Editors' ChoiceCell Biology

Controlling Ectodomain Shedding from the Inside

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Science Signaling  23 Dec 2008:
Vol. 1, Issue 51, pp. ec441
DOI: 10.1126/scisignal.151ec441

Syndecan-1 is a heparan sulfate proteoglycan, and regulated release of the ectodomain of syndecan-1 modulates inflammatory processes. The cytoplasmic domain of syndecan-1 contains several conserved putative phosphorylation sites and a PDZ binding site and is known to interact with several signaling or scaffolding proteins. Hayashida et al. investigated the role of the cytoplasmic domain in controlling syndecan-1 shedding from the cell surface. When wild-type mouse syndecan-1 and a version in which all four tyrosine residues were mutated were expressed in human cultured cells, stimulated release of the tyrosine-mutated form was reduced compared with wild-type. However, tyrosine phosphorylation of wild-type mouse syndecan-1 was not detected after the stimulation that triggered shedding. Affinity purification of proteins that bound to recombinant syndecan-1 cytoplasmic domain revealed a previously unreported interaction with the small guanosine triphosphatase Rab5, which was confirmed by coimmunoprecipitation. Introduction of a dominant-negative form of Rab5 (locked in the GDP-bound form) inhibited syndecan-1 shedding in response to ceramide, a phorbol ester, or β-toxin. Syndecan-1 preferentially interacted with the GDP-bound form of Rab5. Kinetic analysis of Rab5 binding in cells treated with phorbol ester suggested that shedding is associated with dissociation of the GDP-Rab5. The authors speculate that GDP-Rab5 prevents the cytoplasmic domain of syndecan-1 from interacting with β1 integrin, which is also known to interact with the cytoplasmic domain.

K. Hayashida, P. D. Stahl, P. W. Park, Syndecan-1 ectodomain shedding is regulated by the small GTPase Rab5. J. Biol. Chem. 283, 35435–35444 (2008). [Abstract] [Full Text]

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