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J Biol Chem. 2013 Jun 14;288(24):17360-71. doi: 10.1074/jbc.M112.441469. Epub 2013 May 2.

Protein tyrosine phosphatase 1B regulates pyruvate kinase M2 tyrosine phosphorylation.

Author information

1
Nutrition Department, University of California Davis, Davis, California 95616, USA.

Abstract

Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of glucose homeostasis and adiposity and is a drug target for the treatment of obesity and diabetes. Here we identify pyruvate kinase M2 (PKM2) as a novel PTP1B substrate in adipocytes. PTP1B deficiency leads to increased PKM2 total tyrosine and Tyr(105) phosphorylation in cultured adipocytes and in vivo. Substrate trapping and mutagenesis studies identify PKM2 Tyr-105 and Tyr-148 as key sites that mediate PTP1B-PKM2 interaction. In addition, in vitro analyses illustrate a direct effect of Tyr-105 phosphorylation on PKM2 activity in adipocytes. Importantly, PTP1B pharmacological inhibition increased PKM2 Tyr-105 phosphorylation and decreased PKM2 activity. Moreover, PKM2 Tyr-105 phosphorylation is regulated nutritionally, decreasing in adipose tissue depots after high-fat feeding. Further, decreased PKM2 Tyr-105 phosphorylation correlates with the development of glucose intolerance and insulin resistance in rodents, non-human primates, and humans. Together, these findings identify PKM2 as a novel substrate of PTP1B and provide new insights into the regulation of adipose PKM2 activity.

KEYWORDS:

Adipocyte; Diabetes; Metabolism; Pyruvate Kinase; Signal Transduction; Tyrosine Protein Phosphatase (Tyrosine Phosphatase)

PMID:
23640882
PMCID:
PMC3682537
DOI:
10.1074/jbc.M112.441469
[Indexed for MEDLINE]
Free PMC Article

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