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Published 12 May 2003. doi:10.1083/jcb.200303020
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© The Rockefeller University Press, 0021-9525/2003/5/625 $5.00
The Journal of Cell Biology, Volume 161, Number 3, 625-639

Article

Neural cell adhesion molecule (NCAM) association with PKCß2 via ßI spectrin is implicated in NCAM-mediated neurite outgrowth



Iryna Leshchyns'ka1, Vladimir Sytnyk1, Jon S. Morrow2 and Melitta Schachner1

1 Zentrum für Molekulare Neurobiologie, Universität Hamburg, D-20246 Hamburg, Germany
2 Department of Pathology, Yale University School of Medicine, New Haven, CT 06520

Address correspondence to Melitta Schachner, Zentrum für Molekulare Neurobiologie, Universität Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany. Tel.: 49-40-42803-6246. Fax: 49-40-42803-6248. E-mail: melitta.schachner{at}zmnh.uni-hamburg.de

In hippocampal neurons and transfected CHO cells, neural cell adhesion molecule (NCAM) 120, NCAM140, and NCAM180 form Triton X-100–insoluble complexes with ßI spectrin. Heteromeric spectrin ({alpha}IßI) binds to the intracellular domain of NCAM180, and isolated spectrin subunits bind to both NCAM180 and NCAM140, as does the ßI spectrin fragment encompassing second and third spectrin repeats (ßI2–3). In NCAM120-transfected cells, ßI spectrin is detectable predominantly in lipid rafts. Treatment of cells with methyl-ß-cyclodextrin disrupts the NCAM120–spectrin complex, implicating lipid rafts as a platform linking NCAM120 and spectrin. NCAM140/NCAM180–ßI spectrin complexes do not depend on raft integrity and are located both in rafts and raft-free membrane domains. PKCß2 forms detergent-insoluble complexes with NCAM140/NCAM180 and spectrin. Activation of NCAM enhances the formation of NCAM140/NCAM180–spectrin–PKCß2 complexes and results in their redistribution to lipid rafts. The complex is disrupted by the expression of dominant-negative ßI2–3, which impairs binding of spectrin to NCAM, implicating spectrin as the bridge between PKCß2 and NCAM140 or NCAM180. Redistribution of PKCß2 to NCAM–spectrin complexes is also blocked by a specific fibroblast growth factor receptor inhibitor. Furthermore, transfection with ßI2–3 inhibits NCAM-induced neurite outgrowth, showing that formation of the NCAM–spectrin–PKCß2 complex is necessary for NCAM-mediated neurite outgrowth.

Key Words: NCAM; spectrin; PKC; neurons; outgrowth

I. Leshchyns'ka and V. Sytnyk contributed equally to this work.

The online version of this article includes supplemental material.

* Abbreviations used in this paper: FGFR, fibroblast growth factor receptor; MCD, methyl-ß-cyclodextrin; NCAM, neural cell adhesion molecule.


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