Cellular Effects of Small Molecule PTP1B Inhibitors on Insulin Signaling

Laiping Xie, Seung Yub Lee, Jannik N. Andersen, Steve Waters, Kui Shen, Xiaoling Guo, Niels Peter H Moller, Jerrold M. Olefsky, David S. Lawrence, Zhong Yin Zhang

Research output: Contribution to journalArticle

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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 IRβ 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.

Original languageEnglish (US)
Pages (from-to)12792-12804
Number of pages13
JournalBiochemistry
Volume42
Issue number44
DOIs
StatePublished - Nov 11 2003

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Insulin
Molecules
Insulin Receptor
Chemical activation
Cells
Phosphatidylinositol 3-Kinase
Phosphorylation
Cell proliferation
Medical problems
Endoplasmic Reticulum
Type 2 Diabetes Mellitus
Transcriptional Activation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Xie, L., Lee, S. Y., Andersen, J. N., Waters, S., Shen, K., Guo, X., ... Zhang, Z. Y. (2003). Cellular Effects of Small Molecule PTP1B Inhibitors on Insulin Signaling. Biochemistry, 42(44), 12792-12804. https://doi.org/10.1021/bi035238p

Cellular Effects of Small Molecule PTP1B Inhibitors on Insulin Signaling. / Xie, Laiping; Lee, Seung Yub; Andersen, Jannik N.; Waters, Steve; Shen, Kui; Guo, Xiaoling; Moller, Niels Peter H; Olefsky, Jerrold M.; Lawrence, David S.; Zhang, Zhong Yin.

In: Biochemistry, Vol. 42, No. 44, 11.11.2003, p. 12792-12804.

Research output: Contribution to journalArticle

Xie, L, Lee, SY, Andersen, JN, Waters, S, Shen, K, Guo, X, Moller, NPH, Olefsky, JM, Lawrence, DS & Zhang, ZY 2003, 'Cellular Effects of Small Molecule PTP1B Inhibitors on Insulin Signaling', Biochemistry, vol. 42, no. 44, pp. 12792-12804. https://doi.org/10.1021/bi035238p
Xie L, Lee SY, Andersen JN, Waters S, Shen K, Guo X et al. Cellular Effects of Small Molecule PTP1B Inhibitors on Insulin Signaling. Biochemistry. 2003 Nov 11;42(44):12792-12804. https://doi.org/10.1021/bi035238p
Xie, Laiping ; Lee, Seung Yub ; Andersen, Jannik N. ; Waters, Steve ; Shen, Kui ; Guo, Xiaoling ; Moller, Niels Peter H ; Olefsky, Jerrold M. ; Lawrence, David S. ; Zhang, Zhong Yin. / Cellular Effects of Small Molecule PTP1B Inhibitors on Insulin Signaling. In: Biochemistry. 2003 ; Vol. 42, No. 44. pp. 12792-12804.
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