Signaling by ROBO receptors

homologues, ROBO1, ROBO2, ROBO3 ectodomain adhesion with five Ig domains followed by three FN3 repeats, except for ROBO4. ROBO4 two Ig and two FN3 repeats. cytoplasmic of ROBO conserved. there four short conserved cytoplasmic sequence motifs, named CC0-3, serve as binding sites for adaptor proteins. The ligands for the ROBO1 and ROBO2 are the three SLIT proteins SLIT1, SLIT2, and SLIT3; all of the SLIT proteins a tandem of four LRR (leucine rich repeat) domains at the 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 Hohenster Ypsilanti Chedotal Blockus and Chedotal NELL2 is a ligand for ROBO3


Signaling by ROBO receptors ↗ Stable identifier: R-HSA-376176
Compartments: plasma membrane 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, with five Ig domains followed by three FN3 repeats, except for ROBO4. ROBO4 has two Ig and two FN3 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 ROBO1 and ROBO2 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 the 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 (reviewed by Hohenster 2008, Ypsilanti and Chedotal 2014, Blockus and Chedotal 2016. NELL2 is a ligand for ROBO3 (Jaworski et al. 2015).
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 it has been inferred that ROBO induces growth cone repulsion by controlling cytoskeletal dynamics via either Abelson kinase (ABL) and Enabled (Ena), or RAC1 activity (reviewed by Hohenster 2008, Ypsilanti and Chedotal 2014, Blockus and Chedotal 2016. While there is some redundancy in the function of ROBO receptors, ROBO1 is implicated as the predominant receptor for axon guidance in ventral tracts, and ROBO2 is the predominant receptor for axon guidance in dorsal tracts. ROBO2 also repels neuron cell bodies from the floor plate (Kim et al. 2011).
In addition to regulating axon guidance, ROBO1 and ROBO2 receptors are also implicated in regulation of proliferation and transition of primary to intermediate neuronal progenitors through a poorly characterized cross-talk with NOTCH-mediated activation of HES1 transcription (Borrell et al. 2012).
Thalamocortical axon extension is regulated by neuronal activity-dependent transcriptional regulation of ROBO1 transcription. Lower neuronal activity correlates with increased ROBO1 transcription, possibly mediated by the NFKB complex (Mire et al. 2012).
It is suggested that the homeodomain transcription factor NKX2.9 stimulates transcription of ROBO2, which is involved in regulation of motor axon exit from the vertebrate spinal code (Bravo-Ambrosio et al. 2012).

Literature references
Henzel, W., Brose, K., Arnott, D., Goodman, CS., Kidd, T., Wang, KH. et al. (1999). Biochemical purification of a mammalian slit protein as a positive regulator of sensory axon elongation and branching.  Jaworski et al. 2015). SLIT binding with ROBO4 is controversial as the interaction is weak and it has been observed using the in-vitro methods (Wang et al. 1999, Brose et al. 1999, Piper et al. 2003, Andrews et al. 2007. Binding of secreted (cleaved) SLIT2 to ROBO1 and ROBO2 is involved in fasciculation (bundling) of motor axons, which facilitates axon pathfinding and muscle innervation (Jaworski and Tessier-Lavigne 2012).