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.