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Molecular and Cellular Biology, July 2008, p. 4494-4506, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.00074-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Receptor Type Protein Tyrosine Phosphatase {zeta}-Pleiotrophin Signaling Controls Endocytic Trafficking of DNER That Regulates Neuritogenesis{triangledown} ,{dagger}

Nobuna Fukazawa,1 Seisuke Yokoyama,2 Mototsugu Eiraku,2,{ddagger} Mineko Kengaku,2 and Nobuaki Maeda1*

Department of Developmental Neuroscience, Tokyo Metropolitan Institute for Neuroscience, Tokyo 183-8526, Japan,1 Laboratory for Neural Cell Polarity, RIKEN Brain Science Institute, Saitama 351-0198, Japan2

Received 15 January 2008/ Returned for modification 4 March 2008/ Accepted 6 May 2008

Protein tyrosine phosphatase {zeta} (PTP{zeta}) is a receptor type protein tyrosine phosphatase that uses pleiotrophin as a ligand. Pleiotrophin inactivates the phosphatase activity of PTP{zeta}, resulting in the increase of tyrosine phosphorylation levels of its substrates. We studied the functional interaction between PTP{zeta} and DNER, a Notch-related transmembrane protein highly expressed in cerebellar Purkinje cells. PTP{zeta} and DNER displayed patchy colocalization in the dendrites of Purkinje cells, and immunoprecipitation experiments indicated that these proteins formed complexes. Several tyrosine residues in and adjacent to the tyrosine-based and the second C-terminal sorting motifs of DNER were phosphorylated and were dephosphorylated by PTP{zeta}, and phosphorylation of these tyrosine residues resulted in the accumulation of DNER on the plasma membrane. DNER mutants lacking sorting motifs accumulated on the plasma membrane of Purkinje cells and Neuro-2A cells and induced their process extension. While normal DNER was actively endocytosed and inhibited the retinoic-acid-induced neurite outgrowth of Neuro-2A cells, pleiotrophin stimulation increased the tyrosine phosphorylation level of DNER and suppressed the endocytosis of this protein, which led to the reversal of this inhibition, thus allowing neurite extension. These observations suggest that pleiotrophin-PTP{zeta} signaling controls subcellular localization of DNER and thereby regulates neuritogenesis.

* Corresponding author. Mailing address: Department of Developmental Neuroscience, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526, Japan. Phone: 81-42-325-3881. Fax: 81-42-321-8678. E-mail: maedan{at}tmin.ac.jp

{triangledown} Published ahead of print on 12 May 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Organogenesis and Neurogenesis Group, RIKEN, Center for Developmental Biology, Kobe 650-0047, Japan.

Molecular and Cellular Biology, July 2008, p. 4494-4506, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.00074-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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