PathwayStep6209 PathwayStep6213 PathwayStep6212 PathwayStep6211 PathwayStep6210 PathwayStep6218 PathwayStep6223 PathwayStep6228 Inactivation of Cdc42 and Rac Regulation of Commissural axon pathfinding by Slit and Robo Signaling by Robo receptor Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed18363568 Reactome Database ID Release 43376176 Reactome, http://www.reactome.org ReactomeREACT_19351 Reviewed: Kidd, T, 2009-08-18 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.<br><br>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.<br> Role of Abl in Robo-Slit signaling Activation of Rac Recruitment of Profilin by Ena/Vasp proteins Ena/VASP binds Robo1:Slit2 complex Robo1 binds Slit2 Glypican-1 binds Slit2