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NCAM induces CaMKII-mediated RPTP phosphorylation to enhance its catalytic activity and neurite outgrowth

¹ Zentrum für Molekulare Neurobiologie, Universität Hamburg, 20246 Hamburg, Germany
² Hubrecht Laboratory, Netherlands Institute for Developmental Biology, 3584 CT Utrecht, Netherlands
³ Keck Center for Collaborative Neuroscience and ⁴ Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854

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

Receptor protein tyrosine phosphatase (RPTP) phosphatase activity is required for intracellular signaling cascades that are activated in motile cells and growing neurites. Little is known, however, about mechanisms that coordinate RPTP activity with cell behavior. We show that clustering of neural cell adhesion molecule (NCAM) at the cell surface is coupled to an increase in serine phosphorylation and phosphatase activity of RPTP. NCAM associates with T- and L-type voltage-dependent Ca²⁺ channels, and NCAM clustering at the cell surface results in Ca²⁺ influx via these channels and activation of NCAM-associated calmodulin-dependent protein kinase II (CaMKII). Clustering of NCAM promotes its redistribution to lipid rafts and the formation of a NCAM–RPTP–CaMKII complex, resulting in serine phosphorylation of RPTP by CaMKII. Overexpression of RPTP with mutated Ser180 and Ser204 interferes with NCAM-induced neurite outgrowth, which indicates that neurite extension depends on NCAM-induced up-regulation of RPTP activity. Thus, we reveal a novel function for a cell adhesion molecule in coordination of cell behavior with intracellular phosphatase activity.

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

Abbreviations used in this paper: BisI, bisindolylmaleimide I; CaM, calmodulin; CaMKII, CaM-dependent protein kinase II; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GPI, glycosylphosphatidylinositol; NCAM, neural cell adhesion molecule; RPTP, receptor protein tyrosine phosphatase ; RPTP-ID, intracellular domains of RPTP; RPTPWT, wild-type RPTP; VDCC, voltage-dependent Ca²⁺ channels.

© 2008 Bodrikov et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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