title: Protein-tyrosine phosphatase 1B (PTP1B) is a novel regulator of central brain-derived neurotrophic factor and tropomyosin receptor kinase B (TrkB) signaling.
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.
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Ceren
authors.initials: C
authors.lastname: Ozek
authors.affiliation: Department of Biological Sciences, Human and Evolutionary Biology Section, University of Southern California, Los Angeles, California 90089, and.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Kanoski
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, Indiana 46202.
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Department of Psychology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Grill
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,. Electronic address: kbence@vet.upenn.edu.
authors.forename: Kendra K
authors.initials: KK
authors.lastname: Bence
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020813:Receptor, trkB; D015398:Signal Transduction; D013696:Temperature
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Brain-derived Neurotrophic Factor (BDNF); Hypothalamus; Metabolism; Phosphotyrosine Signaling; Receptor Tyrosine Kinase; Signal Transduction; Tyrosine-Protein Phosphatase (Tyrosine Phosphatase)