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MBC in Press, published online ahead of print March 1, 2006
Mol. Biol. Cell 10.1091/mbc.E05-10-0987

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Submitted on October 27, 2005
Revised on January 17, 2006
Accepted on February 16, 2006

NCAM Induces Intracellular Signaling via Multiple Mechanisms of Ca2+ Homeostasis

Darya Kiryushko, Irina Korshunova, Vladimir Berezin, and Elisabeth Bock

Protein Laboratory, Institute of Molecular Pathology, Panum Institute, DK-2200 Copenhagen N, Denmark

Monitoring Editor: Marianne Bronner-Fraser

The neural cell adhesion molecule, NCAM, plays a pivotal role in the development of the nervous system promoting neuronal differentiation via homophilic (NCAM-NCAM) as well as heterophilic (NCAM-fibroblast growth factor receptor, FGFR) interactions. NCAM-induced intracellular signaling has been shown to affect and be dependent on the cytoplasmic Ca2+ concentration ([Ca2+]i). However, the molecular basis of this remains unclear. In this study, we determined [Ca2+]i regulating mechanisms involved in intracellular signaling induced by NCAM. To mimic the effect of homophilic NCAM interaction on [Ca2+]i in vitro, we used a peptide derived from a homophilic binding site of NCAM, termed P2, which triggers signaling cascades similar to those activated by NCAM-NCAM interaction. We found that P2 increased [Ca2+]i in primary hippocampal neurons. This effect depended on two signaling pathways, the first associated with activation of FGFR, phospholipase C{gamma} (PLC{gamma}), and production of diacylglycerol (DAG), and the second involving Src-family kinases. Moreover, NCAM-mediated Ca2+-entry required activation of nonselective cation and T-type voltage-gated Ca2+ channels. These channels, together with the Src-family kinases, were also involved in neuritogenesis induced by physiological., homophilic NCAM interactions. Thus, unanticipated mechanisms of Ca2+ homeostasis are shown to be activated by NCAM and to contribute to neuronal differentiation.


Address correspondence to: Darya Kiryushko (darya{at}plab.ku.dk)




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V. Bodrikov, V. Sytnyk, I. Leshchyns'ka, J. den Hertog, and M. Schachner
NCAM induces CaMKII{alpha}-mediated RPTP{alpha} phosphorylation to enhance its catalytic activity and neurite outgrowth
J. Cell Biol., September 22, 2008; 182(6): 1185 - 1200.
[Abstract] [Full Text] [PDF]




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