Signaling by ROBO receptors (Homo sapiens)

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5, 9, 12, 21, 33...2844426, 2717, 43, 59345115, 38, 53143952515114353517, 435620, 37383539cytosolcytosolnucleoplasmnucleoplasmRPL26L1 RPS13 RPS10 PRKACB ROBO1 LHX2 RPL31 RPS5 ROBO3.1:AKAP5DAG1(30-653) ROBO2 UbCUL2 PPP3CB MAGOH NCBP1 RPL37A RPL22L1 SLIT2SLIT3:ROBO1,ROBO2RBX1 NCK1,NCK2RPL37 ROBO1 SLIT1 ROBO1PSMD2 PSME2 DCC:NTN1ROBO3 gene SLIT2:ROBO1:Ena/VASP:PFNSLIT3 ROBO3.1:DCC:NTN1RPS27A(77-156) RPL37 CAP1 PSMD7 CDC42:GTPELOB H2OSLIT2:DystroglycanROBO1 SOSROBO3.1 SLIT2(31-1121) ROBO1 SLIT1:ROBO1,ROBO2PSMA8 PAK3 CLASP2 PSME4 3x4Hyp-GalHyl-COL4A5 SLIT3 RPL41 SRGAPROBO2:AKAP5RPS17 ROBO2:AKAP5:PRKAR2A-PKA type IIATPRPL4 RPS27 NELL2:ROBO33x4Hyp-5Hyl-COL4A5 RPL31 SLIT2 genePRKACG RPL26L1 RPS12 RPL39L RPL7 NCBP1 RBM8A SLIT1 ROBO1:NRP1ROBO1 RPL22L1 18S rRNA UBB(153-228) RPS7 GPC1:HSPGUbLHX2 CAP2 RPL35A SLIT2 ROBO1 geneABL1 RPL19 HOXA2 PFN1 LDB1 RPS4X CUL2 ROBO3.1:ZSWIM8-CUL2ROBO1 ROBO2:SLIT2p-T497,T638,S657-PRKCA RPS25 ROBO3.1 PABPC128S rRNA PAK4 ATPRPS4Y1 ENAH RPS3 DCC RPL36A SHFM1 SLIT2:ROBO1:NCKPSMA6 5.8S rRNA RBM8A tRNA ELOB GDPRHO GTPases activatePAKsSLIT2:ROBO1:SRGAPSLIT2 ROBO3.1 SLIT1 PSMC2 RPL23A COL4A5 CUL2 RPS18 RPL18 RPL14 GSPT1 CAPRPLP2 p-T497,T638,S657-PRKCA 5Hyl-COL4A5 UBC(229-304) GSPT2 SLIT1 VASP RHOA NCK2 MAGOHB GSPT1 ABL1 AKAP5AKAP5 PRKACB PPP3CBUBB(153-228) GlcGalHyl-COL4A5 RPL39 RPS4X RPL6 CDC42:GDP3x4Hyp-3Hyp-GalHyl-COL4A5 RAC1:GTPROBO1 AKAP5 RPL23A UBB(1-76) Keratan sulfate ROBO1 RPL23 PSMA3 RPS25 SRGAP1 UBC(229-304) ROBO1 3x4Hyp-GlcGalHyl-COL4A5 RAC1:GDPUSP33SLIT2 LHX2 SLIT2 RPS20 PAK6 RPLP0 3x4Hyp-5Hyl-COL4A5 NCK2 NCK2 GPC1 ROBO2 COL4A5 SLIT2,SLIT2 cleavagefragmentsRPS12 SOS1 ABL2 RHOA:GDPRNPS1 SOS2 RPL10 RPL35 RPL12 RPL35 Ena/VASP ProteinsRPL5 RPS9 RPS6 RPS26 ARHGAP39RPL26 p-S1330-ROBO3.1:AKAP5:p-T497,T638,S657-PRKCARPS27L ELOC AKAP5 GalHyl-COL4A5 PSMD4 EVL UBB(1-76) ELOC SOS1 SLIT2:ROBO1:ABL:CAP5Hyl-COL4A5 ETF1CLASPPSMD9 RPL39 3x4Hyp-3Hyp-5Hyl-COL4A5 RPL36A RPL21 ROBO1 p-Y1019-ROBO3.1:DCC:NTN1SLIT3 UPF3A CLASP1 H2OUb-ROBO3.1 RPL11 LHX9 ROBO1 PABPC1 RPL7A PSMD8 PSMB2 GalHyl-COL4A5 PFN2 PSMD13 SLIT2(31-1121)RHOA ROBO3.2 mRNACap Binding Complex(CBC)80S ribosomePRKACA DCC UnidentifiedproteaseNCK2ROBO1,ROBO2RPS8 ROBO2 ROBO1 ROBO3.2 mRNA NCK2 RPL15 ROBO1 SLIT1:COL4A5ROBO1 ROBO1 SRGAP3 ROBO2,(ROBO1):ROBO3.1RPLP2 SRGAP3 ROBO1 ROBO3.1PSMB8 ROBO1 RPL34 RPL27A RPL8 RPS3 RBX1 ROBO2 SLIT2:p-Y1073-ROBO1:ABLRPS21 UBC(77-152) ROBO1 ROBO1 SLIT1:ROBO1:FLRT3RPL3 ROBO3 geneH2OPSMB3 UBB(77-152) PSME3 ABL1 SLIT2 NCK2 PSMD11 PSMD14 NTN1 5S rRNA DCC NCBP2 DCC SLIT1 RPL18 RPLP1 RPS9 RPL10L RPL17 RPL12 PRKAR2A-PKA type IIGDP AKAP5 NTN1 ROBO2 Ub-ROBO3.1:ZSWIM8-CUL2RNPS1 SLIT2(1122-1529) FLRT3RPL13 UBA52(1-76) EIF4G1DAG1(654-895) RPS18 PAK1 SLIT2 UPF3A UBC(609-684) CLASP2 PolyUb-ROBO1GTP GPC1 RPL32 ROBO1 gene ROBO3.1 LHX4 NCK1 LHX2 eRF3:GDPRPL38 RPL17 LDB1 RPS27 RPS6 ISL1:LHX3/4:LDB1:SLIT2 geneABLLHX3 SLIT2(1122-1529) PFN2 ZSWIM8 SLIT2:ROBO1:MYO9BSLIT2:ROBO1:ABLRPL29 RPS27A(1-76) RPL27 ELOC MSI1MyrG-p-Y419-SRCRPL34 ROBO1 RPL7 PSMB11 RPL8 DCC:ROBO1:SLITSLIT2 RPS17 PRKAR2A SLIT1 RHOA:GTPRPL14 LHX9 GTPUBC(533-608) ROBO3.1 mRNASLIT2 EIF4G1 RPL9 ROBO3.2PRKAR2A SLIT2 SLIT2 RPL22 RPS7 RPL36AL tRNARPS20 ROBO23x4Hyp-3Hyp-GalHyl-COL4A5 3x4Hyp-3Hyp-GlcGalHyl-COL4A5 3x4Hyp-GlcGalHyl-COL4A5 FAU CXCL12:CXCR4:ROBO1:SLIT2RPS21 ExonJunction:UPF2:UPF3ComplexRPL39L LHX4 RPLP1 RPS13 RPS27A(1-76) ROBO1 NELL2RBX1 RPL3 ROBO2 UBC(609-684) SLIT2 UBC(153-228) PSMC4 RPS24 AKAP5 ETF1 ROBO1 RPL4 SLIT2 Nonsense-MediatedDecay (NMD)PAK1 SLIT2:ROBO1:NCK:SOSRPSA RPS10 ELOB SLIT2,SLIT2 cleavagefragments:GPC1:HSPGRPS15A ISL1 DAG1(30-653) PFNGDP SRGAP1 ROBO1,ROBO2:Keratansulfate3x4Hyp-3Hyp-5Hyl-COL4A5 ROBO1 SLIT2 RPS15 PSMA2 3x4Hyp-3Hyp-COL4A5 RPL40 RPS16 UBC(1-76) SLIT3 RPS14 ARHGAP39 p-Y1019-ROBO3.1 GlcGalHyl-COL4A5 ROBO1:SLITRPL36 CDC42 FAU DCCUBA52(1-76) PSMC5 RPL40 ABL2 RPL35A FLRT3 p-Y1073-ROBO1 ROBO2 RPL28 RPS8 CDC42 ROBO3.1 ADPRPL13A ROBO2:AKAP5:p-T497,T638,S657-PRKCANELL2 PiRPL5 MAGOHB HOXA2:ROBO2 geneRPL36AL SLIT2 RPS28 RPS23 3x4Hyp-COL4A5 CAP2 RPL3L PAK2 NCBP2 GTP ROBO2,(ROBO1)CASC3 RPS29 PSMD3 RPLP0 UBC(1-76) PAK6 RPL10 ENAH CXCR4 RPS4Y1 p-T497,T638,S657-PRKCAZSWIM8 ROBO3MSI1 ABL2 PRKACA SLIT2,(SLIT3):Keratan sulfateABL1 RPL10L RPS27A(77-156) RPL10A CAP1 ADPRPS11 HOXA2RPL7A RPL30 UPF2 RPS15 PAK5 PSMB9 EIF4A3 3x4Hyp-COL4A5 ROBO2 SLIT2 ROBO2 ROBO2 GTP RPL24 p-T497,T638,S657-PRKCA ABL1 RPL22 RPL30 RPS16 RPL26 SLIT2(31-1121) NCK1 PAK4 PSMB6 VASP RPS3A UBC(381-456) RPS19 RPS4Y2 UBC(305-380) SLIT2 PSMD12 Translated ROBO3.2mRNA in complexwith NMD-initiatingUPF2RPS27L RPL38 PAK5 RPL9 RPL19 NCK1 3x4Hyp-GalHyl-COL4A5 UBC(77-152) ADPNRP1 DAG1(654-895) H2OPRKACG SLIT2 GDP Keratan sulfateSLIT2:ROBO1:Ena/VASPproteinsRPS3A CLASP1 SLIT3AKAP5 SLIT2:ROBO1:NCK:PAKLHX2,(LHX9):ROBO3geneDystroglycanUBC(381-456) RPL15 ROBO1:SLIT2RPL11 LHX3 EVL CXCR4:CXCL12ROBO2 gene RPL18A RPL13A SLIT2:ROBO1:ABL:CLASPSLIT2 p-S1330-ROBO3.1 PSMD5 ROBO1 RPS29 LHX2MYO9BROBO3.2 NCK1 NTN1 ABL2 RPS2 SLIT2 gene PSMB1 ISL1:LHX3/4:LDB1RPL41 PSMB4 EVL RPS23 SLIT1:ROBO1SLIT2 ROBO2 gene UBC(457-532) RAC1 PSMA1 RAC1 AKAP5 SLIT3 RPS28 RPS11 RPS14 RPL13 3x4Hyp-3Hyp-GlcGalHyl-COL4A5 PSMF1 ROBO3.1 mRNA RPS19 RPS4Y2 28S rRNA RPL27A MYO9B RPL24 RPS5 RPL27 PAK3 ROBO2:AKAP5:PPP3CBUPF3B Heparan sulfate N-acetyl-alpha-D-glucosaminide PSMD6 SLIT1:ROBO1,ROBO2:NCK2PSMC6 26S proteasomeENAH PFN1 EIF4A3 ROBO3.1:AKAP5:p-T497,T638,S657-PRKCARPS26 RPL32 UPF3B SLIT2 ISL1 ROBO3.2 LHX2:ROBO2 geneLHX2,(LHX9)SRGAP2 RPL23 MAGOH PSMB7 SLIT1PSMA4 RPL36 VASP Heparan sulfate N-acetyl-alpha-D-glucosaminide PSME1 PSMA5 ATPSOS2 UBB(77-152) PSMC3 PSMA7 PSMB10 5S rRNA ZSWIM8 GSPT2 SLIT2 SLIT2 UBC(533-608) UPF2 RPL29 UBC(305-380) PSMC1 CXCL12(22-93) ROBO1 PSMB5 RPL37A 3x4Hyp-3Hyp-COL4A5 CASC3 Keratan sulfate RPS2 RPL18A SLIT1 ROBO3.1 mRNA:MSI1RPL10A PSMD10 ROBO2 NRP1SRGAP2 RPS15A CXCL12(22-93) RPS24 CXCR4 ABL2 RPL6 SLIT2,(SLIT3)RPSA PiLHX2:ROBO1 geneRHO GTPases ActivateROCKsROBO3.1 GDP RPL3L RPL28 ROBO1:SLIT2:ARHGAP39PAK5.8S rRNA 18S rRNA ROBO2 geneSLIT2(1122-1529)GDP PiUBC(457-532) PSMD1 RPL21 ROBO2 PAK2 ZSWIM8-CUL2 E3ubiquitin ligaseCollagen alpha-5(IV)chainsROBO3.1 UBC(153-228) 161, 11, 19, 24, 25, 31...5635396, 7, 10, 30, 32...22, 23355522, 233540, 552, 3, 8, 13, 18...22, 23391422, 231438


