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Molecular and Cellular Biology, January 2007, p. 208-219, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.00707-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

N-Cadherin Is an In Vivo Substrate for Protein Tyrosine Phosphatase Sigma (PTP) and Participates in PTP-Mediated Inhibition of Axon Growth ^,

Roberta Siu, Chris Fladd, and Daniela Rotin^*

Program in Cell Biology, The Hospital for Sick Children, and Biochemistry Department, University of Toronto, 555 University Ave., Toronto M5G 1X8, Ontario, Canada

Received 24 April 2006/ Returned for modification 12 June 2006/ Accepted 12 October 2006

Protein tyrosine phosphatase sigma (PTP) belongs to the LAR family of receptor tyrosine phosphatases and was previously shown to negatively regulate axon growth. The substrate for PTP and the effector(s) mediating this inhibitory effect were unknown. Here we report the identification of N-cadherin as an in vivo substrate for PTP. Using brain lysates from PTP knockout mice, in combination with substrate trapping, we identified a hyper-tyrosine-phosphorylated protein of 120 kDa in the knockout animals (relative to sibling controls), which was identified by mass spectrometry and immunoblotting as N-cadherin. ß-Catenin also precipitated in the complex and was also a substrate for PTP. Dorsal root ganglion (DRG) neurons, which highly express endogenous N-cadherin and PTP, exhibited a faster growth rate in the knockout mice than in the sibling controls when grown on laminin or N-cadherin substrata. However, when N-cadherin function was disrupted by an inhibitory peptide or lowering calcium concentrations, the differential growth rate between the knockout and sibling control mice was greatly diminished. These results suggest that the elevated tyrosine phosphorylation of N-cadherin in the PTP^–/– mice likely disrupted N-cadherin function, resulting in accelerated DRG nerve growth. We conclude that N-cadherin is a physiological substrate for PTP and that N-cadherin (and likely ß-catenin) participates in PTP-mediated inhibition of axon growth.

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* Corresponding author. Mailing address: Program in Cell Biology, The Hospital for Sick Children, 555 University Ave., Toronto M5G 1X8, Ontario, Canada. Phone: (416) 813-5098. Fax: (416) 813-5771. E-mail: drotin{at}sickkids.ca.

Published ahead of print on 23 October 2006.

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

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Molecular and Cellular Biology, January 2007, p. 208-219, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.00707-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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