Signaling by ROBO receptors (Homo sapiens)
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Description
The Roundabout (Robo) family encodes transmembrane receptors that regulate axonal guidance and cell migration. The major function of the Robo receptors is to mediate repulsion of the navigating growth cones. There are four human Robo homologues, Robo1, Robo2, Robo3 and Robo4. Most of the Robos have the similar ectodomain architecture as the cell adhesion molecules, five Ig domains followed by three FN3 repeats except for Robo4, it has 2Ig and 2FN3 repeats. The cytoplasmic domains of Robo receptors are in general poorly conserved. However, there are four short conserved cytoplasmic sequence motifs, named CC0-3, that serve as binding sites for adaptor proteins. The ligands for the human Robo receptors are the three Slit proteins Slit1, Slit2, and Slit3; all of the Slit proteins contain a tandem of four LRR (leucine rich repeat) domains at N terminus, termed D1 D4 followed by six EGF (epidermal growth factor)-like domains, a laminin G like domain (ALPS), three EGF-like domains, and a C-terminal cysteine knot domain. Most Slit proteins are cleaved within the EGF-like region by unknown proteases.
Slit protein binding modulates Robo interactions with the cytosolic adaptors. The cytoplasmic domain of Robo1 and Robo2 determines the repulsive responses of these receptors. Based on the studies from both invertebrate and vertebrate organisms its been inferred that Robo induces growth cone repulsion by controlling cytoskeletal dynamics via either Abelson kinase (Abl) and Enabled (Ena), or Rac activity.
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Slit protein binding modulates Robo interactions with the cytosolic adaptors. The cytoplasmic domain of Robo1 and Robo2 determines the repulsive responses of these receptors. Based on the studies from both invertebrate and vertebrate organisms its been inferred that Robo induces growth cone repulsion by controlling cytoskeletal dynamics via either Abelson kinase (Abl) and Enabled (Ena), or Rac activity.
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Slit proteins are the ligands for the Robo receptors. In humans there are four robo genes: Robo1, 2, 3 and 4. The extracellular domain of Robo comprises five Ig domains and three Fn domains except for Robo4 (2Ig+2Fn). Ig1 and Ig2 domains of Robo are highly conserved and are important for Slit binding. The concave face of slit's second LRR domain accommodates the Robo's Ig1 and 2 domains. Slit binding with Robo4 is controversial as the interaction is weak and its been observed using the in-vitro methods.
The Ena/VASP family of proteins has a universal role in control of cell motility and actin dynamics. These proteins consist of an N terminal EVH1 domain, a central proline rich region, which acts as a ligand for the actin monomer binding protein Profilin as well as several SH3 domain containing proteins including Abl and a C terminal EVH2 domain involved in oligomerization and F actin binding.
The human homologue of Vilse/CrGAP, KIAA1688, was identified which shares 54.4% sequence similarity with Drosophila CrGAP and is referred as human Vilse/CrGAP protein.