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J. Biol. Chem., Vol. 283, Issue 51, 35435-35444, December 19, 2008

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Syndecan-1 Ectodomain Shedding Is Regulated by the Small GTPase Rab5^*

Kazutaka Hayashida, Philip D. Stahl, and Pyong Woo Park¹

From the Division of Respiratory Diseases, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115 and the Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

The ectodomain shedding of syndecan-1, a major cell surface heparan sulfate proteoglycan, modulates molecular and cellular processes central to the pathogenesis of inflammatory diseases. Syndecan-1 shedding is a highly regulated process in which outside-in signaling accelerates the proteolytic cleavage of syndecan-1 ectodomains at the cell surface. Several extracellular agonists that induce syndecan-1 shedding and metalloproteinases that cleave syndecan-1 ectodomains have been identified, but the intracellular mechanisms that regulate syndecan-1 shedding are largely unknown. Here we examined the role of the syndecan-1 cytoplasmic domain in the regulation of agonist-induced syndecan-1 shedding. Our results showed that the syndecan-1 cytoplasmic domain is essential because mutation of invariant cytoplasmic Tyr residues abrogates ectodomain shedding, but not because it is Tyr phosphorylated upon shedding stimulation. Instead, our data showed that the syndecan-1 cytoplasmic domain binds to Rab5, a small GTPase that regulates intracellular trafficking and signaling events, and this interaction controls the onset of syndecan-1 shedding. Syndecan-1 cytoplasmic domain bound specifically to Rab5 and preferentially to inactive GDP-Rab5 over active GTP-Rab5, and shedding stimulation induced the dissociation of Rab5 from the syndecan-1 cytoplasmic domain. Moreover, the expression of dominant-negative Rab5, unable to exchange GDP for GTP, interfered with the agonist-induced dissociation of Rab5 from the syndecan-1 cytoplasmic domain and significantly inhibited syndecan-1 shedding induced by several distinct agonists. Based on these data, we propose that Rab5 is a critical regulator of syndecan-1 shedding that serves as an on-off molecular switch through its alternation between the GDP-bound and GTP-bound forms.

Received for publication, May 30, 2008 , and in revised form, October 22, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL69050 and HL81474. 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 To whom correspondence should be addressed: 320 Longwood Ave., Enders-144, Boston, MA 02115. Tel.: 617-919-4584; Fax: 617-730-0240; E-mail: Pyong.Park{at}childrens.harvard.edu.

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