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Insulin receptor kinase-independent signaling via tyrosine phosphorylation of phosphatase PHLPP1.
J Cell Biochem 2009; 107(1):65-75JC

Abstract

Most insulin responses correlate well with insulin receptor (IR) Tyr kinase activation; however, critical exceptions to this concept have been presented. Specific IR mutants and stimulatory IR antibodies demonstrate a lack of correlation between IR kinase activity and specific insulin responses in numerous independent studies. IR conformation changes in response to insulin observed with various IR antibodies define an IR kinase-independent signal that alters the C-terminus. IR-related receptors in lower eukaryotes that lack a Tyr kinase point to an alternative mechanism of IR signaling earlier in evolution. However, the implied IR kinase-independent signaling mechanism remained obscure at the molecular level. Here we begin to define the molecular basis of an IR-dependent but IR kinase-independent insulin signal that is equally transmitted by a kinase-inactive mutant IR. This insulin signal results in Tyr phosphorylation and catalytic activation of phosphatase PHLPP1 via a PI 3-kinase-independent, wortmannin-insensitive signaling pathway. Dimerized SH2B1/PSM is a critical activator of the IR kinase and the resulting established insulin signal. In contrast it is an inhibitor of the IR kinase-independent insulin signal and disruption of SH2B1/PSM dimer binding to IR potentiates this signal. Dephosphorylation of Akt2 by PHLPP1 provides an alternative, SH2B1/PSM-regulated insulin-signaling pathway from IR to Akt2 of opposite polarity and distinct from the established PI 3-kinase-dependent signaling pathway via IRS proteins. In combination, both pathways should allow the opposing regulation of Akt2 activity at two phosphorylation sites to specifically define the insulin signal in the background of interfering Akt-regulating signals, such as those controlling cell proliferation and survival.

Authors+Show Affiliations

Department of Biochemistry and Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, West Virginia 26506-9142, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

19277985

Citation

Zhang, Manchao, and Heimo Riedel. "Insulin Receptor Kinase-independent Signaling Via Tyrosine Phosphorylation of Phosphatase PHLPP1." Journal of Cellular Biochemistry, vol. 107, no. 1, 2009, pp. 65-75.
Zhang M, Riedel H. Insulin receptor kinase-independent signaling via tyrosine phosphorylation of phosphatase PHLPP1. J Cell Biochem. 2009;107(1):65-75.
Zhang, M., & Riedel, H. (2009). Insulin receptor kinase-independent signaling via tyrosine phosphorylation of phosphatase PHLPP1. Journal of Cellular Biochemistry, 107(1), pp. 65-75. doi:10.1002/jcb.22095.
Zhang M, Riedel H. Insulin Receptor Kinase-independent Signaling Via Tyrosine Phosphorylation of Phosphatase PHLPP1. J Cell Biochem. 2009 May 1;107(1):65-75. PubMed PMID: 19277985.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Insulin receptor kinase-independent signaling via tyrosine phosphorylation of phosphatase PHLPP1. AU - Zhang,Manchao, AU - Riedel,Heimo, PY - 2009/3/12/entrez PY - 2009/3/12/pubmed PY - 2009/7/15/medline SP - 65 EP - 75 JF - Journal of cellular biochemistry JO - J. Cell. Biochem. VL - 107 IS - 1 N2 - Most insulin responses correlate well with insulin receptor (IR) Tyr kinase activation; however, critical exceptions to this concept have been presented. Specific IR mutants and stimulatory IR antibodies demonstrate a lack of correlation between IR kinase activity and specific insulin responses in numerous independent studies. IR conformation changes in response to insulin observed with various IR antibodies define an IR kinase-independent signal that alters the C-terminus. IR-related receptors in lower eukaryotes that lack a Tyr kinase point to an alternative mechanism of IR signaling earlier in evolution. However, the implied IR kinase-independent signaling mechanism remained obscure at the molecular level. Here we begin to define the molecular basis of an IR-dependent but IR kinase-independent insulin signal that is equally transmitted by a kinase-inactive mutant IR. This insulin signal results in Tyr phosphorylation and catalytic activation of phosphatase PHLPP1 via a PI 3-kinase-independent, wortmannin-insensitive signaling pathway. Dimerized SH2B1/PSM is a critical activator of the IR kinase and the resulting established insulin signal. In contrast it is an inhibitor of the IR kinase-independent insulin signal and disruption of SH2B1/PSM dimer binding to IR potentiates this signal. Dephosphorylation of Akt2 by PHLPP1 provides an alternative, SH2B1/PSM-regulated insulin-signaling pathway from IR to Akt2 of opposite polarity and distinct from the established PI 3-kinase-dependent signaling pathway via IRS proteins. In combination, both pathways should allow the opposing regulation of Akt2 activity at two phosphorylation sites to specifically define the insulin signal in the background of interfering Akt-regulating signals, such as those controlling cell proliferation and survival. SN - 1097-4644 UR - https://www.unboundmedicine.com/medline/citation/19277985/Insulin_receptor_kinase_independent_signaling_via_tyrosine_phosphorylation_of_phosphatase_PHLPP1_ L2 - https://doi.org/10.1002/jcb.22095 DB - PRIME DP - Unbound Medicine ER -