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Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidylinositol 3-kinase pathway
1Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, California 94305, USA.
Abstract:
Serine/threonine phosphorylation of insulin receptor substrate 1 (IRS-1) has been implicated as a negative regulator of insulin signaling. Prior studies have indicated that this negative regulation by protein kinase C involves the mitogen-activated protein kinase and phosphorylation of serine 612 in IRS-1. In the present studies, the negative regulation by platelet-derived growth factor (PDGF) was compared with that induced by endothelin-1, an activator of protein kinase C. In contrast to endothelin-1, the inhibitory effects of PDGF did not require mitogen-activated protein kinase or the phosphorylation of serine 612. Instead, three other serines in the phosphorylation domain of IRS-1 (serines 632, 662, and 731) were required for the negative regulation by PDGF. In addition, the PDGF-activated serine/threonine kinase called Akt was found to inhibit insulin signaling. Moreover, this inhibition required the same IRS-1 serine residues as the inhibition by PDGF. Finally, the negative regulatory effects of PDGF and Akt were inhibited by rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), one of the downstream targets of Akt. These studies implicate the phosphatidylinositol 3-kinase/Akt kinase cascade as an additional negative regulatory pathway for the insulin signaling cascade.
Insights
Platelet-derived growth factor (PDGF) negatively regulates insulin signaling through specific serine residues on IRS-1, distinct from protein kinase C pathways. This regulation involves the Akt kinase cascade and is sensitive to mTOR inhibitors.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Endocrinology
Background:
- Serine/threonine phosphorylation of insulin receptor substrate 1 (IRS-1) is a known negative regulator of insulin signaling.
- Protein kinase C (PKC) mediated regulation involves mitogen-activated protein kinase (MAPK) and IRS-1 serine 612 phosphorylation.
Purpose of the Study:
- To compare the negative regulation of insulin signaling by platelet-derived growth factor (PDGF) with that induced by endothelin-1 (ET-1), a PKC activator.
- To elucidate the specific molecular mechanisms and signaling pathways involved in PDGF-mediated negative regulation of insulin signaling.
Main Methods:
- Comparative analysis of insulin signaling inhibition by PDGF and ET-1.
- Investigation of the role of MAPK and specific IRS-1 serine phosphorylation sites (S612, S632, S662, S731).
- Assessment of Akt kinase activity and its role in PDGF-induced inhibition.
- Evaluation of the effects of rapamycin, an mTOR inhibitor, on PDGF and Akt mediated signaling.
Main Results:
- PDGF-induced inhibition of insulin signaling did not involve MAPK or IRS-1 S612 phosphorylation, unlike ET-1.
- PDGF-mediated negative regulation required phosphorylation of IRS-1 serines 632, 662, and 731.
- The serine/threonine kinase Akt, activated by PDGF, was identified as an inhibitor of insulin signaling.
- Inhibition by both PDGF and Akt required the same IRS-1 serine residues and was sensitive to rapamycin, indicating involvement of the mTOR pathway.
Conclusions:
- The phosphatidylinositol 3-kinase (PI3K)/Akt kinase cascade represents an alternative negative regulatory pathway for insulin signaling, distinct from PKC/MAPK.
- Specific serine residues (632, 662, 731) in IRS-1 are critical for negative regulation mediated by PDGF and Akt.
- The PI3K/Akt/mTOR pathway plays a significant role in modulating insulin receptor substrate 1 function and insulin signal transduction.