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Published 2 August 2004. doi:10.1083/jcb.200402016
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 3, 381-392
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Article

 Differential transactivation of sphingosine-1-phosphate receptors modulates NGF-induced neurite extension

Rachelle E. Toman1,3, Shawn G. Payne1,4, Kenneth R. Watterson1, Michael Maceyka1, Norman H. Lee5, Sheldon Milstien4, John W. Bigbee2, and Sarah Spiegel1

1 Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
2 Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
3 Interdisciplinary Program in Neuroscience and Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007
4 Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892
5 Department of Molecular and Cellular Biology, The Institute for Genomic Research, Rockville, MD 20850

Address correspondence to Sarah Spiegel, Dept. of Biochemistry, VCU Medical Center, P.O. Box 980614, 1101 E. Marshall St., Richmond, VA 23298-0614. Tel.: (804) 828-9330. Fax: (804) 828-8999. email: sspiegel{at}vcu.edu

The process of neurite extension after activation of the TrkA tyrosine kinase receptor by nerve growth factor (NGF) involves complex signaling pathways. Stimulation of sphingosine kinase 1 (SphK1), the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P), is part of the functional TrkA signaling repertoire. In this paper, we report that in PC12 cells and dorsal root ganglion neurons, NGF translocates SphK1 to the plasma membrane and differentially activates the S1P receptors S1P1 and S1P2 in a SphK1-dependent manner, as determined with specific inhibitors and small interfering RNA targeted to SphK1. NGF-induced neurite extension was suppressed by down-regulation of S1P1 expression with antisense RNA. Conversely, when overexpressed in PC12 cells, transactivation of S1P1 by NGF markedly enhanced neurite extension and stimulation of the small GTPase Rac, important for the cytoskeletal changes required for neurite extension. Concomitantly, differentiation down-regulated expression of S1P2 whose activation would stimulate Rho and inhibit neurite extension. Thus, differential transactivation of S1P receptors by NGF regulates antagonistic signaling pathways that modulate neurite extension.

Key Words: NGF; neurite extension; TrkA; dorsal root ganglion; PC12

J.W. Bigbee and S. Spiegel contributed equally to this paper.

Abbreviations used in this paper: DMS, N,N-dimethylsphingosine; DRG, dorsal root ganglion; GPCR, G protein–coupled receptor; PI3K, phosphoinositide 3-kinase; PTX, pertussis toxin; S1P, sphingosine-1-phosphate; siRNA, small interfering RNA; SphK, sphingosine kinase.


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