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J Biol Chem. 2014 Nov 14;289(46):31682-92. doi: 10.1074/jbc.M114.603621. Epub 2014 Oct 6.

Protein-tyrosine phosphatase 1B (PTP1B) is a novel regulator of central brain-derived neurotrophic factor and tropomyosin receptor kinase B (TrkB) signaling.

Author information

1
From the Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
2
the Department of Biological Sciences, Human and Evolutionary Biology Section, University of Southern California, Los Angeles, California 90089, and.
3
the Department of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, Indiana 46202.
4
the Department of Psychology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
5
From the Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, kbence@vet.upenn.edu.

Abstract

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.

KEYWORDS:

Brain-derived Neurotrophic Factor (BDNF); Hypothalamus; Metabolism; Phosphotyrosine Signaling; Receptor Tyrosine Kinase; Signal Transduction; Tyrosine-Protein Phosphatase (Tyrosine Phosphatase)

PMID:
25288805
PMCID:
PMC4231649
DOI:
10.1074/jbc.M114.603621
[Indexed for MEDLINE]
Free PMC Article

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