RPTPα is essential for NCAM-mediated p59fyn activation and neurite elongation

The neural cell adhesion molecule (NCAM) forms a complex with p59(fyn) kinase and activates it via a mechanism that has remained unknown. We show that the NCAM140 isoform directly interacts with the intracellular domain of the receptor-like protein tyrosine phosphatase RPTPalpha, a known activator of p59(fyn). Whereas this direct interaction is Ca2+ independent, formation of the complex is enhanced by Ca2+-dependent spectrin cytoskeleton-mediated cross-linking of NCAM and RPTPalpha in response to NCAM activation and is accompanied by redistribution of the complex to lipid rafts. Association between NCAM and P59(fyn) is lost in RPTPalpha-deficient brains and is disrupted by dominant-negative RPTPalpha mutants, demonstrating that RPTPalpha is a link between NCAM and P59fyn. NCAM-mediated p59fyn activation is abolished in RPTPalpha-deficient neurons, and disruption of the NCAM-p59(fyn) complex in RPTPalpha-deficient neurons or with dominant-negative RPTPalpha mutants blocks NCAM-dependent neurite outgrowth, implicating RPTPalpha as a major phosphatase involved in NCAM-mediated signaling.