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Journal of Biochemistry Advance Access originally published online on May 13, 2008
Journal of Biochemistry 2008 144(2):259-266; 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

Takafumi Shintani and Masaharu Noda*

Division of Molecular Neurobiology, National Institute for Basic Biology, and School of Life Science, Graduate University for Advanced Studies, Okazaki 444-8787, Japan

*To whom correspondence should be addressed. Tel: +81 564 59 5846, Fax: +81 564 59 5845, E-mail: madon{at}nibb.ac.jp

Received April 5, 2008; Accepted May 2, 2008


  Abstract

Protein tyrosine phosphatase receptor type Z (Ptprz/Ptp{zeta} / 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. Co-expression 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). Co-expression 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 signalling of TrkA receptors.

Key Words: Ptprz, TrkA, NGF, dephosphorylation, neurite extension

Abbreviations: CNS, central nervous system; FRS2, fibroblast growth factor receptor substrate 2; Grb2, growth factor receptor-bound protein 2; ICR, intra-cellular region; NGF, nerve growth factor; PLC-{gamma}, phospholipase C-{gamma}; PSD-95, postsynaptic density-95; PTK, protein tyrosine kinase; PTP, protein tyrosine phosphatase; Ptprg, protein tyrosine phosphatase receptor type G; Ptprz, protein tyrosine phosphatase receptor type Z; RPTK, receptor PTK; RPTP, receptor-like PTP; Shc, Src-homology and collagen; Trk, tropomyosin-related kinase


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The Protein Phosphatase 2A Regulatory Subunits B'{beta} and B'{delta} Mediate Sustained TrkA Neurotrophin Receptor Autophosphorylation and Neuronal Differentiation
Mol. Cell. Biol., February 1, 2009; 29(3): 662 - 674.
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