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 ϳ120 kDa in the knockout animals (relative to sibling controls), which was identified by mass spectrometry and immunoblotting as N-cadherin. ␤-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 ␤-catenin) participates in PTP-mediated inhibition of axon growth.Protein tyrosine phosphatase sigma (PTP) (also known as LAR-PTP2, PTP-P1, CRYP␣, PTP-NU3, PTP-NE3, and CPTP1 [42,51,58,68,71,81,84]) belongs to the LAR family of receptor PTPs (class IIa) (3, 4, 13). In mammals, this family includes LAR, PTP, and PTP␦, whereas DLAR is the Drosophila melanogaster orthologue of all three family members (13,61,62). In this class (IIa) of PTPs, the ectodomain is comprised of three immunoglobulin (Ig) domains and usually four or eight FNIII repeats, resembling cell adhesion molecules (CAMs) such as N-CAM and L1, a single pass transmembrane domain, and two tandem intracellular catalytic domains, the first of which (D1) is active and the second of which (D2) is inactive (13). Like other CAMs, LAR family PTPs have been demonstrated to play an important role in nervous system development (reviewed in references 13, 22, and 59).In flies, DLAR and its relative PTP69D play a key role in axon guidance of motoneurons and axon pathfinding in the visual system (14, 17-19, 30, 34). Likewise, in the leech, HmLAR2 was shown to concentrate in the growth cone and direct growth of its processes (6, 26). Moreover, retinal ganglion outgrowth and growth cone integrity in developing Xenopus laevis and avian embryos require a functional PTP (CRYP␣) (27,31,38,47,60). PTP␦ is also expressed in Xenopus retinal ganglion cells during axonogenesis (27), and it acts as an attractive cue for growth cone steering and for driving axonal growth of forebrain neurons (63,73).In mammals, PTP is expressed primarily in the nervous system and in select epithelia, and its expression is develop...

Background: The LAR family Protein Tyrosine Phosphatase sigma (PTPσ) has been implicated in neuroendocrine and neuronal development, and shows strong expression in specific regions within the CNS, including the subventricular zone (SVZ). We established neural stem cell cultures, grown as neurospheres, from the SVZ of PTPσ knockout mice and sibling controls to determine if PTPσ influences the generation and the phenotype of the neuronal, astrocyte and oligodendrocyte cell lineages.