Syndecan Recyling Is Controlled by Syntenin-PIP 2 Interaction and Arf6

SummarySyndecans are heparan sulfate proteoglycans thatmodulate the activity of several growth factors andcell adhesion molecules. PDZ domains in the adaptorprotein syntenin interact with syndecans and with thephosphoinositide PIP 2 , which is involved in the regu-lation of the actin cytoskeleton and membrane traf-ficking. Here, we show that the syntenin PDZ domain-PIP 2 interaction controls Arf6-mediated syndecanrecycling through endosomal compartments. FGF re-ceptor accompanies syndecan along the syntenin-mediated recycling pathway, in a heparan sulfate- andFGF-dependent manner. Syndecans that cannot recy-cle via this pathway become trapped intracellularlyand inhibit cell spreading. This syntenin-mediatedsyndecan recycling pathway may regulate the surfaceavailability of a number of cell adhesion and signal-ing molecules.Introduction Syndecans are abundant type I membrane proteins thatbear heparan sulfate (HS) chains on their extracellulardomains. Via their HS chains, syndecans act as versa-tile coreceptors, attracting and concentrating variousgrowth factors, morphogens, and adhesion moleculesat the cell surface and facilitating their interaction withtheir specific receptors ( Bernfield et al., 1999; Gallagher,2001). The functions of the syndecans also depend ontheir strongly conserved cytoplasmic domains that es-tablish connections with signaling and cytoskeletalmolecules (Couchman, 2003) and with several PDZ pro-teins, including syntenin (Grootjans et al., 1997).PDZ proteins in general are implicated in the correctorganization and subcellular localization of receptorsand signal transduction components. As such, they are