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

Background: The tropomyosin receptor kinase B (TrkB) is a potential novel substrate of protein-tyrosine phosphatase 1B (PTP1B). Results: PTP1B associates with and plays a modulatory role in BDNF-induced TrkB signaling. Conclusion: PTP1B is a novel negative regulator of central BDNF/TrkB signaling. Significance: This is the first evidence that PTP1B deficiency enhances central TrkB signaling and alters BDNF-induced thermogenesis in vivo. 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.

• Publication year

  2014

• Venue

  Journal of Biological Chemistry

• Publication date

  2014-10-06

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.M114.603621PMID 25288805PMCID PMC4231649
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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