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Cellular effects of small molecule PTP1B inhibitors on insulin signaling.
Biochemistry 2003; 42(44):12792-804B

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor (IR) signaling and a potential drug target for the treatment of type 2 diabetes and other associated metabolic syndromes. To further define the role of PTP1B in insulin signaling and to test the hypothesis that blocking the activity of PTP1B would augment the action of insulin, we prepared several cell permeable, potent and selective, small molecule PTP1B inhibitors, and evaluated their biological effects in several insulin sensitive cell lines. Our data indicate that PTP1B inhibitors bind to and colocalize with PTP1B on the surface of the endoplasmic reticulum and PTP1B exerts its negative effect on insulin signaling upstream of phosphatidylinositol 3-kinase and MEK1. Treatment of cells with PTP1B inhibitors, both in the presence and in the absence of insulin, markedly enhances IRbeta and IRS-1 phosphorylation, Akt and ERK1/2 activation, Glut4 translocation, glucose uptake, and Elk1 transcriptional activation and cell proliferation. These results indicate that small molecule inhibitors targeted to PTP1B can act as both insulin mimetics and insulin sensitizers. Taken together, our findings combined with results from PTP1B knockout, antisense, and biochemical studies provide strong evidence that PTP1B negatively regulates insulin signaling and that small molecule PTP1B inhibitors have the ability to potentiate and augment the action of insulin.

Authors+Show Affiliations

Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

14596593

Citation

Xie, Laiping, et al. "Cellular Effects of Small Molecule PTP1B Inhibitors On Insulin Signaling." Biochemistry, vol. 42, no. 44, 2003, pp. 12792-804.
Xie L, Lee SY, Andersen JN, et al. Cellular effects of small molecule PTP1B inhibitors on insulin signaling. Biochemistry. 2003;42(44):12792-804.
Xie, L., Lee, S. Y., Andersen, J. N., Waters, S., Shen, K., Guo, X. L., ... Zhang, Z. Y. (2003). Cellular effects of small molecule PTP1B inhibitors on insulin signaling. Biochemistry, 42(44), pp. 12792-804.
Xie L, et al. Cellular Effects of Small Molecule PTP1B Inhibitors On Insulin Signaling. Biochemistry. 2003 Nov 11;42(44):12792-804. PubMed PMID: 14596593.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cellular effects of small molecule PTP1B inhibitors on insulin signaling. AU - Xie,Laiping, AU - Lee,Seung-Yub, AU - Andersen,Jannik N, AU - Waters,Steve, AU - Shen,Kui, AU - Guo,Xiao-Ling, AU - Moller,Niels Peter H, AU - Olefsky,Jerrold M, AU - Lawrence,David S, AU - Zhang,Zhong-Yin, PY - 2003/11/5/pubmed PY - 2004/1/30/medline PY - 2003/11/5/entrez SP - 12792 EP - 804 JF - Biochemistry JO - Biochemistry VL - 42 IS - 44 N2 - Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor (IR) signaling and a potential drug target for the treatment of type 2 diabetes and other associated metabolic syndromes. To further define the role of PTP1B in insulin signaling and to test the hypothesis that blocking the activity of PTP1B would augment the action of insulin, we prepared several cell permeable, potent and selective, small molecule PTP1B inhibitors, and evaluated their biological effects in several insulin sensitive cell lines. Our data indicate that PTP1B inhibitors bind to and colocalize with PTP1B on the surface of the endoplasmic reticulum and PTP1B exerts its negative effect on insulin signaling upstream of phosphatidylinositol 3-kinase and MEK1. Treatment of cells with PTP1B inhibitors, both in the presence and in the absence of insulin, markedly enhances IRbeta and IRS-1 phosphorylation, Akt and ERK1/2 activation, Glut4 translocation, glucose uptake, and Elk1 transcriptional activation and cell proliferation. These results indicate that small molecule inhibitors targeted to PTP1B can act as both insulin mimetics and insulin sensitizers. Taken together, our findings combined with results from PTP1B knockout, antisense, and biochemical studies provide strong evidence that PTP1B negatively regulates insulin signaling and that small molecule PTP1B inhibitors have the ability to potentiate and augment the action of insulin. SN - 0006-2960 UR - https://www.unboundmedicine.com/medline/citation/14596593/Cellular_effects_of_small_molecule_PTP1B_inhibitors_on_insulin_signaling_ L2 - https://dx.doi.org/10.1021/bi035238p DB - PRIME DP - Unbound Medicine ER -