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, 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).<p>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).<p>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).<p>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). View original pathway at:Reactome.</div>

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Reactome-Converter 
Pathway is converted from Reactome ID: 376176
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Reactome version: 65
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Reactome Author: Garapati, Phani Vijay

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History

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CompareRevisionActionTimeUserComment
114743view16:23, 25 January 2021ReactomeTeamReactome version 75
113187view11:25, 2 November 2020ReactomeTeamReactome version 74
112415view15:35, 9 October 2020ReactomeTeamReactome version 73
101319view11:20, 1 November 2018ReactomeTeamreactome version 66
100856view20:53, 31 October 2018ReactomeTeamreactome version 65
100397view19:27, 31 October 2018ReactomeTeamreactome version 64
99945view16:11, 31 October 2018ReactomeTeamreactome version 63
99501view14:44, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94032view13:52, 16 August 2017ReactomeTeamreactome version 61
93654view11:30, 9 August 2017ReactomeTeamreactome version 61
86772view09:26, 11 July 2016ReactomeTeamreactome version 56
83078view09:53, 18 November 2015ReactomeTeamVersion54
81399view12:55, 21 August 2015ReactomeTeamVersion53
76868view08:14, 17 July 2014ReactomeTeamFixed remaining interactions
76573view11:55, 16 July 2014ReactomeTeamFixed remaining interactions
75906view09:56, 11 June 2014ReactomeTeamRe-fixing comment source
75606view10:45, 10 June 2014ReactomeTeamReactome 48 Update
74961view13:48, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74605view08:39, 30 April 2014ReactomeTeamReactome46
68889view17:27, 8 July 2013MaintBotUpdated to 2013 gpml schema
45209view17:22, 7 October 2011KhanspersOntology Term : 'signaling pathway' added !
42134view21:59, 4 March 2011MaintBotAutomatic update
39944view05:57, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
18S rRNA ProteinX03205 (EMBL)
26S proteasomeComplexR-HSA-68819 (Reactome)
28S rRNA ProteinM11167 (EMBL)
3x4Hyp-3Hyp-5Hyl-COL4A5 ProteinP29400 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-COL4A5 ProteinP29400 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GalHyl-COL4A5 ProteinP29400 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GlcGalHyl-COL4A5 ProteinP29400 (Uniprot-TrEMBL)
3x4Hyp-5Hyl-COL4A5 ProteinP29400 (Uniprot-TrEMBL)
3x4Hyp-COL4A5 ProteinP29400 (Uniprot-TrEMBL)
3x4Hyp-GalHyl-COL4A5 ProteinP29400 (Uniprot-TrEMBL)
3x4Hyp-GlcGalHyl-COL4A5 ProteinP29400 (Uniprot-TrEMBL)
5.8S rRNA ProteinJ01866 (EMBL)
5Hyl-COL4A5 ProteinP29400 (Uniprot-TrEMBL)
5S rRNA ProteinV00589 (EMBL)
80S ribosomeComplexR-HSA-72500 (Reactome)
ABL1 ProteinP00519 (Uniprot-TrEMBL)
ABL2 ProteinP42684 (Uniprot-TrEMBL)
ABLComplexR-HSA-376002 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AKAP5 ProteinP24588 (Uniprot-TrEMBL)
AKAP5ProteinP24588 (Uniprot-TrEMBL)
ARHGAP39 ProteinQ9C0H5 (Uniprot-TrEMBL)
ARHGAP39ProteinQ9C0H5 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
CAP1 ProteinQ01518 (Uniprot-TrEMBL)
CAP2 ProteinP40123 (Uniprot-TrEMBL)
CAPComplexR-HSA-428868 (Reactome)
CASC3 ProteinO15234 (Uniprot-TrEMBL)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CDC42:GDPComplexR-HSA-418830 (Reactome)
CDC42:GTPComplexR-HSA-182921 (Reactome)
CLASP1 ProteinQ7Z460 (Uniprot-TrEMBL)
CLASP2 ProteinO75122 (Uniprot-TrEMBL)
CLASPComplexR-HSA-428867 (Reactome)
COL4A5 ProteinP29400 (Uniprot-TrEMBL)
CUL2 ProteinQ13617 (Uniprot-TrEMBL)
CXCL12(22-93) ProteinP48061 (Uniprot-TrEMBL)
CXCL12:CXCR4:ROBO1:SLIT2ComplexR-HSA-8986277 (Reactome)
CXCR4 ProteinP61073 (Uniprot-TrEMBL)
CXCR4:CXCL12ComplexR-HSA-8986275 (Reactome)
Cap Binding Complex (CBC)ComplexR-HSA-162460 (Reactome)
Collagen alpha-5(IV) chainsComplexR-HSA-2127390 (Reactome)
DAG1(30-653) ProteinQ14118 (Uniprot-TrEMBL)
DAG1(654-895) ProteinQ14118 (Uniprot-TrEMBL)
DCC ProteinP43146 (Uniprot-TrEMBL)
DCC:NTN1ComplexR-HSA-373667 (Reactome)
DCC:ROBO1:SLITComplexR-HSA-373666 (Reactome)
DCCProteinP43146 (Uniprot-TrEMBL)
DystroglycanComplexR-HSA-2328140 (Reactome)
EIF4A3 ProteinP38919 (Uniprot-TrEMBL)
EIF4G1 ProteinQ04637 (Uniprot-TrEMBL)
EIF4G1ProteinQ04637 (Uniprot-TrEMBL)
ELOB ProteinQ15370 (Uniprot-TrEMBL)
ELOC ProteinQ15369 (Uniprot-TrEMBL)
ENAH ProteinQ8N8S7 (Uniprot-TrEMBL)
ETF1 ProteinP62495 (Uniprot-TrEMBL)
ETF1ProteinP62495 (Uniprot-TrEMBL)
EVL ProteinQ9UI08 (Uniprot-TrEMBL)
Ena/VASP ProteinsComplexR-HSA-428478 (Reactome)
Exon

