Journal of Biochemistry Advance Access published online on May 13, 2008
Journal of Biochemistry, doi:10.1093/jb/mvn064
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© 2008 The Japanese Biochemical Society
Protein Tyrosine Phosphatase Receptor Type Z Dephosphorylates TrkA Receptors and Attenuates NGF-dependent Neurite Outgrowth of PC12 Cells
Division of Molecular Neurobiology, National Institute for Basic Biology, and School of Life Science, Graduate University for Advanced Studies, Okazaki 444-8787, Japan
Correspondence should be addressed to Prof. Masaharu Noda. (e-mail: madon{at}nibb.ac.jp) Division of Molecular Neurobiology, National Institute for Basic Biology, 5-1 Higashiyama, Myodaiji-cho, Okazaki 444-8787, Japan. Tel.: 81-564-59-5846 Fax: 81-564-59-5845
Received April 5, 2008; Accepted May 2, 2008
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Abstract |
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SUMMARY
Protein tyrosine phosphatase receptor type Z (Ptprz/Ptp
/RPTPβ) is a receptor-like protein tyrosine phosphatase (RPTP) which is predominantly expressed in the central nervous system. Tropomyosin-related kinases (Trks) are single-pass transmembrane molecules that are highly expressed in the developing nervous system. Upon the ligand binding of neurotrophins, Trk receptors are activated through autophosphorylation of tyrosine residues; however, the PTPs responsible for the negative regulation of Trk receptors have not been fully elucidated. Here, we identified Ptprz as a specific PTP that efficiently dephosphorylates TrkA as a substrate. Coexpression of Ptprz with Trk receptors in 293T cells showed that Ptprz suppresses the ligand-independent tyrosine phosphorylation of TrkA, but not of TrkB or TrkC, and that Ptprz attenuates TrkA activation induced by nerve growth factor (NGF). Coexpression analyses with TrkA mutants revealed that Ptprz dephosphorylates phosphotyrosine residues in the activation loop of the kinase domain, which are requisite for activation of the TrkA receptor. Consistent with these findings, forced expression of Ptprz in PC12D cells markedly inhibited neurite extension induced by a low dose of NGF. In addition, an increment in the tyrosine phosphorylation of TrkA was observed in the brain of Ptprz-deficient mice. Ptprz thus appears to be one of the PTPs which regulate the activation and signaling of TrkA receptors.
Key Words: Ptprz, TrkA, NGF, dephosphorylation, neurite extension
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