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

doi:10.1016/j.cmet.2006.03.006

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 journal › Article › peer-review

59 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 language	English
Pages (from-to)	367-378
Number of pages	12
Journal	Cell Metabolism
Volume	3
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2006.03.006
Publication status	Published - 2006 May
Externally published	Yes

Bibliographical note

Funding Information:
The authors would like to thank Dr. Nathanael Gray and Prof. William Sellers for helpful discussions, Dr. Shihmin Huang and Dr. Nicholas Gekakis for cell lines and discussion, and Abel Gutierrez, Paul DeJesus, Myleen Medina, Suhaila White, Brendan Smith, and Sandy Bohan for technical support. This work was supported by the Novartis Research Foundation. This paper is dedicated to the memory of Dr. Thomas Byung-Mo Cho.

Keywords

SIGNALING

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2006.03.006

Cite this

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title = "Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling",

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.",

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note = "Funding Information: The authors would like to thank Dr. Nathanael Gray and Prof. William Sellers for helpful discussions, Dr. Shihmin Huang and Dr. Nicholas Gekakis for cell lines and discussion, and Abel Gutierrez, Paul DeJesus, Myleen Medina, Suhaila White, Brendan Smith, and Sandy Bohan for technical support. This work was supported by the Novartis Research Foundation. This paper is dedicated to the memory of Dr. Thomas Byung-Mo Cho. ",

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doi = "10.1016/j.cmet.2006.03.006",

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AU - Callaway, Scott

AU - Hedrick, Susan

AU - Mak, Puiying A.

AU - Orth, Anthony P.

AU - Peters, Eric C.

AU - Saez, Enrique

AU - Montminy, Marc

AU - Schultz, Peter G.

AU - Chanda, Sumit K.

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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