Junction:UPF2:UPF3

Complex
ComplexR-HSA-927798 (Reactome)
FAU ProteinP62861 (Uniprot-TrEMBL)
FLRT3 ProteinQ9NZU0 (Uniprot-TrEMBL)
FLRT3ProteinQ9NZU0 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GPC1 ProteinP35052 (Uniprot-TrEMBL)
GPC1:HSPGComplexR-HSA-428493 (Reactome)
GSPT1 ProteinP15170 (Uniprot-TrEMBL)
GSPT2 ProteinQ8IYD1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
GalHyl-COL4A5 ProteinP29400 (Uniprot-TrEMBL)
GlcGalHyl-COL4A5 ProteinP29400 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
HOXA2 ProteinO43364 (Uniprot-TrEMBL)
HOXA2:ROBO2 geneComplexR-HSA-9010504 (Reactome)
HOXA2ProteinO43364 (Uniprot-TrEMBL)
Heparan sulfate N-acetyl-alpha-D-glucosaminide MetaboliteCHEBI:17421 (ChEBI)
ISL1 ProteinP61371 (Uniprot-TrEMBL)
ISL1:LHX3/4:LDB1:SLIT2 geneComplexR-HSA-9010606 (Reactome)
ISL1:LHX3/4:LDB1ComplexR-HSA-9010608 (Reactome)
Keratan sulfate MetaboliteCHEBI:60924 (ChEBI)
Keratan sulfateMetaboliteCHEBI:60924 (ChEBI)
LDB1 ProteinQ86U70 (Uniprot-TrEMBL)
LHX2 ProteinP50458 (Uniprot-TrEMBL)
LHX2,(LHX9):ROBO3 geneComplexR-HSA-9011164 (Reactome)
LHX2,(LHX9)ComplexR-HSA-9011165 (Reactome)
LHX2:ROBO1 geneComplexR-HSA-9011114 (Reactome)
LHX2:ROBO2 geneComplexR-HSA-9011108 (Reactome)
LHX2ProteinP50458 (Uniprot-TrEMBL)
LHX3 ProteinQ9UBR4 (Uniprot-TrEMBL)
LHX4 ProteinQ969G2 (Uniprot-TrEMBL)
LHX9 ProteinQ9NQ69 (Uniprot-TrEMBL)
MAGOH ProteinP61326 (Uniprot-TrEMBL)
MAGOHB ProteinQ96A72 (Uniprot-TrEMBL)
MSI1 ProteinO43347 (Uniprot-TrEMBL)
MSI1ProteinO43347 (Uniprot-TrEMBL)
MYO9B ProteinQ13459 (Uniprot-TrEMBL)
MYO9BProteinQ13459 (Uniprot-TrEMBL)
MyrG-p-Y419-SRCProteinP12931 (Uniprot-TrEMBL)
NCBP1 ProteinQ09161 (Uniprot-TrEMBL)
NCBP2 ProteinP52298 (Uniprot-TrEMBL)
NCK1 ProteinP16333 (Uniprot-TrEMBL)
NCK1,NCK2ComplexR-HSA-381949 (Reactome)
NCK2 ProteinO43639 (Uniprot-TrEMBL)
NCK2ProteinO43639 (Uniprot-TrEMBL)
NELL2 ProteinQ99435 (Uniprot-TrEMBL)
NELL2:ROBO3ComplexR-HSA-9010200 (Reactome)
NELL2ProteinQ99435 (Uniprot-TrEMBL)
NRP1 ProteinO14786 (Uniprot-TrEMBL)
NRP1ProteinO14786 (Uniprot-TrEMBL)
NTN1 ProteinO95631 (Uniprot-TrEMBL)
Nonsense-Mediated Decay (NMD)PathwayR-HSA-927802 (Reactome) The Nonsense-Mediated Decay (NMD) pathway activates the destruction of mRNAs containing premature termination codons (PTCs) (reviewed in Isken and Maquat 2007, Chang et al. 2007, Behm-Ansmant et al. 2007, Neu-Yilik and Kulozik 2008, Rebbapragada and Lykke-Andersen 2009, Bhuvanagiri et al. 2010, Nicholson et al. 2010, Durand and Lykke-Andersen 2011). In mammalian cells a termination codon can be recognized as premature if it precedes an exon-exon junction by at least 50-55 nucleotides or if it is followed by an abnormal 3' untranslated region (UTR). While length of the UTR may play a part, the qualifications for being "abnormal" have not been fully elucidated. Also, some termination codons preceding exon junctions are not degraded by NMD so the criteria for triggering NMD are not yet fully known (reviewed in Rebbapragada and Lykke-Andersen 2009). While about 30% of disease-associated mutations in humans activate NMD, about 10% of normal human transcripts are also degraded by NMD (reviewed in Stalder and Muhlemann 2008, Neu-Yilik and Kulozik 2008, Bhuvanagiri et al. 2010, Nicholson et al. 2010). Thus NMD is a normal physiological process controlling mRNA stability in unmutated cells.
Exon junction complexes (EJCs) are deposited on an mRNA during splicing in the nucleus and are displaced by ribosomes during the first round of translation. When a ribosome terminates translation the A site encounters the termination codon and the eRF1 factor enters the empty A site and recruits eRF3. Normally, eRF1 cleaves the translated polypeptide from the tRNA in the P site and eRF3 interacts with Polyadenylate-binding protein (PABP) bound to the polyadenylated tail of the mRNA.
During activation of NMD eRF3 interacts with UPF1 which is contained in a complex with SMG1, SMG8, and SMG9. NMD can arbitrarily be divided into EJC-enhanced and EJC-independent pathways. In EJC-enhanced NMD, an exon junction is located downstream of the PTC and the EJC remains on the mRNA after termination of the pioneer round of translation. The core EJC is associated with UPF2 and UPF3, which interact with UPF1 and stimulate NMD. Once bound near the PTC, UPF1 is phosphorylated by SMG1. The phosphorylation is the rate-limiting step in NMD and causes UPF1 to recruit either SMG6, which is an endoribonuclease, or SMG5 and SMG7, which recruit ribonucleases. SMG6 and SMG5:SMG7 recruit phosphatase PP2A to dephosphorylate UPF1 and allow further rounds of degradation. How EJC-independent NMD is activated remains enigmatic but may involve competition between PABP and UPF1 for eRF3.
PABPC1 ProteinP11940 (Uniprot-TrEMBL)
PABPC1ProteinP11940 (Uniprot-TrEMBL)
PAK1 ProteinQ13153 (Uniprot-TrEMBL)
PAK2 ProteinQ13177 (Uniprot-TrEMBL)
PAK3 ProteinO75914 (Uniprot-TrEMBL)
PAK4 ProteinO96013 (Uniprot-TrEMBL)
PAK5 ProteinQ9P286 (Uniprot-TrEMBL)
PAK6 ProteinQ9NQU5 (Uniprot-TrEMBL)
PAKComplexR-HSA-428475 (Reactome)
PFN1 ProteinP07737 (Uniprot-TrEMBL)
PFN2 ProteinP35080 (Uniprot-TrEMBL)
PFNComplexR-HSA-203077 (Reactome)
PPP3CB ProteinP16298 (Uniprot-TrEMBL)
PPP3CBProteinP16298 (Uniprot-TrEMBL)
PRKACA ProteinP17612 (Uniprot-TrEMBL)
PRKACB ProteinP22694 (Uniprot-TrEMBL)
PRKACG ProteinP22612 (Uniprot-TrEMBL)
PRKAR2A ProteinP13861 (Uniprot-TrEMBL)
PRKAR2A-PKA type IIComplexR-HSA-9010715 (Reactome)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMA8 ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB11 ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSME4 ProteinQ14997 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
PolyUb-ROBO1ProteinQ9Y6N7 (Uniprot-TrEMBL)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GDPComplexR-HSA-5674631 (Reactome)
RAC1:GTPComplexR-HSA-442641 (Reactome)
RBM8A ProteinQ9Y5S9 (Uniprot-TrEMBL)
RBX1 ProteinP62877 (Uniprot-TrEMBL)
RHO GTPases Activate ROCKsPathwayR-HSA-5627117 (Reactome) RHO associated, coiled-coil containing protein kinases ROCK1 and ROCK2 consist of a serine/threonine kinase domain, a coiled-coil region, a RHO-binding domain and a plekstrin homology (PH) domain interspersed with a cysteine-rich region. The PH domain inhibits the kinase activity of ROCKs by an intramolecular fold. ROCKs are activated by binding of the GTP-bound RHO GTPases RHOA, RHOB and RHOC to the RHO binding domain of ROCKs (Ishizaki et al. 1996, Leung et al. 1996), which disrupts the autoinhibitory fold. Once activated, ROCK1 and ROCK2 phosphorylate target proteins, many of which are involved in the stabilization of actin filaments and generation of actin-myosin contractile force. ROCKs phosphorylate LIM kinases LIMK1 and LIMK2, enabling LIMKs to phosphorylate cofilin, an actin depolymerizing factor, and thereby regulate the reorganization of the actin cytoskeleton (Ohashi et al. 2000, Sumi et al. 2001). ROCKs phosphorylate MRLC (myosin regulatory light chain), which stimulates the activity of non-muscle myosin II (NMM2), an actin-based motor protein involved in cell migration, polarity formation and cytokinesis (Amano et al. 1996, Riento and Ridley 2003, Watanabe et al. 2007, Amano et al. 2010). ROCKs also phosphorylate the myosin phosphatase targeting subunit (MYPT1) of MLC phosphatase, inhibiting the phosphatase activity and preventing dephosphorylation of MRLC. This pathway acts synergistically with phosphorylation of MRLC by ROCKs towards stimulation of non-muscle myosin II activity (Kimura et al. 1996, Amano et al. 2010).
RHO GTPases activate PAKsPathwayR-HSA-5627123 (Reactome) The PAKs (p21-activated kinases) are a family of serine/threonine kinases mainly implicated in cytoskeletal rearrangements. All PAKs share a conserved catalytic domain located at the carboxyl terminus and a highly conserved motif in the amino terminus known as p21-binding domain (PBD) or Cdc42/Rac interactive binding (CRIB) domain. There are six mammalian PAKs that can be divided into two classes: class I (or conventional) PAKs (PAK1-3) and class II PAKs (PAK4-6). Conventional PAKs are important regulators of cytoskeletal dynamics and cell motility and are additionally implicated in transcription through MAPK (mitogen-activated protein kinase) cascades, death and survival signaling and cell cycle progression (Chan and Manser 2012).

