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

Protein tyrosine phosphatase sigma (PTPσ) belongs to the LAR family of receptor tyrosine phosphatases and was previously shown to negatively regulate axon growth. The substrate for PTPσ and the effector(s) mediating this inhibitory effect were unknown. Here we report the identification of N-cadherin as an in vivo substrate for PTPσ. Using brain lysates from PTPσ 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. β-Catenin also precipitated in the complex and was also a substrate for PTPσ. Dorsal root ganglion (DRG) neurons, which highly express endogenous N-cadherin and PTPσ, 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 PTPσ−/− mice likely disrupted N-cadherin function, resulting in accelerated DRG nerve growth. We conclude that N-cadherin is a physiological substrate for PTPσ and that N-cadherin (and likely β-catenin) participates in PTPσ-mediated inhibition of axon growth.