 and identification of the epidermal growth factor receptor, Gabl, and three other proteins as target substrates. J Biol Chem 278 13952-13958... 

However, constitutive expression of these genes conld have nndesirable conseqnences. Therefore, there are a nnmber of regnlatory mechanisms that act to control signaling throngh the cytokine receptor pathway. One snch mechanism involves a protein tyrosine phosphatase called SHP2 this catalyzes dephosphorylation of phosphotyrosine residnes on the cytokine receptors, as well as on JAKs and STATs, and this inactivates the pathway. 

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