Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling

Charles Y. Cho, Seung-Hoi Koo, Yan Wang, Scott Callaway, Susan Hedrick, Puiying A. Mak, Anthony P. Orth, Eric C. Peters, Enrique Saez, Marc Montminy, Peter G. Schultz, Sumit K. Chanda

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Insulin resistance is a primary defect in type 2 diabetes characterized by impaired peripheral glucose uptake and insufficient suppression of hepatic glucose output. Insulin signaling inhibits liver glucose production by inducing nuclear exclusion of the gluconeogenic transcription factor FOXO1 in an Akt-dependent manner. Through the concomitant application of genome-scale functional screening and quantitative image analysis, we have identified PTP-MEG2 as a modulator of insulin-dependent FOXO1 subcellular localization. Ectopic expression of PTP-MEG2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while RNAi-mediated reduction of PTP-MEG2 transcript levels enhanced insulin action. Additionally, adenoviral-mediated depletion of PTP-MEG2 in livers of diabetic (db/db) mice resulted in insulin sensitization and normalization of hyperglycemia. These data implicate PTP-MEG2 as a mediator of blood glucose homeostasis through antagonism of insulin signaling, and suggest that modulation of PTP-MEG2 activity may be an effective strategy in the treatment of type 2 diabetes.

Original languageEnglish
Pages (from-to)367-378
Number of pages12
JournalCell Metabolism
Volume3
Issue number5
DOIs
Publication statusPublished - 2006 May 1
Externally publishedYes

Fingerprint

Insulin Antagonists
Phosphoric Monoester Hydrolases
Tyrosine
Insulin
Liver
Glucose
Type 2 Diabetes Mellitus
Insulin Receptor
RNA Interference
Hyperglycemia
Insulin Resistance
Blood Glucose
Homeostasis
Transcription Factors
Phosphorylation
Genome

Keywords

  • SIGNALING

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling. / Cho, Charles Y.; Koo, Seung-Hoi; Wang, Yan; Callaway, Scott; Hedrick, Susan; Mak, Puiying A.; Orth, Anthony P.; Peters, Eric C.; Saez, Enrique; Montminy, Marc; Schultz, Peter G.; Chanda, Sumit K.

In: Cell Metabolism, Vol. 3, No. 5, 01.05.2006, p. 367-378.

Research output: Contribution to journalArticle

Cho, CY, Koo, S-H, Wang, Y, Callaway, S, Hedrick, S, Mak, PA, Orth, AP, Peters, EC, Saez, E, Montminy, M, Schultz, PG & Chanda, SK 2006, 'Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling', Cell Metabolism, vol. 3, no. 5, pp. 367-378. https://doi.org/10.1016/j.cmet.2006.03.006
Cho, Charles Y. ; Koo, Seung-Hoi ; Wang, Yan ; Callaway, Scott ; Hedrick, Susan ; Mak, Puiying A. ; Orth, Anthony P. ; Peters, Eric C. ; Saez, Enrique ; Montminy, Marc ; Schultz, Peter G. ; Chanda, Sumit K. / Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling. In: Cell Metabolism. 2006 ; Vol. 3, No. 5. pp. 367-378.
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