Protein tyrosine phosphatase 1B regulates pyruvate kinase M2 tyrosine phosphorylation Academic Article uri icon

Overview

MeSH Major

  • Phosphotyrosine
  • Protein Processing, Post-Translational
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Pyruvate Kinase

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.

publication date

  • June 14, 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3682537

Digital Object Identifier (DOI)

  • 10.1074/jbc.M112.441469

PubMed ID

  • 23640882

Additional Document Info

start page

  • 17360

end page

  • 71

volume

  • 288

number

  • 24