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J. Biol. Chem., Vol. 282, Issue 39, 28991-29001, September 28, 2007

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Mammalian NOTCH-1 Activates 1 Integrins via the Small GTPase R-Ras^*

From the University of Edinburgh, MRC Centre for Inflammation Research, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4SA, Scotland, United Kingdom

Notch is a central regulator of important cell fate decisions. Notch activation produces diverse cellular effects suggesting the presence of context-dependent control mechanisms. Genetic studies have demonstrated that Notch and integrin mutations have related phenotypes in key developmental processes such as vascular development and somitogenesis. We show that the intracellular domain of mammalian Notch-1 activates integrins without affecting integrin expression. Integrin activation is dependent on -secretase-mediated intramembranous cleavage of membrane-bound Notch releasing intracellular Notch that activates R-Ras, independent of CSL-transcription. Notch also reverses H-Ras and Raf-mediated integrin suppression without affecting ERK phosphorylation. Membrane-bound Notch mutants that are inefficiently cleaved or intracellular Notch mutants lacking the ankyrin repeat sequence do not activate R-Ras or integrins. Co-expression of Msx2-interacting nuclear target (MINT) protein with Notch or expression of intracellular Notch-1 truncation mutants lacking the C-terminal transactivation/PEST domain suppresses Notch transcriptional activity without affecting integrin activation. Notch ligand, Delta-like ligand-4, stimulates R-Ras-dependent 51 integrin-mediated adhesion, demonstrating the physiological relevance of this pathway. This new CSL-independent Notch/R-Ras pathway provides a molecular mechanism to explain Notch, integrin, and Ras cross-talk during the development of multicellular organisms.

Received for publication, May 1, 2007 , and in revised form, July 11, 2007.

^* This work was supported in part by a Wellcome Trust Senior Leave fellowship (to T. S.) and a Scottish Health Research and Education Trust Project grant (to Y. L.). 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.

¹ Supported by the Medical Research Council.

² Supported by a Junior Fellowship from the British Heart Foundation.

³ Supported by the Medical Research Council. To whom correspondence should be addressed: 47 Little France Crescent, Edinburgh EH16 4SA, Scotland, UK. Tel.: 44-131-2426550; Fax: 44-131-2426578; E-mail: t.sethi{at}ed.ac.uk.

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