RPTPα is essential for NCAM-mediated p59^fyn 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 RPTPα, 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 RPTPα 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 RPTPα-deficient brains and is disrupted by dominant-negative RPTPα mutants, demonstrating that RPTPα is a link between NCAM and p59^fyn. NCAM-mediated p59^fyn activation is abolished in RPTPα-deficient neurons, and disruption of the NCAM–p59^fyn complex in RPTPα-deficient neurons or with dominant-negative RPTPα mutants blocks NCAM-dependent neurite outgrowth, implicating RPTPα as a major phosphatase involved in NCAM-mediated signaling.