Regulating Syndecan Recycling

Abstract

Syndecans, transmembrane heparan sulfate (HS) proteoglycans that regulate the activity of various growth factors and adhesion molecules, interact through their cytoplasmic domains with the PDZ domain-containing protein syntenin. Zimmermann et al. , who previously showed that syntenin also binds phosphatidylinositol 4,5-bisphosphate (PIP 2 ), explored the role of syntenin's interaction with PIP 2 in syndecan recycling. They found that, when syndecans were coexpressed with mutant syntenins that did not bind PIP 2 , they colocalized to a perinuclear compartment. In cultured cells coexpressing syndecan-2 and an enhanced green fluorescent protein-labeled syntenin mutant (eGFP-syntenin-PIP 2 — ), syndecan-2 and eGFP-syntenin-PIP 2 — colocalized with endocytic markers as well as with Arf6, a small GTPase involved in recycling. Expression of a dominant negative Arf6 mutant (Arf6 T27N) or of a dominant negative form of PIPK (phosphatidylinositol phosphate kinase) led to perinuclear accumulation of syndecan and syntenin. Serum stimulation promoted recycling to the cell membrane of endocytosed syndecans; whereas transfection with eGFP-labeled wild-type syntenin accelerated syndecan-2 recycling, expression of either Arf6 T27N or eGFP-syntenin-PIP 2 — slowed it. Fibroblast growth factor receptor (FGFR) signaling is regulated by syndecan through HS binding to FGF. When cells were exposed to FGF, FGFR accumulated in endosomes with syndecan-syntenin-PIP 2 — ; this did not occur in cells expressing a form of syndecan that lacked HS. Expression of syntenin-PIP 2 — or of syndecans that lacked PDZ inhibited cell spreading, an effect that depended on the presence of HS on syndecan. The authors conclude that release of syndecan from Arf6-regulated recycling endosomes depends on syndecan's interaction with syntenin-PIP 2 and that the syndecan-recycling pathway may play a role in regulating the cell surface expression of adhesion and signaling molecules that interact with the syndecan HS chains. P. Zimmermann, Z. Zhang, G. Degeest, E. Mortier, I. Leenaerts, C. Coomans, J. Schulz, F. N'Kuli, P. J. Courtoy, G. David, Syndecan recycling is controlled by syntenin-PIP2 interaction and Arf6. Dev. Cell 9 , 377-388 (2005). [PubMed]