1. Protein Tyrosine Phosphatase 1B Regulates Pyruvate Kinase M2 Tyrosine Phosphorylation*
- Author
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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, and Haj, Fawaz G
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Diabetes ,Obesity ,Nutrition ,Underpinning research ,1.1 Normal biological development and functioning ,Metabolic and endocrine ,3T3-L1 Cells ,Adipose Tissue ,Brown ,Adult ,Aged ,Amino Acid Substitution ,Animals ,Diet ,High-Fat ,Energy Metabolism ,Gene Knockdown Techniques ,Glucose Intolerance ,Humans ,Insulin Resistance ,Macaca mulatta ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Middle Aged ,Phosphorylation ,Phosphotyrosine ,Protein Interaction Domains and Motifs ,Protein Interaction Mapping ,Protein Processing ,Post-Translational ,Protein Tyrosine Phosphatase ,Non-Receptor Type 1 ,Pyruvate Kinase ,Signal Transduction ,Adipocyte ,Metabolism ,Tyrosine Protein Phosphatase ,Chemical Sciences ,Medical and Health Sciences ,Biochemistry & Molecular Biology ,Biological sciences ,Biomedical and clinical sciences ,Chemical sciences - 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.
- Published
- 2013