- 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 G
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.