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Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation by Hepatic S6 Kinase.
J Biol Chem. 2016 Apr 15; 291(16):8602-17.JB

Abstract

Constitutive activation of the mammalian target of rapamycin complex 1 and S6 kinase (mTORC1→ S6K) attenuates insulin-stimulated Akt activity in certain tumors in part through "feedback" phosphorylation of the upstream insulin receptor substrate 1 (IRS1). However, the significance of this mechanism for regulating insulin sensitivity in normal tissue remains unclear. We investigated the function of Ser-302 in mouse IRS1, the major site of its phosphorylation by S6K in vitro, through genetic knock-in of a serine-to-alanine mutation (A302). Although insulin rapidly stimulated feedback phosphorylation of Ser-302 in mouse liver and muscle, homozygous A302 mice (A/A) and their knock-in controls (S/S) exhibited similar glucose homeostasis and muscle insulin signaling. Furthermore, both A302 and control primary hepatocytes from which Irs2 was deleted showed marked inhibition of insulin-stimulated IRS1 tyrosine phosphorylation and PI3K binding after emetine treatment to raise intracellular amino acids and activate mTORC1 → S6K signaling. To specifically activate mTORC1 in mouse tissue, we deleted hepatic Tsc1 using Cre adenovirus. Although it moderately decreased IRS1/PI3K association and Akt phosphorylation in liver, Tsc1 deletion failed to cause glucose intolerance or promote hyperinsulinemia in mixed background A/A or S/S mice. Moreover, Tsc1 deletion failed to stimulate phospho-Ser-302 or other putative S6K sites within IRS1, whereas ribosomal S6 protein was constitutively phosphorylated. Following acute Tsc1 deletion from hepatocytes, Akt phosphorylation, but not IRS1/PI3K association, was rapidly restored by treatment with the mTORC1 inhibitor rapamycin. Thus, within the hepatic compartment, mTORC1 → S6K signaling regulates Akt largely through IRS-independent means with little effect upon physiologic insulin sensitivity.

Authors+Show Affiliations

From the Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.From the Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.From the Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.From the Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115 morris.white@childrens.harvard.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26846849

Citation

Copps, Kyle D., et al. "Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation By Hepatic S6 Kinase." The Journal of Biological Chemistry, vol. 291, no. 16, 2016, pp. 8602-17.
Copps KD, Hançer NJ, Qiu W, et al. Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation by Hepatic S6 Kinase. J Biol Chem. 2016;291(16):8602-17.
Copps, K. D., Hançer, N. J., Qiu, W., & White, M. F. (2016). Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation by Hepatic S6 Kinase. The Journal of Biological Chemistry, 291(16), 8602-17. https://doi.org/10.1074/jbc.M116.714915
Copps KD, et al. Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation By Hepatic S6 Kinase. J Biol Chem. 2016 Apr 15;291(16):8602-17. PubMed PMID: 26846849.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation by Hepatic S6 Kinase. AU - Copps,Kyle D, AU - Hançer,Nancy J, AU - Qiu,Wei, AU - White,Morris F, Y1 - 2016/02/04/ PY - 2016/01/08/received PY - 2016/2/6/entrez PY - 2016/2/6/pubmed PY - 2016/10/8/medline KW - S6 kinase KW - amino acids KW - gene knock-in KW - insulin receptor substrate 1 (IRS-1) KW - insulin resistance KW - insulin signaling KW - mammalian target of rapamycin (mTOR) KW - serine/threonine phosphorylation KW - tuberous sclerosis complex (TSC) SP - 8602 EP - 17 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 291 IS - 16 N2 - Constitutive activation of the mammalian target of rapamycin complex 1 and S6 kinase (mTORC1→ S6K) attenuates insulin-stimulated Akt activity in certain tumors in part through "feedback" phosphorylation of the upstream insulin receptor substrate 1 (IRS1). However, the significance of this mechanism for regulating insulin sensitivity in normal tissue remains unclear. We investigated the function of Ser-302 in mouse IRS1, the major site of its phosphorylation by S6K in vitro, through genetic knock-in of a serine-to-alanine mutation (A302). Although insulin rapidly stimulated feedback phosphorylation of Ser-302 in mouse liver and muscle, homozygous A302 mice (A/A) and their knock-in controls (S/S) exhibited similar glucose homeostasis and muscle insulin signaling. Furthermore, both A302 and control primary hepatocytes from which Irs2 was deleted showed marked inhibition of insulin-stimulated IRS1 tyrosine phosphorylation and PI3K binding after emetine treatment to raise intracellular amino acids and activate mTORC1 → S6K signaling. To specifically activate mTORC1 in mouse tissue, we deleted hepatic Tsc1 using Cre adenovirus. Although it moderately decreased IRS1/PI3K association and Akt phosphorylation in liver, Tsc1 deletion failed to cause glucose intolerance or promote hyperinsulinemia in mixed background A/A or S/S mice. Moreover, Tsc1 deletion failed to stimulate phospho-Ser-302 or other putative S6K sites within IRS1, whereas ribosomal S6 protein was constitutively phosphorylated. Following acute Tsc1 deletion from hepatocytes, Akt phosphorylation, but not IRS1/PI3K association, was rapidly restored by treatment with the mTORC1 inhibitor rapamycin. Thus, within the hepatic compartment, mTORC1 → S6K signaling regulates Akt largely through IRS-independent means with little effect upon physiologic insulin sensitivity. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/26846849/Serine_302_Phosphorylation_of_Mouse_Insulin_Receptor_Substrate_1__IRS1__Is_Dispensable_for_Normal_Insulin_Signaling_and_Feedback_Regulation_by_Hepatic_S6_Kinase_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=26846849 DB - PRIME DP - Unbound Medicine ER -