Protein tyrosine phosphatase 1B regulates pyruvate kinase M2 tyrosine phosphorylation

Ahmed Bettaieb, Jesse Bakke, Naoto Nagata, Kosuke Matsuo, Yannan Xi, Siming Liu, Daniel AbouBechara, Ramzi Melhem, Kimber Stanhope, Bethany Cummings, James Graham, Andrew Bremer, Sheng Zhang, Costas A. Lyssiotis, Zhong Yin Zhang, Lewis C. Cantley, Peter J Havel, Fawaz Haj

Research output: Contribution to journalArticle

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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 Tyr105 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.

Original languageEnglish (US)
Pages (from-to)17360-17371
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number24
DOIs
StatePublished - Jun 14 2013

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Phosphorylation
Pyruvate Kinase
Tyrosine
Adipocytes
Substrates
Glucose
Mutagenesis
Glucose Intolerance
Adiposity
Medical problems
Primates
Insulin Resistance
Adipose Tissue
Rodentia

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Protein tyrosine phosphatase 1B regulates pyruvate kinase M2 tyrosine phosphorylation. / Bettaieb, Ahmed; Bakke, Jesse; Nagata, Naoto; Matsuo, Kosuke; Xi, Yannan; Liu, Siming; AbouBechara, Daniel; Melhem, Ramzi; Stanhope, Kimber; Cummings, Bethany; Graham, James; Bremer, Andrew; Zhang, Sheng; Lyssiotis, Costas A.; Zhang, Zhong Yin; Cantley, Lewis C.; Havel, Peter J; Haj, Fawaz.

In: Journal of Biological Chemistry, Vol. 288, No. 24, 14.06.2013, p. 17360-17371.

Research output: Contribution to journalArticle

Bettaieb, A, Bakke, J, Nagata, N, Matsuo, K, Xi, Y, Liu, S, AbouBechara, D, Melhem, R, Stanhope, K, Cummings, B, Graham, J, Bremer, A, Zhang, S, Lyssiotis, CA, Zhang, ZY, Cantley, LC, Havel, PJ & Haj, F 2013, 'Protein tyrosine phosphatase 1B regulates pyruvate kinase M2 tyrosine phosphorylation', Journal of Biological Chemistry, vol. 288, no. 24, pp. 17360-17371. https://doi.org/10.1074/jbc.M112.441469
Bettaieb, Ahmed ; Bakke, Jesse ; Nagata, Naoto ; Matsuo, Kosuke ; Xi, Yannan ; Liu, Siming ; AbouBechara, Daniel ; Melhem, Ramzi ; Stanhope, Kimber ; Cummings, Bethany ; Graham, James ; Bremer, Andrew ; Zhang, Sheng ; Lyssiotis, Costas A. ; Zhang, Zhong Yin ; Cantley, Lewis C. ; Havel, Peter J ; Haj, Fawaz. / Protein tyrosine phosphatase 1B regulates pyruvate kinase M2 tyrosine phosphorylation. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 24. pp. 17360-17371.
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AU - AbouBechara, Daniel

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AU - Zhang, Sheng

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