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

he 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 RPTP , a known activator of p59 fyn . Whereas this direct interaction is Ca 2 independent, formation of the complex is enhanced by Ca 2 -dependent spectrin cytoskeleton–mediated cross-linking of NCAM and RPTP in response to NCAM activation and is acT companied by redistribution of the complex to lipid rafts. Association between NCAM and p59 fyn is lost in RPTP deficient brains and is disrupted by dominant-negative RPTP mutants, demonstrating that RPTP is a link between NCAM and p59 fyn . NCAM-mediated p59 fyn activation is abolished in RPTP -deficient neurons, and disruption of the NCAM–p59 fyn complex in RPTP -deficient neurons or with dominant-negative RPTP mutants blocks NCAMdependent neurite outgrowth, implicating RPTP as a major phosphatase involved in NCAM-mediated signaling.