Interaction of the guidance molecule Slit with cellular receptors

Slits are large secreted glycoproteins characterized by an unusual tandem of four LRR (leucine-rich repeat) domains in their N-terminal half. Slit proteins were initially described as repulsive guidance cues in neural development, but it has become clear that they have additional important functions, for instance in the vasculature and immune system. Genetic studies have identified two types of cellular receptors for Slits: Robos (Roundabout) and the HS (heparan sulphate) proteoglycan syndecan. The intracellular signalling cascade downstream of Robo activation is slowly being elucidated, but the mechanism of transmembrane signalling by Robo has remained obscure. No active signalling role for syndecan has yet been demonstrated. Slit–HS interactions may be important for shaping the presumed Slit gradient or presenting Slit at its target cell surface. Recent studies have mapped the binding sites for Robos and HS/heparin to discrete Slit domains. Robos bind to the second LRR domain of Slit, whereas HS/heparin binds with very high affinity to the C-terminal portion of Slit. Slit activity is likely to be modulated by physiological proteolytic cleavage in the region separating the Robo and HS/heparin-binding sites.