PAK1, PAK2 and PAK3 are direct effectors of RAC1 and CDC42 GTPases. RAC1 and CDC42 bind to the CRIB domain. This binding induces a conformational change that disrupts inactive PAK homodimers and relieves autoinhibition of the catalytic carboxyl terminal domain (Manser et al. 1994, Manser et al. 1995, Zhang et al. 1998, Lei et al. 2000, Parrini et al. 2002; reviewed by Daniels and Bokoch 1999, Szczepanowska 2009). Autophosphorylation of a conserved threonine residue in the catalytic domain of PAKs (T423 in PAK1, T402 in PAK2 and T436 in PAK3) is necessary for the kinase activity of PAK1, PAK2 and PAK3. Autophosphorylation of PAK1 serine residue S144, PAK2 serine residue S141, and PAK3 serine residue S154 disrupts association of PAKs with RAC1 or CDC42 and enhances kinase activity (Lei et al. 2000, Chong et al. 2001, Parrini et al. 2002, Jung and Traugh 2005, Wang et al. 2011). LIMK1 is one of the downstream targets of PAK1 and is activated through PAK1-mediated phosphorylation of the threonine residue T508 within its activation loop (Edwards et al. 1999). Further targets are the myosin regulatory light chain (MRLC), myosin light chain kinase (MLCK), filamin, cortactin, p41Arc (a subunit of the Arp2/3 complex), caldesmon, paxillin and RhoGDI, to mention a few (Szczepanowska 2009).

Class II PAKs also have a CRIB domain, but lack a defined autoinhibitory domain and proline-rich regions. They do not require GTPases for their kinase activity, but their interaction with RAC or CDC42 affects their subcellular localization. Only conventional PAKs will be annotated here.

RHOA ProteinP61586 (Uniprot-TrEMBL)
RHOA:GDPComplexR-HSA-8964174 (Reactome)
RHOA:GTPComplexR-HSA-5665993 (Reactome)
RNPS1 ProteinQ15287 (Uniprot-TrEMBL)
ROBO1 ProteinQ9Y6N7 (Uniprot-TrEMBL)
ROBO1 gene ProteinENSG00000169855 (Ensembl)
ROBO1 geneGeneProductENSG00000169855 (Ensembl)
ROBO1,ROBO2:Keratan sulfateComplexR-HSA-9014813 (Reactome)
ROBO1,ROBO2ComplexR-HSA-428477 (Reactome)
ROBO1:NRP1ComplexR-HSA-9010959 (Reactome)
ROBO1:SLIT2:ARHGAP39ComplexR-HSA-428491 (Reactome)
ROBO1:SLIT2ComplexR-HSA-390371 (Reactome)
ROBO1:SLITComplexR-HSA-204367 (Reactome)
ROBO1ProteinQ9Y6N7 (Uniprot-TrEMBL)
ROBO2 ProteinQ9HCK4 (Uniprot-TrEMBL)
ROBO2 gene ProteinENSG00000185008 (Ensembl)
ROBO2 geneGeneProductENSG00000185008 (Ensembl)
ROBO2,(ROBO1):ROBO3.1ComplexR-HSA-428496 (Reactome)
ROBO2,(ROBO1)ComplexR-HSA-9014787 (Reactome)
ROBO2:AKAP5:PPP3CBComplexR-HSA-9010760 (Reactome)
ROBO2:AKAP5:PRKAR2A-PKA type IIComplexR-HSA-9010716 (Reactome)
ROBO2:AKAP5:p-T497,T638,S657-PRKCAComplexR-HSA-9010732 (Reactome)
ROBO2:AKAP5ComplexR-HSA-9010687 (Reactome)
ROBO2:SLIT2ComplexR-HSA-9010899 (Reactome)
ROBO2ProteinQ9HCK4 (Uniprot-TrEMBL)
ROBO3 gene ProteinENSG00000154134 (Ensembl)
ROBO3 geneGeneProductENSG00000154134 (Ensembl)
ROBO3.1 ProteinQ96MS0-1 (Uniprot-TrEMBL)
ROBO3.1 mRNA ProteinENST00000397801 (Ensembl)
ROBO3.1 mRNA:MSI1ComplexR-HSA-9011401 (Reactome)
ROBO3.1 mRNARnaENST00000397801 (Ensembl)
ROBO3.1:AKAP5:p-T497,T638,S657-PRKCAComplexR-HSA-9010754 (Reactome)
ROBO3.1:AKAP5ComplexR-HSA-9010700 (Reactome)
ROBO3.1:DCC:NTN1ComplexR-HSA-9011213 (Reactome)
ROBO3.1:ZSWIM8-CUL2ComplexR-HSA-9011286 (Reactome)
ROBO3.1ProteinQ96MS0-1 (Uniprot-TrEMBL)
ROBO3.2 R-HSA-9014651 (Reactome)
ROBO3.2 mRNA R-HSA-9014585 (Reactome)
ROBO3.2 mRNAR-HSA-9014585 (Reactome)
ROBO3.2R-HSA-9014651 (Reactome)
ROBO3ComplexR-HSA-9014794 (Reactome)
RPL10 ProteinP27635 (Uniprot-TrEMBL)
RPL10A ProteinP62906 (Uniprot-TrEMBL)
RPL10L ProteinQ96L21 (Uniprot-TrEMBL)
RPL11 ProteinP62913 (Uniprot-TrEMBL)
RPL12 ProteinP30050 (Uniprot-TrEMBL)
RPL13 ProteinP26373 (Uniprot-TrEMBL)
RPL13A ProteinP40429 (Uniprot-TrEMBL)
RPL14 ProteinP50914 (Uniprot-TrEMBL)
RPL15 ProteinP61313 (Uniprot-TrEMBL)
RPL17 ProteinP18621 (Uniprot-TrEMBL)
RPL18 ProteinQ07020 (Uniprot-TrEMBL)
RPL18A ProteinQ02543 (Uniprot-TrEMBL)
RPL19 ProteinP84098 (Uniprot-TrEMBL)
RPL21 ProteinP46778 (Uniprot-TrEMBL)
RPL22 ProteinP35268 (Uniprot-TrEMBL)
RPL22L1 ProteinQ6P5R6 (Uniprot-TrEMBL)
RPL23 ProteinP62829 (Uniprot-TrEMBL)
RPL23A ProteinP62750 (Uniprot-TrEMBL)
RPL24 ProteinP83731 (Uniprot-TrEMBL)
RPL26 ProteinP61254 (Uniprot-TrEMBL)
RPL26L1 ProteinQ9UNX3 (Uniprot-TrEMBL)
RPL27 ProteinP61353 (Uniprot-TrEMBL)
RPL27A ProteinP46776 (Uniprot-TrEMBL)
RPL28 ProteinP46779 (Uniprot-TrEMBL)
RPL29 ProteinP47914 (Uniprot-TrEMBL)
RPL3 ProteinP39023 (Uniprot-TrEMBL)
RPL30 ProteinP62888 (Uniprot-TrEMBL)
RPL31 ProteinP62899 (Uniprot-TrEMBL)
RPL32 ProteinP62910 (Uniprot-TrEMBL)
RPL34 ProteinP49207 (Uniprot-TrEMBL)
RPL35 ProteinP42766 (Uniprot-TrEMBL)
RPL35A ProteinP18077 (Uniprot-TrEMBL)
RPL36 ProteinQ9Y3U8 (Uniprot-TrEMBL)
RPL36A ProteinP83881 (Uniprot-TrEMBL)
RPL36AL ProteinQ969Q0 (Uniprot-TrEMBL)
RPL37 ProteinP61927 (Uniprot-TrEMBL)
RPL37A ProteinP61513 (Uniprot-TrEMBL)
RPL38 ProteinP63173 (Uniprot-TrEMBL)
RPL39 ProteinP62891 (Uniprot-TrEMBL)
RPL39L ProteinQ96EH5 (Uniprot-TrEMBL)
RPL3L ProteinQ92901 (Uniprot-TrEMBL)
RPL4 ProteinP36578 (Uniprot-TrEMBL)
RPL40 ProteinP62987 (Uniprot-TrEMBL)
RPL41 ProteinP62945 (Uniprot-TrEMBL)
RPL5 ProteinP46777 (Uniprot-TrEMBL)
RPL6 ProteinQ02878 (Uniprot-TrEMBL)
RPL7 ProteinP18124 (Uniprot-TrEMBL)
RPL7A ProteinP62424 (Uniprot-TrEMBL)
RPL8 ProteinP62917 (Uniprot-TrEMBL)
RPL9 ProteinP32969 (Uniprot-TrEMBL)
RPLP0 ProteinP05388 (Uniprot-TrEMBL)
RPLP1 ProteinP05386 (Uniprot-TrEMBL)
RPLP2 ProteinP05387 (Uniprot-TrEMBL)
RPS10 ProteinP46783 (Uniprot-TrEMBL)
RPS11 ProteinP62280 (Uniprot-TrEMBL)
RPS12 ProteinP25398 (Uniprot-TrEMBL)
RPS13 ProteinP62277 (Uniprot-TrEMBL)
RPS14 ProteinP62263 (Uniprot-TrEMBL)
RPS15 ProteinP62841 (Uniprot-TrEMBL)
RPS15A ProteinP62244 (Uniprot-TrEMBL)
RPS16 ProteinP62249 (Uniprot-TrEMBL)
RPS17 ProteinP08708 (Uniprot-TrEMBL)
RPS18 ProteinP62269 (Uniprot-TrEMBL)
RPS19 ProteinP39019 (Uniprot-TrEMBL)
RPS2 ProteinP15880 (Uniprot-TrEMBL)
RPS20 ProteinP60866 (Uniprot-TrEMBL)
RPS21 ProteinP63220 (Uniprot-TrEMBL)
RPS23 ProteinP62266 (Uniprot-TrEMBL)
RPS24 ProteinP62847 (Uniprot-TrEMBL)
RPS25 ProteinP62851 (Uniprot-TrEMBL)
RPS26 ProteinP62854 (Uniprot-TrEMBL)
RPS27 ProteinP42677 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
RPS27A(77-156) ProteinP62979 (Uniprot-TrEMBL)
RPS27L ProteinQ71UM5 (Uniprot-TrEMBL)
RPS28 ProteinP62857 (Uniprot-TrEMBL)
RPS29 ProteinP62273 (Uniprot-TrEMBL)
RPS3 ProteinP23396 (Uniprot-TrEMBL)
RPS3A ProteinP61247 (Uniprot-TrEMBL)
RPS4X ProteinP62701 (Uniprot-TrEMBL)
RPS4Y1 ProteinP22090 (Uniprot-TrEMBL)
RPS4Y2 ProteinQ8TD47 (Uniprot-TrEMBL)
RPS5 ProteinP46782 (Uniprot-TrEMBL)
RPS6 ProteinP62753 (Uniprot-TrEMBL)
RPS7 ProteinP62081 (Uniprot-TrEMBL)
RPS8 ProteinP62241 (Uniprot-TrEMBL)
RPS9 ProteinP46781 (Uniprot-TrEMBL)
RPSA ProteinP08865 (Uniprot-TrEMBL)
SHFM1 ProteinP60896 (Uniprot-TrEMBL)
SLIT1 ProteinO75093 (Uniprot-TrEMBL)
SLIT1:COL4A5ComplexR-HSA-9010400 (Reactome)
SLIT1:ROBO1,ROBO2:NCK2ComplexR-HSA-8985808 (Reactome)
SLIT1:ROBO1,ROBO2ComplexR-HSA-8985807 (Reactome)
SLIT1:ROBO1:FLRT3ComplexR-HSA-9010236 (Reactome)
SLIT1:ROBO1ComplexR-HSA-9010245 (Reactome)
SLIT1ProteinO75093 (Uniprot-TrEMBL)
SLIT2 ProteinO94813 (Uniprot-TrEMBL)
SLIT2 gene ProteinENSG00000145147 (Ensembl)
SLIT2 geneGeneProductENSG00000145147 (Ensembl)
SLIT2(1122-1529) ProteinO94813 (Uniprot-TrEMBL)
SLIT2(1122-1529)ProteinO94813 (Uniprot-TrEMBL)
SLIT2(31-1121) ProteinO94813 (Uniprot-TrEMBL)
SLIT2(31-1121)ProteinO94813 (Uniprot-TrEMBL)
SLIT2,(SLIT3):Keratan sulfateComplexR-HSA-9010818 (Reactome)
SLIT2,(SLIT3)ComplexR-HSA-9010822 (Reactome)
SLIT2,SLIT2 cleavage fragments:GPC1:HSPGComplexR-HSA-428489 (Reactome)
SLIT2,SLIT2 cleavage fragmentsComplexR-HSA-9014805 (Reactome)
SLIT2:DystroglycanComplexR-HSA-9010869 (Reactome)
SLIT2:ROBO1:ABL:CAPComplexR-HSA-428875 (Reactome)
SLIT2:ROBO1:ABL:CLASPComplexR-HSA-428876 (Reactome)
SLIT2:ROBO1:ABLComplexR-HSA-428873 (Reactome)
SLIT2:ROBO1:Ena/VASP proteinsComplexR-HSA-376032 (Reactome)
SLIT2:ROBO1:Ena/VASP:PFNComplexR-HSA-428492 (Reactome)
SLIT2:ROBO1:MYO9BComplexR-HSA-8985583 (Reactome)
SLIT2:ROBO1:NCK:PAKComplexR-HSA-428482 (Reactome)
SLIT2:ROBO1:NCK:SOSComplexR-HSA-428481 (Reactome)
SLIT2:ROBO1:NCKComplexR-HSA-428486 (Reactome)
SLIT2:ROBO1:SRGAPComplexR-HSA-376031 (Reactome)
SLIT2:p-Y1073-ROBO1:ABLComplexR-HSA-376027 (Reactome)
SLIT2ProteinO94813 (Uniprot-TrEMBL)
SLIT3 ProteinO75094 (Uniprot-TrEMBL)
SLIT3:ROBO1,ROBO2ComplexR-HSA-9014835 (Reactome)
SLIT3ProteinO75094 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SOS2 ProteinQ07890 (Uniprot-TrEMBL)
SOSComplexR-HSA-167215 (Reactome)
SRGAP1 ProteinQ7Z6B7 (Uniprot-TrEMBL)
SRGAP2 ProteinO75044 (Uniprot-TrEMBL)
SRGAP3 ProteinO43295 (Uniprot-TrEMBL)
SRGAPComplexR-HSA-428474 (Reactome)
Translated ROBO3.2

