Insulin-sensitive protein kinase

Fig. 7.21. Activation of glycogen-bound protein phosphatase I by insulin. Insulin has a stimulating effect on glycogen synthesis by initiating the dephosphorylation and activation of glycogen synthase and the dephosphorylation and inhibition of glycogen phosphorylase. Both enzymes (substrate S in the figure) are dephosphorylated by protein phosphatase PPIG. Insulin mediates the activation of a protein kinase (insulin-sensitive protein kinase) within an insulin-stimulated signal pathway, which phosphorylates and thus activates protein phosphatase PPIG at the PI site.

Farese RV, Sajan MP, Standaert ML. 2005. Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt) actions and defects in obesity and type II diabetes. Exp Biol Med (Maywood) 230 593-605. 

Figure 21.20. Insulin Activates Protein Phosphatase 1. Insulin triggers a cascade leading to the activation of protein phosphatase 1, which results in the stimulation of glycogen synthesis and inhibition of its breakdovm. The activated receptor tyrosine kinase switches on a putative master kinase that phosphorylates the insulin-sensitive protein kinase. In turn, the glycogen-targeting suhunit (Rgj suhunit) of the phosphatase is phosphorylated, which activates the enzyme. [After P. Dent, A. Lavoirme, S. Nakielny, F. B. Caudwell, P. Watt, and P. Cohen. Nature 348(1990) 306.]...

Insulin results in the activation of PPl. The hormone activates an insulin-sensitive protein kinase that phosphorylates a subunit of PPl, rendering the phosphatase more active. The activated phosphatase dephosphorylates phosphorylase, protein kinase, and glycogen synthase. These changes result in a decrease in glycogen degradation and the stimulation of glycogen synthesis. 

J. Deprez, L. Bertrand, D.R. Alessi, U. Krause, L. Hue and M.H. Rider, Partial purification and characterization of a wortmannin-sensitive and insulin-stimulated protein kinase that activates heart 6-phos-phofructo-2-kinase, Biochem. J. 347, 305-312 (2000). 

The insulin receptor is a transmembrane receptor tyrosine kinase located in the plasma membrane of insulin-sensitive cells (e.g., adipocytes, myocytes, hepatocytes). It mediates the effect of insulin on specific cellular responses (e.g., glucose transport, glycogen synthesis, lipid synthesis, protein synthesis). 

S6K1 (also known as p70S6 kinase) is a serine/ threonine protein kinase which is involved in the regulation of translation by phosphorylating the 40S ribosomal protein S6. Insulin and several growth factors activate the kinase by phosphorylation in a PI 3-kinase dependent and rapamycin-sensitive manner. Phosphorylation of S6 protein leads to the translation of mRNA with a characteristic 5 polypyrimidine sequence motif. 

Sandiez-Margalet V, Lucas M, Solano F, Goberna R (1993) Sensitivity of insulin-secreting RIN m5F cells to undergoing apoptosis by the protein kinase C inhibitor staurosporine. Exp Cell Res 209 160-163... 

Regulation The concentration of free fatty acids in the blood is controlled by the rate at which hormone-sensitive triacylglycerol lipase hydrolyzes the triacylglycerols stored in adipose tissue. Glucagon, epinephrine and norepinephrine cause an increase in the intracellular level of cAMP which allosterically activates cAMP-dependent protein kinase. The kinase in turn phosphorylates hormone-sensitive lipase, activating it, and leading to the release of fatty acids into the blood. Insulin has the opposite effect it decreases the level of cAMP which leads to the dephosphorylation and inactivation of hormone-sensitive lipase. 

If beta cells are incubated in media containing 2 mM glucose and then treated with forskolin and/or tolbutamide, there is a small transient increase in insulin secretion. The subsequent addition of CCK8S leads to a very marked first phase of insulin secretion, but causes no sustained increase or second phase of insulin secretion. These results mean that an increase in cAMP alters the Ca2+ sensitivity of the response elements underlying the first phase of secretion. These elements, presumed to be Ca2+-calmodulin-dependent processes including CaM-dependent protein kinases, become more sensitive to activation by Ca2+ either because cAMP acts to enhance the sensitivity of CaM-dependent kinases to Ca2+, or because cAMP inhibits, by an unknown mechanism, the activity of phosphoprotein phosphatases. 

Insulin also exerts a stimulatory effect on the synthesis of cholesterol in the liver. In this tissue, HMG-CoA reductase is activated. HMG-CoA reductase, like hormone-sensitive lipase, can exist in two forms one is phosphorylated (inactive) and the other is dephosphorylated (active). Phosphorylation of the enzyme depends on an increase in the cellular concentration of cAMP and activation of protein kinase. The dephosphorylation (activation) is catalyzed by a phosphatase. In fat cells, a similar phosphatase dephosphorylates (inactivates) hormone-sensitive lipase. Insulin stimulates the activity of the phosphatase in both liver and fat cells. In this way, active HMG-CoA reductase predominates in the liver cell and directs HMG-CoA into cholesterol synthesis, and in the fat cell hormone-sensitive lipase is inactivated. 

Takikawa, M. Inoue, S. Horio, F. Tsuda, T. 2010. Dietary anthocyanin-richbilberry extract ameliorates hyperglycemia and insulin sensitivity via activation of AMP-activated protein kinase in diabetic mice. J. Nutr. 140 527-533. 

The mechanisms by which insulin antagonizes the effects of glucagon and exerts its glucagon-iiidependent effects are not clear Much attention has been given to the insulin receptor, a protein embedded in the plasma membranes of insulin-sensitive cells. Binding of plasma insulin to a receptor results in phosphorylation of a tyrosine residue present in the polypeptide chaiir of the receptor protein. It also results in activation of kinases that catalyze phosphorylation of serine residues of specific proteins. Another effect is a decline in the degree of phosphorylation of a number of other proteins. 

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