Signaling by ROBO receptors

Stable Identifier
R-HSA-376176
Type
Pathway
Species
Homo sapiens
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Summation

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).

Of the four ROBO proteins, ROBO4 is not involved in neuronal system development but is, instead, involved in angiogenesis. The interaction of ROBO4 with SLIT3 is involved in proliferation, motility and chemotaxis of endothelial cells, and accelerates formation of blood vessels (Zhang et al. 2009).

Literature References
PubMed ID Title Journal Year
18363568 Structural insight into Slit-Robo signalling

Hohenester, E

Biochem Soc Trans 2008
27578174 Slit-Robo signaling

Blockus, H, Chédotal, A

Development 2016
19741192 Repulsive axon guidance molecule Slit3 is a novel angiogenic factor

Zhang, B, Dietrich, UM, Geng, JG, Bicknell, R, Esko, JD, Wang, L

Blood 2009
26586761 Operational redundancy in axon guidance through the multifunctional receptor Robo3 and its ligand NELL2

Jaworski, A, Tom, I, Tong, RK, Gildea, HK, Koch, AW, Gonzalez, LC, Tessier-Lavigne, M

Science 2015
25300136 Roundabout receptors

Ypsilanti, AR, Chédotal, A

Adv Neurobiol 2014
22399681 Motor axon exit from the mammalian spinal cord is controlled by the homeodomain protein Nkx2.9 via Robo-Slit signaling

Bravo-Ambrosio, A, Mastick, G, Kaprielian, Z

Development 2012
23083737 Slit/Robo signaling modulates the proliferation of central nervous system progenitors

Borrell, V, Cárdenas, A, Ciceri, G, Galcerán, J, Flames, N, Pla, R, Nóbrega-Pereira, S, García-Frigola, C, Peregrín, S, Zhao, Z, Ma, L, Tessier-Lavigne, M, Marín, O

Neuron 2012
22772332 Spontaneous activity regulates Robo1 transcription to mediate a switch in thalamocortical axon growth

Mire, E, Mezzera, C, Leyva-Díaz, E, Paternain, AV, Squarzoni, P, Bluy, L, Castillo-Paterna, M, López, MJ, Peregrín, S, Tessier-Lavigne, M, Garel, S, Galcerán, J, Lerma, J, López-Bendito, G

Nat. Neurosci. 2012
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