mRNA in complex with NMD-initiating

UPF2
ComplexR-HSA-9014609 (Reactome)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UPF2 ProteinQ9HAU5 (Uniprot-TrEMBL)
UPF3A ProteinQ9H1J1 (Uniprot-TrEMBL)
UPF3B ProteinQ9BZI7 (Uniprot-TrEMBL)
USP33ProteinQ8TEY7 (Uniprot-TrEMBL)
Ub-ROBO3.1 ProteinQ96MS0-1 (Uniprot-TrEMBL)
Ub-ROBO3.1:ZSWIM8-CUL2ComplexR-HSA-9011309 (Reactome)
UbComplexR-HSA-113595 (Reactome)
Unidentified proteaseR-HSA-428470 (Reactome)
VASP ProteinP50552 (Uniprot-TrEMBL)
ZSWIM8 ProteinA7E2V4 (Uniprot-TrEMBL)
ZSWIM8-CUL2 E3 ubiquitin ligaseComplexR-HSA-9011265 (Reactome)
eRF3:GDPComplexR-HSA-143378 (Reactome)
p-S1330-ROBO3.1 ProteinQ96MS0-1 (Uniprot-TrEMBL)
p-S1330-ROBO3.1:AKAP5:p-T497,T638,S657-PRKCAComplexR-HSA-9010778 (Reactome)
p-T497,T638,S657-PRKCA ProteinP17252 (Uniprot-TrEMBL)
p-T497,T638,S657-PRKCAProteinP17252 (Uniprot-TrEMBL)
p-Y1019-ROBO3.1 ProteinQ96MS0-1 (Uniprot-TrEMBL)
p-Y1019-ROBO3.1:DCC:NTN1ComplexR-HSA-9011242 (Reactome)
p-Y1073-ROBO1 ProteinQ9Y6N7 (Uniprot-TrEMBL)
tRNA R-HSA-141679 (Reactome)
tRNAR-HSA-141679 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
26S proteasomemim-catalysisR-HSA-9011313 (Reactome)
80S ribosomeR-HSA-9014610 (Reactome)
ABLR-HSA-376141 (Reactome)
ADPArrowR-HSA-428888 (Reactome)
ADPArrowR-HSA-9010681 (Reactome)
ADPArrowR-HSA-9011241 (Reactome)
AKAP5R-HSA-9010647 (Reactome)
AKAP5R-HSA-9010648 (Reactome)
ARHGAP39R-HSA-428536 (Reactome)
ATPR-HSA-428888 (Reactome)
ATPR-HSA-9010681 (Reactome)
ATPR-HSA-9011241 (Reactome)
CAPR-HSA-428883 (Reactome)
CDC42:GDPArrowR-HSA-428533 (Reactome)
CDC42:GTPR-HSA-428533 (Reactome)
CLASPR-HSA-428885 (Reactome)
CXCL12:CXCR4:ROBO1:SLIT2ArrowR-HSA-8986258 (Reactome)
CXCR4:CXCL12R-HSA-8986258 (Reactome)
Cap Binding Complex (CBC)R-HSA-9014610 (Reactome)
Collagen alpha-5(IV) chainsR-HSA-9010396 (Reactome)
DCC:NTN1R-HSA-9011224 (Reactome)
DCC:ROBO1:SLITArrowR-HSA-373715 (Reactome)
DCCR-HSA-373715 (Reactome)
DystroglycanR-HSA-9010872 (Reactome)
EIF4G1R-HSA-9014610 (Reactome)
ETF1R-HSA-9014610 (Reactome)
Ena/VASP ProteinsR-HSA-376140 (Reactome)
Exon

