Tyrosine Phosphorylation of Insulin Receptor Substrate-1 and Activation of the PI-3-Kinase Pathway by Glycine-Extended Gastrin Precursors

1997 ◽  
Vol 236 (3) ◽  
pp. 687-692 ◽  
Author(s):  
Aline Kowalski-Chauvel ◽  
Lucien Pradayrol ◽  
Nicole Vaysse ◽  
Catherine Seva
Keyword(s):  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Kinase Pathway

scholarly journals Insulin receptor substrate 1 rescues insulin action in CHO cells expressing mutant insulin receptors that lack a juxtamembrane NPXY motif.

1995 ◽  
Vol 15 (9) ◽  
pp. 4711-4717 ◽  
Author(s):  
D Chen ◽  
D J Van Horn ◽  
M F White ◽  
J M Backer
Keyword(s):  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Cho Cells ◽  
Glycogen Synthesis ◽  
Insulin Receptors ◽  
Insulin Receptor Substrate ◽  
Insulin Stimulation ◽  
Insulin Receptor Substrate 1 ◽  
Npxy Motif ◽  
Stimulation Of

Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (IRS-1) and Shc by the activated insulin receptor (IR). Phosphorylation of both proteins is nearly abolished by an alanine substitution at Tyr-960 (A960) in the beta-subunit of the receptor. However, overexpression of IRS-1 in CHO cells expressing the mutant receptor (A960 cells) restored sufficient tyrosine phosphorylation of IRS-1 to rescue IRS-1/Grb-2 binding and phosphatidylinositol 3' kinase activation during insulin stimulation. Shc tyrosine phosphorylation and its binding to Grb-2 were impaired in the A960 cells and were unaffected by overexpression of IRS-1. Although overexpression of IRS-1 increased IRS-1 binding to Grb-2, ERK-1/ERK-2 activation was not rescued. These data suggest that signaling molecules other than IRS-1, perhaps including Shc, are critical for insulin stimulation of p21ras. Interestingly, overexpression of IRS-1 in the A960 cells restored insulin-stimulated mitogenesis and partially restored insulin stimulation of glycogen synthesis. Thus, IRS-1 tyrosine phosphorylation is sufficient to increase the mitogenic response to insulin, whereas insulin stimulation of glycogen synthesis appears to involve other factors. Moreover, IRS-1 phosphorylation is either not sufficient or not involved in insulin stimulation of ERK.

scholarly journals Angiotensin II induces tyrosine phosphorylation of insulin receptor substrate 1 and its association with phosphatidylinositol 3-kinase in rat heart

1995 ◽  
Vol 310 (3) ◽  
pp. 741-744 ◽  
Author(s):  
M J A Saad ◽  
L A Velloso ◽  
C R O Carvalho
Keyword(s):  
Angiotensin Ii ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Rat Heart ◽  
Fold Increase ◽  
At1 Receptor ◽  
Insulin Receptor Substrate ◽  
Phosphatidylinositol 3 Kinase ◽  
Insulin Receptor Substrate 1

We have investigated whether angiotensin II (AII) is able to induce insulin receptor substrate 1 (IRS-1) phosphorylation and its association with phosphatidylinositol 3-kinase (PI 3-kinase) in the rat heart in vivo. The phosphorylation state of IRS-1 following infusion of insulin or AII via the vena cava was assessed after immunoprecipitation with an anti-peptide antibody to IRS-1 followed by immunoblotting with an anti-phosphotyrosine antibody and an anti-PI 3-kinase antibody. Densitometry indicated a 5.6 +/- 1.3-fold increase in IRS-1 phosphorylation after stimulation with AII and a 12.8 +/- 3.1-fold increase after insulin. The effect was maximal at an AII concentration of 10(-8) M and occurred 1 min after infusion. There was also a 6.1 +/- 1.2-fold increase in IRS-1-associated PI 3-kinase in response to AII. In the isolated perfused heart the result was similar, showing a direct effect of AII on this pathway. When the animals were pretreated for 1 h with DuP 753, a non-peptide AII-receptor 1 (AT1 receptor) antagonist, there was a marked reduction in the AII-induced tyrosine phosphorylation of IRS-1, suggesting that phosphorylation is initially mediated by the AT1 receptor. We conclude that AII stimulates tyrosine phosphorylation of IRS-1 and its association with PI 3-kinase. This pathway thus represents an additional signalling mechanism stimulated by AII in the rat heart in vivo.

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