Interaction of the guidance molecule Slit with cellular receptors

Abstract

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.

Slits and Roundabouts in cancer, tumour angiogenesis and endothelial cell migration

“…In addition, in vitro binding assays with Robo1 deletion proteins has mapped Robo1-Slit binding to Ig domains 1 and 2 [15]. The binding to Slit is enhanced by the heparan sulphate proteoglycan coreceptor syndecan, which can form a ternary complex with Robo/Slit and is proposed to concentrate Slit at the growth cone surface [13,16]. Slit-Robo1-3 interactions in neurons have been reviewed previously and so will not be discussed further here [17].…”

“…The Ig domains in Robo1 are required for binding to its ligand Slit [13]. Surface plasmon resonance studies have detected binding between Drosophila Slit and the first two [14] Ig domains of Drosophila Robo1, whereas no binding was detected with Ig domains 3-5 [13,14]. In addition, in vitro binding assays with Robo1 deletion proteins has mapped Robo1-Slit binding to Ig domains 1 and 2 [15].…”

“…Human Robo1 is alternatively spliced to generate two similar proteins that differ in length at their extreme N-termini (data not shown). The Ig domains in Robo1 are required for binding to its ligand Slit [13]. Surface plasmon resonance studies have detected binding between Drosophila Slit and the first two [14] Ig domains of Drosophila Robo1, whereas no binding was detected with Ig domains 3-5 [13,14].…”

Netrin-DCC Signaling Regulates Corpus Callosum Formation Through Attraction of Pioneering Axons and by Modulating Slit2-Mediated Repulsion

“…As there are 3 Slit molecules and 4 Robo receptors expressed in mammals (Unni et al 2012 and for reviews see Hohenester et al 2006;Chédotal 2007), understanding the key family member(s) involved in callosal axon guidance is critical. In mice, the predominant ligand involved in callosal development is Slit2, although other Slits also make a contribution, as evidenced by an increase in the severity of the phenotype in double knockout mice in comparison to Slit2 single knockout mice (Bagri et al 2002;Unni et al 2012).…”

Repulsive axon guidance molecule Slit3 is a novel angiogenic factor

“…Slits bind to Robo receptors to induce repulsive signaling during axon guidance and neuronal migration. 5,6 Slit1-3 show both overlapping and distinct expression patterns. [7][8][9] Slit1 and Slit2 are expressed prominently in the central nervous system.…”