Junction:UPF2:UPF3

Complex
R-HSA-9014610 (Reactome)
FLRT3R-HSA-9010231 (Reactome)
GDPArrowR-HSA-428535 (Reactome)
GPC1:HSPGR-HSA-428518 (Reactome)
GTPR-HSA-428535 (Reactome)
H2OR-HSA-428522 (Reactome)
H2OR-HSA-428533 (Reactome)
H2OR-HSA-8985594 (Reactome)
H2OR-HSA-8986083 (Reactome)
HOXA2:ROBO2 geneArrowR-HSA-9010503 (Reactome)
HOXA2:ROBO2 geneArrowR-HSA-9010523 (Reactome)
HOXA2R-HSA-9010503 (Reactome)
ISL1:LHX3/4:LDB1:SLIT2 geneArrowR-HSA-9010539 (Reactome)
ISL1:LHX3/4:LDB1:SLIT2 geneArrowR-HSA-9010541 (Reactome)
ISL1:LHX3/4:LDB1R-HSA-9010541 (Reactome)
Keratan sulfateR-HSA-9010815 (Reactome)
Keratan sulfateR-HSA-9014812 (Reactome)
LHX2,(LHX9):ROBO3 geneArrowR-HSA-9011143 (Reactome)
LHX2,(LHX9):ROBO3 geneArrowR-HSA-9011145 (Reactome)
LHX2,(LHX9)R-HSA-9011145 (Reactome)
LHX2:ROBO1 geneArrowR-HSA-9011074 (Reactome)
LHX2:ROBO1 geneTBarR-HSA-9011083 (Reactome)
LHX2:ROBO2 geneArrowR-HSA-9011077 (Reactome)
LHX2:ROBO2 geneTBarR-HSA-9010523 (Reactome)
LHX2R-HSA-9011074 (Reactome)
LHX2R-HSA-9011077 (Reactome)
MSI1R-HSA-9011346 (Reactome)
MYO9BR-HSA-8985591 (Reactome)
MYO9Bmim-catalysisR-HSA-8985594 (Reactome)
MyrG-p-Y419-SRCmim-catalysisR-HSA-9011241 (Reactome)
NCK1,NCK2R-HSA-428511 (Reactome)
NCK2R-HSA-8985812 (Reactome)
NELL2:ROBO3ArrowR-HSA-9010190 (Reactome)
NELL2R-HSA-9010190 (Reactome)
NRP1R-HSA-9010951 (Reactome)
PABPC1R-HSA-9014610 (Reactome)
PAKR-HSA-428531 (Reactome)
PFNR-HSA-428534 (Reactome)
PPP3CBR-HSA-9010645 (Reactome)
PRKAR2A-PKA type IIR-HSA-9010641 (Reactome)
PiArrowR-HSA-428522 (Reactome)
PiArrowR-HSA-428533 (Reactome)
PiArrowR-HSA-8985594 (Reactome)
PolyUb-ROBO1R-HSA-8986083 (Reactome)
R-HSA-204364 (Reactome) SLIT2 ligand forms a complex with the ROBO1 receptor (Brose et al. 1999). The SLIT family consists of three members that are all expressed in the ventral midline (floor plate) of the neural tube. SLIT1 is predominantly expressed in the nervous system whereas SLIT2 and SLIT3 are also expressed outside the nervous system.
SLIT proteins are the ligands for the ROBO receptors. In humans, there are four ROBO genes: ROBO1, ROBO2, ROBO3 and ROBO4. The extracellular domain of ROBO comprises five Ig domains and three FN domains except for ROBO4 (two Ig + two FN). Ig1 and Ig2 domains of ROBO1 and ROBO2 are highly conserved and are important for SLIT binding. The concave face of SLIT's second LRR domain accommodates the Ig1 and Ig2 domains of ROBO1 and ROBO2. ROBO3 does not bind SLITs (Camurri et al. 2005, Mambetisaeva et al. 2005, Zelina et al. 2014, 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).
R-HSA-373715 (Reactome) DCC and ROBO1 heterodimerize via conserved sequence elements in their cytoplasmic domains, namely CC1 (conserved cytoplasmic region1) in ROBO1 and P3 in DCC. The formation of this complex is dependent on the previous interaction between ROBO and its ligand (SLIT). This physical interaction between ROBO:SLIT and DCC silences the attractive effect of Netrin:DCC and regulates the midline crossing of axons.
From the analysis of multiple double mutant combinations of the ROBO:SLIT and Netrin:DCC receptor-ligand pairs, it was deduced that ROBO repulsion on its own is sufficient to prevent commissural axons from re-crossing the midline, and that Netrin:DCC is not the only source of attraction at the midline (Stein and Tessier-Lavigne 2001, Garbe and Bashaw 2007).
R-HSA-376140 (Reactome) Ena/VASP proteins (ENAH, EVL and VASP) are required in part for ROBO's repulsive output. Ena/VASP proteins are drawn as effectors downstream of Robo signaling via a direct interaction with ROBO. ROBO's CC2 (LPPPP) motif is the consensus binding site for the EVH1 domain of Ena/VASP proteins.
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 (PFN), as well as several SH3 domain-containing proteins, such as ABL, and a C-terminal EVH2 domain involved in oligomerization and F-actin binding (Bashaw et al. 2000).
R-HSA-376141 (Reactome) ABL (ABL1 or ABL2) binds directly, via its SH3 domain, to the CC3 motif in the cytoplasmic domain of human ROBO1 (Bashaw et al. 2000).
R-HSA-376145 (Reactome) The ROBO1 receptor regulates Rho GTPase activity through a ligand-dependent association with members of a GAP protein family called SRGAPs (SLIT-ROBO GAPs), SRGAP1, SRGAP2 and SRGAP3 (Wong et al. 2001, Bacon et al. 2011). Extracellular interaction between SLIT and ROBO increases the intracellular interaction between the CC3 motif of ROBO1 and the SH3 motif of the SRGAPs (Wong et al. 2001).
R-HSA-376149 (Reactome) The full length SLIT proteins are membrane bound via the extracellular matrix proteins when not bound to ROBO receptors. These full length SLITs undergo posttranslational modification and proteolytic processing to generate an N-terminal fragment (SLIT2-N) and a corresponding C-terminal fragment (SLIT2-C). SLIT2 is cleaved within the EGF repeats, between EGF5 and EGF6, by unknown proteases. Cleavage of SLIT proteins is evolutionarily conserved, although the molecular biological significance is unknown. The N-terminal fragment of SLIT2 stimulates growth and branching of dorsal root ganglia (DRG) axons, and this activity is opposed by un-cleaved SLIT. The stimulation of axon branching is mediated by ROBO receptors. Additional functional differences between the full-length and N-terminal forms have been discovered in their abilities to repel different populations of axons and dendrites. Finally, SLIT can attract migrating muscles in the fly, and also human endothelial cells, both via ROBO receptors (Brose et al. 1999, Wang et al. 1999).

SLIT C-terminal fragments may transduce signaling independently of ROBO receptors and Neuropilins (semaphorin receptors) by directly binding to Plexin A1. This process will be annotated in future Reactome releases (Delloye-Bourgeois et al. 2015).

R-HSA-428510 (Reactome) ROBO3 antagonizes ROBO1/ROBO2 function to prevent their response to SLIT, thus allowing cells that are expressing ROBO1/ROBO2 to progress towards and across the floor plate. Exactly how ROBO3 interferes with ROBO1/ROBO2 function is not yet clear (Chen et al. 2008). It was shown that ROBO3 isoform ROBO3.1 reduces the amount of ROBO1 and ROBO2 at the cell surface and suggested that ROBO3.1 acts by directing ROBO1 and ROBO2 to late endosome- and lysosome-dependent degradation pathway (Li et al. 2014). Direct binding of ROBO3.1 to ROBO2 was demonstrated (Li et al. 2014).

During commissural axon midline crossing in Drosophila, Robo1 signaling can also be antagonized with Robo2 expressed in trans. Extracellular domains of Robo1 and Robo2 may interact through their Ig domains, preventing Robo1 activation by Slits and interfering with axon repulsion (Evans et al. 2015).

