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Published online 28 December 2004. doi:10.1083/jcb.200405073
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 1, 127-139
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Article

RPTP{alpha} is essential for NCAM-mediated p59fyn activation and neurite elongation



Vsevolod Bodrikov1, Iryna Leshchyns'ka1, Vladimir Sytnyk1, John Overvoorde2, Jeroen den Hertog2, and Melitta Schachner1

1 Zentrum für Molekulare Neurobiologie, Universität Hamburg, 20246 Hamburg, Germany
2 Hubrecht Laboratory, Netherlands Institute for Developmental Biology, 3584 CT Utrecht, Netherlands

Correspondence to Melitta Schachner: melitta.schachner{at}zmnh.uni-hamburg.de

The neural cell adhesion molecule (NCAM) forms a complex with p59fyn 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{alpha}, a known activator of p59fyn. Whereas this direct interaction is Ca2+ independent, formation of the complex is enhanced by Ca2+-dependent spectrin cytoskeleton–mediated cross-linking of NCAM and RPTP{alpha} in response to NCAM activation and is accompanied by redistribution of the complex to lipid rafts. Association between NCAM and p59fyn is lost in RPTP{alpha}-deficient brains and is disrupted by dominant-negative RPTP{alpha} mutants, demonstrating that RPTP{alpha} is a link between NCAM and p59fyn. NCAM-mediated p59fyn activation is abolished in RPTP{alpha}-deficient neurons, and disruption of the NCAM–p59fyn complex in RPTP{alpha}-deficient neurons or with dominant-negative RPTP{alpha} mutants blocks NCAM-dependent neurite outgrowth, implicating RPTP{alpha} as a major phosphatase involved in NCAM-mediated signaling.

V. Bodrikov, I. Leshchyns'ka, and V. Sytnyk contributed equally to this paper.

Abbreviations used in this paper: FGFR, FGF receptor; NCAM, neural cell adhesion molecule.


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