Signal transduction, insulin

Marandi, S. De Keyser, N. Saliez, A. Maernoudt, A.-S. Sokal, E.M. Stil-mant, C. Rider, M.H. Buts, J.-P. Insulin signal transduction in rat small intestine role of MAP kinases in expression of mucosal hydrolases. Am. J. Physiol., 280, G229-Ci240 (2001)... 

PTB domains (phosphotyrosine-binding domains) also bind (P)-Tyr in partner proteins, but their critical sequences and three-dimensional structures distinguish them from SH2 domains. The human genome encodes 24 proteins that contain PTB domains, including IRS-1, which we have already met in its role as a scaffold protein in insulin-signal transduction (Fig. 12-6). 

Biener, Y., Feinstein, R., Mayak, M., Kaburaqi, Y., Kadowaki, T. and Y. Zick, 1996, Annexin II is a novel player in insulin signal transduction. Possible association between annexin II phosphorylation and insulin receptor internalization. J. Biol. Chem. 271, 29489-29496. 

Bjornholm M, Zierath JR. Insulin signal transduction in human skeletal muscle identifying the defects in type II diabetes. Biochem Soc Trans. 2005 33(Pt 2) 354-357. 

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]. 

Cheng, A., Dube, N., Gu, F. andTremblay M.L. (2002) Coordinated action ofprotein tyrosine phosphatases in insulin signal transduction. Eur. J. Biochem. 269, 1050-1059. 

It has been known for a long time that a number of enzymes are regulated by insulin through phosphorylation and dephosphorylation at serine residues (Kahn, 1985). Therefore, a signal transduction from the tyrosine-specific insulin receptor kinase to a serine-specific kinase must occur. The serine kinase that might fulfil both functions in the insulin signal-transduction chain has not yet been identified however, there are several possible candidates for these so called switch kinases (Fig. 10). 

Figure 1 Insulin signal transduction cascade (simplified). Intracellular kinases affected by tyrosine phosphorylation activation/deactivation under phosphotyrosine phosphatase (PTPase) regulation (vanadium-inhibitable) include (especially) IRS-I, IRS-2, she, and MAPK. V indicates possible sites of vanadium s mechanism of action. Cytosolic protein tyrosine kinase (CytPTK, not shown) stimulation by phosphatase inhibition is independent of the insulin cascade, but is also multi-step, and is particularly susceptible to vanadyl stimulation...

Figure 27.1 How insulin signal transduction stimulates glycogen synthesis (PDK/AKT hypothesis). See figure key on page 8 for explanation of cartoons.

When feeding has finished, insulin secretion stops and insulin signal transduction within the cell must be terminated. Dephosphorylation of the insulin receptor by protein tyrosine phosphatase (PTPase) occurs, which inactivates the insulin receptor and insulin signalling ceases. However, there is evidence that some diabetic patients have a form of PTPase that is inappropriately active and opposes normal activation of the receptor by phosphorylation. Currently, there is a major research effort to develop drugs that inhibit PTPase and provide a new treatment for type 2 diabetes. 

Insulin signal transduction and diabetes mellltus Carbohydrates 63... 

Autophosphorylation of the insulin receptor leads to phosphorylation of insulin receptor substrate (IRS). IRS comes in four different forms (IRS-1, IRS-2, IRS-3 and IRS-4). In muscle tissue, IRS-1 is the most important form for mediating insulin-signal transduction and lRS-1 impairment has been observed in muscle tissue of humans with DM-2 (Glund and Zierath, 2005). lRS-1 has many tyrosine phosphorylation sites. When these sites are phosphorylated by the insulin receptor, multiple insulin signals are enabled (Sun et al., 1993). IRS-1 also has several serine phosphorylation sites phosphorylation of serine residue 1101 results in inhibition of insulin signalling and provides a possible mechanism for IR (Li et al., 2004). After IRS is phosphorylated, it recruits and activates phosphatidylinositol 3-kinase (PI3-kinase). PI3-kinase phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to... 

Many cells also contain significant amounts of free GPIs, not linked to proteins or glyco-polymers [12]. The function of these molecules is unclear, although there exist controversial proposals that they may be the source of phospho-oligosaccharides involved in insulin signal transduction [13, 14]. 

Ji, P., J.S. Osorio, J.K. Drackley and J.J. Loor, 2010. Insulin signal transduction in adipose tissue of peripartal dairy cows fed two levels of dietary energy pre partum. J. Dairy Sci. 93 (E-Suppl. 1), Abs 870. 

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