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Published 15 March 2004. doi:10.1083/jcb.200309081
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 6, 851-862
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Article

 Nesca, a novel adapter, translocates to the nuclear envelope and regulates neurotrophin-induced neurite outgrowth

James I.S. MacDonald1, Chris J. Kubu1, and Susan O. Meakin1,2,3

1 Laboratory of Neural Signalling, Cell Biology Group, The Robarts Research Institute
2 Department of Biochemistry, University of Western Ontario, London, Ontario, N6A 5K8 Canada
3 Graduate Program in Neuroscience, University of Western Ontario, London, Ontario, N6A 5K8 Canada

Address correspondence to S.O. Meakin, Laboratory of Neural Signalling, Cell Biology Group, The Robarts Research Institute, 100 Perth Dr., London, Ontario, N6A 5K8 Canada. Tel.: (519) 663-5777, ext. 34304. Fax: (519) 663-3789. email: smeakin{at}robarts.ca

We provide the first characterization of a novel signaling adapter, Nesca, in neurotrophic signal transduction. Nesca contains a RUN domain, a WW domain, a leucine zipper, a carboxyl-terminal SH3 domain, and several proline-rich regions. Nesca is highly expressed in the brain, is serine phosphorylated, and mobilizes from the cytoplasm to the nuclear membrane in response to neurotrophin, but not epidermal growth factor, stimulation in a MEK-dependent process. Overexpression studies in PC12 cells indicate that Nesca facilitates neurotrophin-dependent neurite outgrowth at nonsaturating doses of nerve growth factor (NGF). Similarly, short interfering RNA studies significantly reduce NGF-dependent neuritogenesis in PC12 cells. Mutational analyses demonstrate that the RUN domain is an important structural determinant for the nuclear translocation of Nesca and that the nuclear redistribution of Nesca is essential to its neurite outgrowth-promoting properties. Collectively, these works provide the first functional characterization of Nesca in the context of neurotrophin signaling and suggest that Nesca serves a novel, nuclear-dependent role in neurotrophin-dependent neurite outgrowth.

Key Words: RUN domain; Trk receptor tyrosine kinase; nuclear transport; Map/Erk; neuritogenesis

Abbreviations used in this paper: BDNF, brain-derived neurotrophic factor; CHK, Csk homologous kinase; EGFR, EGF receptor; GAPDH, glycerol-3-phosphate dehydrogenase; NT-3, neurotrophin-3; RFP, red fluorescent protein; siRNA, short interfering RNA.


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