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J. Biol. Chem., Vol. 282, Issue 4, 2333-2345, January 26, 2007

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SCLIP, a Microtubule-destabilizing Factor, Interacts with RasGRF1 and Inhibits Its Ability to Promote Rac Activation and Neurite Outgrowth^*

Simona Baldassa¹, Nerina Gnesutta², Umberto Fascio, Emmapaola Sturani, and Renata Zippel

From the Department of Biomolecular Sciences and Biotechnology and the Interdepartmental Center for Advanced Microscopy, University of Milan, Via Celoria 26, 20133 Milan, Italy

RasGRF1 is a neuron-specific guanine nucleotide exchange factor for the small GTPases Ras and Rac. It is implicated in the regulation of memory formation and in the development of tolerance to drug abuse, although the mechanisms have been elucidated only in part. Here we report the isolation, by the yeast two-hybrid screen, of the microtubule-destabilizing factor SCLIP (SCG10-like protein) as a novel RasGRF1-interacting protein. This interaction requires the region spanning the Dblhomology domain of RasGRF1, endowed with catalytic activity on Rac. In search for a possible function we found by biochemical means that SCLIP influences the signaling properties of RasGRF1, greatly reducing its ability to activate the Rac/p38 MAPK pathway, while the Ras/Erk one remains unaffected. Moreover, a potential role is suggested by transfection studies in neuronal PC12 cells in which RasGRF1 induces neurite outgrowth, and coexpression of SCLIP counteracts this effect, causing a dramatic decrease in the percentage of cells bearing neurites, which also appear significantly shortened. This study unveils a physical and functional interaction between RasGRF1 and SCLIP. We suggest that this novel interplay may have possible implications in mechanisms that regulate neuronal morphology and structural plasticity.

Received for publication, May 10, 2006 , and in revised form, November 22, 2006.

^* This work was supported in part by grants from MIUR (PRIN 2005) and by FIRST 2004-5. Confocal facilities were supported by the Centro Interdisciplinare di Materiali e Interfacce Nanostrutturali-Università di Milano. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Supported by E. C. Marie Curie IRG (Grant MIRG-CT-2004-003902).

¹ To whom correspondence should be addressed: Tel.: 39-02-5031-4914; Fax: 39-02-5031-4912; E-mail: simona.baldassa{at}unimi.it.

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