Syndecans shed their reputation as inert molecules

Abstract

The syndecan transmembrane proteoglycans synergize with receptors for extracellular matrix molecules and growth factors to initiate cytoplasmic signals in response to a range of extracellular stimuli. Syndecans influence a wide range of physiological processes, but their contribution is most apparent during wound repair. Aspects of syndecan biology that have attracted research interest include extracellular matrix binding, outside-to-inside plasma membrane signal propagation, activation of cytoplasmic signals, and shedding of the syndecan extracellular domain, but the mechanisms by which syndecan cytoplasmic signals modulate extracellular function remain largely unresolved. Hayashida et al. have now discovered that association between an endocytic regulator, Rab5, and the syndecan-1 cytoplasmic domain controlled the shedding of the syndecan-1 extracellular domain. The work describes a mechanistic investigation into inside-to-outside syndecan signaling and highlights several gaps in our understanding of the relation between cell-surface receptors and proteases. In this Perspective, we summarize the current understanding of receptor interplay and identify the challenges that face investigators of adhesion- and growth factor-dependent signaling.

Fig. 1

The proposed functions of syndecan extracellular domain shedding. Extracellular matrix engagement of syndecans (A) elicits syndecan-specific intracellular signals, which are (B) terminated by proteolytic cleavage of the syndecan extracellular domain. (C) Cleaved syndecan ectodomains further disrupt syndecan signaling by competing with intact syndecan for matrix engagement. (D) The extracellular domain of membrane-bound syndecan promotes prototypic growth factor and chemokine receptor signaling by facilitating association with their ligands in a heparan sulfate–dependent manner, and (E) it is believed that shed syndecan ectodomains disrupt this signaling by sequestering the ligands away from their primary receptors. (F) Syndecan-1 proteolytic cleavage is regulated by a cytoplasmic domain interaction with Rab5-GDP. It was proposed that release of Rab5 from syndecan-1 permits Rab5 activation and modulates trafficking of integrins, which could serve to shield syndecans from proteolysis (15). Alternatively, regulation of Rab5 activity could mediate shedding by coordinating protease recycling.