Protein-tyrosine Phosphatase 1B (PTP1B) Is a Novel Regulator of Central Brain-derived Neurotrophic Factor and Tropomyosin Receptor Kinase B (TrkB) Signaling

• Published in: The Journal of biological chemistry Vol. 289; no. 46; pp. 31682 - 31692
• Main Authors: Ozek, Ceren, Kanoski, Scott E., Zhang, Zhong-Yin, Grill, Harvey J., Bence, Kendra K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.11.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Brain-Derived Neurotrophic Factor - metabolism; Cell Line, Tumor; Gene Expression Regulation, Enzymologic; Humans; Hypothalamus - metabolism; Male; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons - metabolism; Phosphorylation; Protein Binding; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Protein-Tyrosine Kinases - metabolism; Receptor, trkB; Signal Transduction; Temperature; Tyrosine-Protein Phosphatase (Tyrosine Phosphatase); Signal Transduction; Brain-derived Neurotrophic Factor (BDNF); Phosphotyrosine Signaling; Hypothalamus; Metabolism; Receptor Tyrosine Kinase
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.603621

Neuronal protein-tyrosine phosphatase 1B (PTP1B) deficiency in mice results in enhanced leptin signaling and protection from diet-induced obesity; however, whether additional signaling pathways in the brain contribute to the metabolic effects of PTP1B deficiency remains unclear. Here, we show that the tropomyosin receptor kinase B (TrkB) receptor is a direct PTP1B substrate and implicate PTP1B in the regulation of the central brain-derived neurotrophic factor (BDNF) signaling. PTP1B interacts with activated TrkB receptor in mouse brain and human SH-SY5Y neuroblastoma cells. PTP1B overexpression reduces TrkB phosphorylation and activation of downstream signaling pathways, whereas PTP1B inhibition augments TrkB signaling. Notably, brains of Ptpn1−/− mice exhibit enhanced TrkB phosphorylation, and Ptpn1−/− mice are hypersensitive to central BDNF-induced increase in core temperature. Taken together, our findings demonstrate that PTP1B is a novel physiological regulator of TrkB and that enhanced BDNF/TrkB signaling may contribute to the beneficial metabolic effects of PTP1B deficiency.