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J. Biol. Chem., Vol. 283, Issue 49, 34457-34468, December 5, 2008

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Interaction of the RAGE Cytoplasmic Domain with Diaphanous-1 Is Required for Ligand-stimulated Cellular Migration through Activation of Rac1 and Cdc42^*

Barry I. Hudson¹, Anastasia Z. Kalea², Maria del Mar Arriero, Evis Harja, Eric Boulanger³, Vivette D'Agati, and Ann Marie Schmidt⁴

From the Division of Surgical Science, Departments of Surgery and Pathology, Columbia University Medical Center, Columbia University, New York, New York, 10032

Cellular migration is a fundamental process linked to diverse pathological states such as diabetes and its complications, atherosclerosis, inflammation, and cancer. The receptor for advanced glycation end products (RAGE) is a multiligand cell surface macromolecule which binds distinct ligands that accumulate in these settings. RAGE-ligand interaction evokes central changes in key biological properties of cells, including proliferation, generation of inflammatory mediators, and migration. Although RAGE-dependent signal transduction is critically dependent on its short cytoplasmic domain, to date the proximate mechanism by which this RAGE domain engages and stimulates cytoplasmic signaling pathways has yet to be identified. Here we show that the RAGE cytoplasmic domain interacts with Diaphanous-1 (Dia-1) both in vitro and in vivo. We employed the human RAGE cytoplasmic domain as "bait" in the yeast two-hybrid assay and identified the formin homology (FH1) domain of Dia-1 as a potential binding partner of this RAGE domain. Immunoprecipitation studies revealed that the RAGE cytoplasmic domain interacts with the FH1 domain of Dia-1. Down-regulation of Dia-1 expression by RNA interference blocks RAGE-mediated activation of Rac-1 and Cdc42 and, in parallel, RAGE ligand-stimulated cellular migration. Taken together, these findings indicate that the interaction of the RAGE cytoplasmic domain with Dia-1 is required to transduce extracellular environmental cues evoked by binding of RAGE ligands to their cell surface receptor, a chief consequence of which is Rac-1 and Cdc42 activation and cellular migration. Because RAGE and Dia-1 are implicated in the regulation of inflammatory, vascular, and transformed cell migration, these findings highlight this interaction as a novel target for therapeutic intervention in inflammation, atherosclerosis, diabetes, and cancer.

Received for publication, February 22, 2008 , and in revised form, October 14, 2008.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ067452 [GenBank] and DQ067453.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL60901 and CA 087677 (United States Public Health Service). This work was also funded by the Juvenile Diabetes Research Foundation and by the Surgical Research Fund. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

² Recipient of a Juvenile Diabetes Research Foundation Fellowship.

³ Recipient of an Alfediam (French Language Association for the Study of Diabetes and Metabolic Diseases) grant.

¹ Recipient of a Career Development Award from the Juvenile Diabetes Research Foundation. To whom correspondence may be addressed: Division of Surgical Science, Dept. of Surgery, College of Physicians and Surgeons, Columbia University, 630 W. 168th St., P&S 17-401, New York, NY 10032. Tel.: 212-342-9015; Fax: 212-305-5337; E-mail: bh2021{at}columbia.edu.

⁴ Recipient of a Juvenile Diabetes Research Foundation Scholar Award. To whom correspondence may be addressed: Division of Surgical Science, Dept. of Surgery, College of Physicians and Surgeons, Columbia University, 630 W. 168th St., P&S 17-401, New York, NY 10032. Tel.: 212-342-9015; Fax: 212-305-5337; E-mail: ams11{at}columbia.edu.

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				A. Z. Kalea, N. Reiniger, H. Yang, M. Arriero, A. M. Schmidt, and B. I. Hudson Alternative splicing of the murine receptor for advanced glycation end-products (RAGE) gene FASEB J, June 1, 2009; 23(6): 1766 - 1774. [Abstract] [Full Text] [PDF]