R-HSA-428511 (Reactome) SLIT stimulation recruits SH3-SH2 adaptor protein Dreadlocks (Dock) (NCK in vertebrates) to the ROBO1 receptor. This interaction involves the CC2 and CC3 motifs of ROBO1 (Fan et al. 2003, Ang et al. 2003).
R-HSA-428515 (Reactome) Upon SLIT-mediated ROBO stimulation, SOS1 or SOS2 is recruited into the multiprotein complex consisting of SLIT2, ROBO1 and the SH3-SH2 protein NCK1 or NCK2 (orthologues of Drosophila Dock). NCK bridges the physical association between ROBO and SOS. This interaction was demonstrated in both Drosophila and human cells (Hu et al. 1995, Fritz et al. 2000, Yang and Bashaw 2006).
R-HSA-428518 (Reactome) SLIT2 and both its natural cleavage products bind glypican-1 (GPC1), a glycosyl phosphatidyl inositol (GPI) anchored heparan sulfate proteoglycan (HSPG), through its C-terminus. Besides glypican-1, other HSPG may also be involved in SLIT2 binding. GPC1:HSPG is important for high affinity binding of SLIT to its receptor and for the repulsive activity of SLIT. SLIT-ROBO signaling strictly requires binding to heparan sulfate. HSPGs may also modulate the extracellular distribution or stability of SLIT proteins (Ronca et al. 2001, Zhang et al. 2004).
R-HSA-428522 (Reactome) Vilse and its human homolog ARHGAP39 bind directly to the intracellular domains of the corresponding ROBO receptors and promote the hydrolysis of GTP bound to RAC1 (Lundstrom et al. 2004, Hu et al. 2005).
R-HSA-428531 (Reactome) NCK1 or NCK2, orthologues of Drosophila Dock, bound to ROBO1 receptor, recruits PAK to specific sites at the growth cone membrane, where PAK, activated by RAC1, regulates the recycling and retrograde flow of actin filaments. In mammals, there are six PAK isoforms (PAK1-6) and PAK binds to the 2nd SH3 domain of NCK with its proline rich PxxP motif (Galisteo et al. 1996, Fan et al. 2003). PAK autophosphorylation triggered by RAC1/CDC42 activation disrupts PAK interaction with NCK proteins (Zhao et al. 2000).
R-HSA-428533 (Reactome) SRGAP bound to ROBO's cytoplasmic tail increases the intrinsic GTPase activity of CDC42, converting the GTP-bound form of CDC42 into its GDP-bound form, therefore inactivating CDC42. Inactivation of CDC42 leads to a reduction in the activation of the Neuronal Wiskott-Aldrich Syndrome protein (NWASP), thus decreasing the level of the active Arp2/3 complex. Because active Arp2/3 promotes actin polymerization, the reduction of active CDC42 eventually decreases actin polymerization. SLIT regulates SRGAP interaction with ROBO1 and CDC42, increasing SRGAP binding to CDC42 (Wong et al. 2001, Li et al. 2006).
R-HSA-428534 (Reactome) Ena/VASP proteins (ENAH, EVL1 and VASP) enhance actin filament elongation via the recruitment of profilin:actin complexes to the tips of spreading lamellipodia. Profilin (PFN1 or PFN2) binds to the central proline rich domain of an Ena/VASP protein (Bashaw et al. 2000).
R-HSA-428535 (Reactome) SOS (SOS1 or SOS2), bound to Dock orholog NCK (NCK1 or NCK2), has a Rac GEF activity and activates RAC1. Son of sevenless (SOS) is a dual specificity guanine nucleotide exchange factor (GEF) that regulates both Ras and Rho family GTPases. The Ras and Rac-GEF activities of Sos can be uncoupled during ROBO-mediated axon repulsion; SOS axon guidance function depends on its Rac-GEF activity, but not its Ras-GEF activity (Yang and Bashaw 2006).
R-HSA-428536 (Reactome) Vilse/CrossGAP (CrGAP), a conserved Rac-specific GAP in Drosophila, is involved in Robo mediated repulsion. CrGAP directly interacts with Robo, both biochemically and genetically. The biochemical interaction is mediated by the WW domains in CrGAP and the CC2 motif of Robo.
The human homologue of Vilse/CrGAP, ARHGAP39 (also known as KIAA1688), was identified. ARHGAP39 shares 54.4% sequence identity with Drosophila CrGAP and is referred to as human Vilse/CrGAP protein (Lundstrom et al. 2004, Hu et al. 2005).
R-HSA-428883 (Reactome) ABL (ABL1 or ABL2) associated with the complex of ROBO1, SLIT2, and glypican-1 (GPC1) at the plasma membrane binds CAP (CAP1 or CAP2) and regulates its activity to inhibit net actin assembly. Studies of CAP homologs from yeast, Dictyostelium, mouse, pig, and human suggest that the C-terminal actin binding domain acts to sequester actin monomers to prevent actin polymerization (Wills et al. 2002).
R-HSA-428885 (Reactome) CLASP (CLASP1 or CLASP2) acts positively downstream of ABL (ABL1 or ABL2) as part of the repellent response initiated by activation of ROBO1. CLASP is spatially positioned to interact with ROBO receptors. SLIT mediated repulsion results in activation of CLASP, presumably through its phosphorylation by the ABL kinase. Activation of CLASP in turn results in inhibition of microtubule polymerization on the side of the growth cone receiving the repulsive signal and consequently the growth cone turns to the opposite side. A direct link between ABL and CLASP, notably the mechanism of CLASP activation, has not been demonstrated, however (Wills et al. 2002, Lee et al. 2004, Kalil and Dent 2004).
R-HSA-428888 (Reactome) ABL kinase (ABL1 or ABL2) phosphorylates the tyrosine residue Y1073 of the conserved CC1 motif (PTPYATT) in human ROBO1 (Bashaw et al. 2000).
R-HSA-8985591 (Reactome) ROBO1, bound to SLIT2, binds to the RHO GAP protein MYO9B. The interaction involves all four cytoplasmic conserved (CC) motifs in the intracellular domain of ROBO1 and the RHO GAP domain of MYO9B. Binding to ROBO1 inhibits the RHOA GAP activity of MYO9B and increases the amount of active GTP-bound RHOA (RHOA:GTP). ROBO1-mediated inhibition of MYO9B and the resulting increase in RHOA activity is implicated as a negative regulator of invasiveness of lung cancer cells (Kong et al. 2015).
R-HSA-8985594 (Reactome) MYO9B (MYR5) is a RHO GAP protein that stimulates RHOA GTPase activity, resulting in hydrolysis of RHOA bound GTP to GDP, and conversion of the active form of RHOA, RHOA:GTP, to the inactive form, RHOA:GDP (Post et al. 1998, Graf et al. 2000, Kong et al. 2015). MYO9B does not act on CDC42 and RAC1. The GAP activity of MYO9B is inhibited by binding to ROBO1 receptor activated by SLIT2 (Kong et al. 2015).
R-HSA-8985799 (Reactome) Based on mouse experiments, SLIT1 binds to ROBO1 and/or ROBO2 to stimulate cortical dendrite branching (Round and Sun 2011). SLIT1-mediated activation of ROBO1 and/or ROBO2 may also be involved in regulation of midline crossing in the spinal cord (Mambetisaeva et al. 2015). SLIT1 is expressed by new neurons in the adult brain which migrate from the subventricular zone to the olfactory bulb through the rostral migratory stream. Astrocytes in the rostral migratory stream express ROBO receptors, mostly ROBO2, but also ROBO1 and ROBO3. These ROBO-expressing astrocytes are repelled by SLIT1-expressing young migrating neurons, which results in the formation and maintenance of the astrocytic tunnels. Astrocytic tunnels allow rapid directional migration of new neurons in the adult brain (Kaneko et al. 2010). Signaling through SLIT1-ROBO2 is implicated in regulation of peripheral nerve regeneration (Zhang et al. 2010).
R-HSA-8985812 (Reactome) Based on mouse experiments, SLIT1-activated ROBO receptors ROBO1 and/or ROBO2 bind to NCK2. The interaction involves three SH3 domains of NCK2 and the PxxP-rich region between CC2 and CC3 motifs in the cytoplasmic domain of ROBO. While NCK1 can also associate with ROBO receptors, only NCK2 is implicated in SLIT1-induced cortical dendrite branching (Round and Sun 2011).
R-HSA-8986083 (Reactome) The ubiquitin protease USP33 deubiquitinates ROBO1, thus stabilizing it and increasing the concentration of ROBO1 at the plasma membrane (Yuasa-Kawada et al. 2009, Huang et al. 2015). USP33 is frequently downregulated in colorectal cancer, which is associated with lymph node metastasis and poor survival (Huang et al. 2015). USP33 is required for SLIT-ROBO1-mediated inhibition of breast cancer cell migration (Yuasa-Kawada et al. 2009). Ubiquitin ligases that ubiquitinate ROBO1 are not known.
R-HSA-8986258 (Reactome) SLIT2-activated ROBO1 receptor can form a complex with a G-protein coupled receptor (GPCR) CXCR4 (Prasad et al. 2007), resulting in downregulation of CXCR4 signaling (Prasad et al. 2004, Prasad et al. 2007). Formation of the complex between ROBO1 and CXCR4, which involves the CC3 motif of ROBO1, does not interfere with CXCR4 binding to its ligand, CXCL12 (Prasad et al. 2007). SLIT-ROBO signaling may also downregulate CXCR4 expression (Marlow et al. 2008). Downregulation of CXCL12-CXCR4 signaling is thought to contribute to SLIT-ROBO-mediated inhibition of cell migration (Prasad et al. 2004, Prasad et al. 2007, Marlow et al. 2008).
R-HSA-9010190 (Reactome) Based on studies in mice, ROBO3 isoforms ROBO3.1 and ROBO3.2 bind to a secreted ligand NELL2 (neural epidermal growth factor-like-like 2). This interaction involves the EGF-like domains of NELL2 and the FN3 (FNIII) domain of ROBO3. Pre-crossing commissural axons which express ROBO3.1 are repelled by NELL2. Post-crossing axons, which express ROBO3 isoform ROBO3.2 are not repelled by NELL2, despite interaction between ROBO3.2 and NELL2. NELL1 can also bind to both ROBO3.1 and ROBO3.2, but since NELL1 is not expressed in mouse spinal cord during commissural axon guidance, these interactions are not considered to be physiologically relevant. ROBO1 and ROBO2 do not interact with NELL proteins (Jaworski et al. 2015).
R-HSA-9010231 (Reactome) Based on studies in mice, ROBO1, activated by SLIT1 binding, forms a complex with FLRT3. This interaction involves the intracellular domains of FLRT3 and ROBO1. FLRT3 is a member of the fibronectin leucine-rich repeat transmembrane protein family. The interaction of FLRT3 and ROBO1 in the presence of SLIT1 increases Netrin-1 attraction of thalamocortical axons by increasing the amount of DCC receptors at the plasma membrane via an unknown mechanism that may involve PKA activation (Leyva-Diaz et al. 2014).
R-HSA-9010396 (Reactome) Based on studies in zebrafish, SLIT1 binds to a type IV collagen COL4A5, which forms the basement membrane on the surface of the optical tectum. COL4A5 and HSPGs may act synergistically to anchor SLIT1 in the basement membrane. ROBO2 receptor is required for lamina-specific axon pathfinding of retinal ganglion cells in the optical tectum (Xiao et al. 2011).
R-HSA-9010503 (Reactome) Based on studies in mice, the homeobox transcription factor HOXA2 binds to an evolutionarily conserved (also present in the human gene) HOX-PBX binding site in the second intron of the ROBO2 gene (Geisen et al. 2008). The heterodimerization partner of HOXA2 at the ROBO2 gene binding site is not known.
R-HSA-9010523 (Reactome) Based on studies in mice, the homeobox transcription factor HOXA2, which directly binds to an evolutionarily conserved site in the second intron of the ROBO2 gene, is needed for the maintenance of ROBO2 expression during pontine neuron migration (Geisen et al. 2008).

