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Originally published In Press as doi:10.1074/jbc.M201092200 on March 25, 2002

J. Biol. Chem., Vol. 277, Issue 23, 20160-20168, June 7, 2002
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Induction of Neurite Extension and Survival in Pheochromocytoma Cells by the Rit GTPase*

Michael L. Spencer, Haipeng Shao, and Douglas A. AndresDagger

From the Department of Molecular and Cellular Biochemistry, University of Kentucky, College of Medicine, Lexington, Kentucky 40536-0298

The Rit, Rin, and Ric proteins comprise a distinct and evolutionarily conserved subfamily of the Ras-like small G-proteins. Although these proteins share the majority of core effector domain residues with Ras, recent studies suggest that Rit uses novel effector pathways to regulate NIH3T3 cell proliferation and transformation, while the functions of Rin and Ric remain largely unknown. Since we demonstrate that Rit is expressed in neurons, we investigated the role of Rit signaling in promoting the differentiation and survival of pheochromocytoma cells. In this study, we show that expression of constitutively active Rit (RitL79) in PC6 cells results in neuronal differentiation, characterized by the elaboration of an extensive network of neurite-like processes that are morphologically distinct from those mediated by the expression of oncogenic Ras. Although activated Rit fails to stimulate mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) signaling pathways in COS cells, RitL79 induced the phosphorylation of ERK1/2 in PC6 cells. We also find that Rit-mediated effects on neurite outgrowth can be blocked by co-expression of dominant-negative mutants of C-Raf1 or mitogen-activated protein kinase kinase 1 (MEK1). Moreover, expression of dominant-negative Rit is sufficient to inhibit NGF-induced neurite outgrowth. Expression of active Rit inhibits growth factor-withdrawal mediated apoptosis of PC6 cells, but does not induce phosphorylation of Akt/protein kinase B, suggesting that survival does not utilize the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Instead, pharmacological inhibitors of MEK block Rit-stimulated cell survival. Taken together, these studies suggest that Rit represents a distinct regulatory protein, capable of mediating differentiation and cell survival in PC6 cells using a MEK-dependent signaling pathway to achieve its effects.

* This work was supported in part by a grant from the Kentucky Lung Cancer Research Fund and by support from the American Heart Association.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, 800 Rose St., Lexington, KY 40536-0298. Tel.: 859-257-6775; Fax: 859-323-1037; E-mail: dandres@pop.uky.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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