scholarly journals Insulin and Metabolic Stress Stimulate Multisite Serine/Threonine Phosphorylation of Insulin Receptor Substrate 1 and Inhibit Tyrosine Phosphorylation

2014 ◽  
Vol 289 (18) ◽  
pp. 12467-12484 ◽  
Author(s):  
Nancy J. Hançer ◽  
Wei Qiu ◽  
Christine Cherella ◽  
Yedan Li ◽  
Kyle D. Copps ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Metabolic Stress ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1

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.

scholarly journals Identification of SH2B2β as an Inhibitor for SH2B1- and SH2B2α-Promoted Janus Kinase-2 Activation and Insulin Signaling

Endocrinology ◽  
2007 ◽  
Vol 148 (4) ◽  
pp. 1615-1621 ◽  
Author(s):  
Minghua Li ◽  
Zhiqin Li ◽  
David L. Morris ◽  
Liangyou Rui
Keyword(s):  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Sh2 Domain ◽  
Janus Kinase ◽  
Pleckstrin Homology Domain ◽  
Insulin Receptor Substrate ◽  
Janus Kinase 2 ◽  
Pleckstrin Homology ◽  
Insulin Receptor Substrate 1

The SH2B family has three members (SH2B1, SH2B2, and SH2B3) that contain conserved dimerization (DD), pleckstrin homology, and SH2 domains. The DD domain mediates the formation of homo- and heterodimers between members of the SH2B family. The SH2 domain of SH2B1 (previously named SH2-B) or SH2B2 (previously named APS) binds to phosphorylated tyrosines in a variety of tyrosine kinases, including Janus kinase-2 (JAK2) and the insulin receptor, thereby promoting the activation of JAK2 or the insulin receptor, respectively. JAK2 binds to various members of the cytokine receptor family, including receptors for GH and leptin, to mediate cytokine responses. In mice, SH2B1 regulates energy and glucose homeostasis by enhancing leptin and insulin sensitivity. In this work, we identify SH2B2β as a new isoform of SH2B2 (designated as SH2B2α) derived from the SH2B2 gene by alternative mRNA splicing. SH2B2β has a DD and pleckstrin homology domain but lacks a SH2 domain. SH2B2β bound to both SH2B1 and SH2B2α, as demonstrated by both the interaction of glutathione S-transferase-SH2B2β fusion protein with SH2B1 or SH2B2α in vitro and coimmunoprecipitation of SH2B2β with SH2B1 or SH2B2α in intact cells. SH2B2β markedly attenuated the ability of SH2B1 to promote JAK2 activation and subsequent tyrosine phosphorylation of insulin receptor substrate-1 by JAK2. SH2B2β also significantly inhibited SH2B1- or SH2B2α-promoted insulin signaling, including insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1. These data suggest that SH2B2β is an endogenous inhibitor of SH2B1 and/or SH2B2α, negatively regulating insulin signaling and/or JAK2-mediated cellular responses.

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