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Published 8 December 2003. doi:10.1083/jcb.200308070
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© The Rockefeller University Press, 0021-9525/2003/12/1067 $8.00
The Journal of Cell Biology, Volume 163, Number 5, 1067-1076

Article

Small GTPase Rin induces neurite outgrowth through Rac/Cdc42 and calmodulin in PC12 cells



Mitsunobu Hoshino and Shun Nakamura

Division of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan

Address correspondence to Mitsunobu Hoshino, Division of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. Tel.: 81-42-346-1722. Fax: 81-42-346-1752. email: hoshinom{at}ncnp.go.jp

The novel Ras-like small GTPase Rin is expressed prominently in adult neurons, and binds calmodulin (CaM) through its COOH-terminal–binding motif. It might be involved in calcium/CaM-mediated neuronal signaling, but Rin-mediated signal transduction pathways have not yet been elucidated. Here, we show that expression of Rin induces neurite outgrowth without nerve growth factor or mitogen-activated protein kinase activation in rat pheochromocytoma PC12 cells. Rin-induced neurite outgrowth was markedly inhibited by coexpression with dominant negative Rac/Cdc42 protein or CaM inhibitor treatment. We also found that expression of Rin elevated the endogenous Rac/Cdc42 activity. Rin mutant proteins, in which the mutation disrupted association with CaM, failed to induce neurite outgrowth irrespective of Rac/Cdc42 activation. Disruption of endogenous Rin function inhibited the neurite outgrowth stimulated by forskolin and extracellular calcium entry through voltage-dependent calcium channel evoked by KCl. These findings suggest that Rin-mediated neurite outgrowth signaling requires not only endogenous Rac/Cdc42 activation but also Rin–CaM association, and that endogenous Rin is involved in calcium/CaM-mediated neuronal signaling pathways.

Key Words: calcium; MAPK; Ras; Rho

Abbreviations used in this paper: CaMK, calcium/CaM-dependent protein kinase; CRIB, Cdc42/Rac interactive binding; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; LPA, lysophosphatidic acid; PAK, p21-activated kinase; PI3K, phosphatidylinositol 3-kinase; siRNA, short interfering RNA.


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