Also based on mouse studies, LHX2, a LIM-homeodomain transcription factor, directly represses transcription of the ROBO2 gene by binding to evolutionarily conserved LHX2 binding sites about 50 kb downstream from the ROBO2 gene transcription start site. LHX2 is involved in thalamocortical axon guidance (Marcos-Mondejar et al. 2012). In commissural relay neurons of the dorsal spinal cord, however, ROBO2 expression is not affected by LHX2 (Wilson et al. 2008).

In zebrafish, transcription of Robo2 is directly stimulated by Mecp2 (Leong et al. 2015).

R-HSA-9010539 (Reactome) Based on studies in mice, the transcription factor ISL1, in complex with either LHX3 or LHX4, directly stimulates transcription of the SLIT2 gene. ISL1-mediated regulation of SLIT2 gene transcription in branchiomotor (BM) neurons and somatic motor (SM) neurons involves LHX4 and LHX3, respectively (Kim et al. 2016). Slit2 expression is diminished in Isl1 mutant mice (Lee et al. 2015).

SLIT2 is one of gene suggested to be repressed by the transcription factor ARX, involved in neuronal proliferation, migration, maturation and differentiation, as well as axon guidance (reviewed by Friocourt and Parnavelas, 2011).

R-HSA-9010541 (Reactome) Based on studies in mice, the transcription factor ISL1, in complex with either LHX3 or LHX4, binds to an evolutionarily conserved LIM-HD binding site in the enhancer of the SLIT2 gene, located in the sixth intron of the SLIT2 gene. The complex of ISL1 and LHX4 regulates SLIT2 expression in branchiomotor neurons, while the complex of ISL1 and LHX3 regulates SLIT2 expression in somatic motor neurons (Kim et al. 2016). From the previous structural studies of the ISL1 complex with LHX3, conducted using mouse and rat proteins, it is known that LDB1 is also part of this complex (Thaler et al. 2002).
R-HSA-9010641 (Reactome) Based on studies in mice, AKAP5 (also known as AKAP79) recruits protein kinase A (PKA) to the ROBO2 receptor, by interacting with the PKA regulatory subunit RIIalpha (Samelson et al. 2015).
R-HSA-9010643 (Reactome) Based on studies in mice, AKAP5 (also known as AKAP79) recruits activated protein kinase C - PRKCA and possibly other isoforms - to the ROBO2 receptor. This interaction was also confirmed using recombinant human AKAP5 and mouse Robo2 (Samelson et al. 2015).
R-HSA-9010645 (Reactome) Based on studies in mice, AKAP5 (also known as AKAP79) recruits protein phosphatase PP2B subunit B (PPP3CB) to ROBO2 receptor. It is not known whether prior binding of PPP3CB to calcium-activated calmodulin is needed for this interaction to occur (Samelson et al. 2015).
R-HSA-9010646 (Reactome) AKAP5 (also known as AKAP79) recruits activated protein kinase C - PRKCA and possibly other isoforms - to the ROBO3 receptor isoform ROBO3.1 (Samelson et al. 2015).
R-HSA-9010647 (Reactome) AKAP5 (also known as AKAP79) forms a complex with the ROBO3 receptor isoform ROBO3.1 (Samelson et al. 2015).
R-HSA-9010648 (Reactome) Based on studies in mice, AKAP5 (also known as AKAP79), an A-kinase anchoring protein, forms a complex with ROBO2. The interaction involves the intracellular domain of ROBO2. It has not been investigated whether SLIT-mediated activation of ROBO2 is needed for this interaction (Samelson et al. 2015).
R-HSA-9010681 (Reactome) PKC (PRKCA, and possibly other isoforms), recruited to ROBO3 receptor isoform ROBO3.1 by AKAP5 (AKAP79) phosphorylates ROBO3.1 on serine residue S1330 (Samelson et al. 2015).
R-HSA-9010815 (Reactome) SLIT2 is expressed by corneal epithelial cells and able to bind to keratan sulfate, which is part of the corneal stroma extracellular matrix. This interaction may influence corneal nerve growth cone penetration. SLIT3 may also interact with keratan sulfate, as well as ROBO receptors ROBO1 and ROBO2 (Conrad et al. 2010).
R-HSA-9010872 (Reactome) SLIT2 binds to dystroglycan (DAG1). The interaction involves the C-terminal region of human SLIT2. The species origin of the DAG1 construct was not specified and is assumed to be human. Dystroglycan is required for proper SLIT2 localization within the basement membrane and the floor plate. Dystroglycan glycosylation, mediated at least in part by B4GAT1 (B3GNT1) and ISPD, is likely required for its interaction with SLIT2, but it has not been annotated. Mice mutant for B4gat1, Ispd or Dag1 have axon guidance defects similar to those observed in Slit or Robo mutant mice (Wright et al. 2012).
R-HSA-9010898 (Reactome) ROBO2 receptor binds to SLIT2 ligand (Brose et al. 1999, Nguyen Ba-Charvet et al. 2001).
R-HSA-9010951 (Reactome) Based on studies in mice, ROBO1 binds semaphorin receptor NRP1. Other NRP1-binding proteins, such as NRP2, Plexin A1 and Plexin A2, also co-immunoprecipitate with ROBO1, but it is thought that the direct interaction involves ROBO1 and NRP1 only. ROBO1 binds to NRP1 via Ig1and Ig2 domains in the extracellular region of ROBO1. Interaction with ROBO1 may increase the stability of NRP1 and NRP1-associated proteins, or increase their abundance at the plasma membrane. Semaphorins direct the migration of cortical interneurons, and mice deficient in Robo1 function show reduced responsiveness of cortical interneurons to semaphorins (Hernandez-Miranda et al. 2011).
R-HSA-9011074 (Reactome) Based on studies in mice, a LIM-homeodomain transcription factor LHX2 binds to evolutionarily conserved LHX2 binding elements about 30 kb downstream from the ROBO1 gene transcription start site (Marcos-Mondejar et al. 2012).
R-HSA-9011077 (Reactome) Based on studies in mice, a LIM-homeodomain transcription factor LHX2 binds to evolutionarily conserved LHX2 binding elements about 50 kb downstream from the ROBO2 gene transcription start site (Marcos-Mondejar et al. 2012).
R-HSA-9011083 (Reactome) Based on studies in mice, LHX2, a LIM-homeodomain transcription factor, directly represses transcription of the ROBO1 gene by binding to evolutionarily conserved LHX2 binding sites upstream of the ROBO1 gene promoter region. LHX2 is involved in thalamocortical axon guidance (Marcos-Mondejar et al. 2012). In commissural relay neurons of the dorsal spinal cord, however, ROBO1 expression is not affected by LHX2 (Wilson et al. 2008).

Transcription factors GBX2 and LMO3 may be indirectly involved in ROBO1 gene expression regulation by LHX2 (Chatterjee et al. 2012).

R-HSA-9011143 (Reactome) Based on studies in mice, expression of the ROBO3.1 isoform from the ROBO3 gene is directly stimulated by LHX2 and possibly LHX9. LHX2/9-mediated regulation of ROBO3.1 levels is involved in midline crossing by commissural relay neurons of the dorsal spinal cord (Wilson et al. 2008). ROBO3.1 levels, however, seem to be unaffected by LHX2 in thalamocortical neurons (Marcos-Mondejar et al. 2012).
R-HSA-9011145 (Reactome) Based on studies in mice, a LIM-homeodomain transcription factor LHX2, and possibly LHX9, binds to conserved LHX2 binding elements in the promoter region of the ROBO3 gene (Wilson et al. 2008).
R-HSA-9011224 (Reactome) Based on studies in mice and biochemical studies with human DCC and mouse Robo3.1, ROBO3.1 (also known as ROBO3A.1) can bind to DCC both in the presence and absence of netrin-1 (NTN1). The two proteins interact via their intracellular domains through the P3 domain of DCC and the CC2 and CC3 motifs of ROBO3. Binding of ROBO3.1 to DCC apparently contributes to NTN1-mediated attraction of commissural axons to the midline (Zelina et al. 2014).
R-HSA-9011241 (Reactome) In response to NTN1 (netrin-1)-mediated activation of DCC, based on mouse studies, SRC phosphorylates ROBO3.1 on a conserved tyrosine Y1019. The mechanism of SRC recruitment to ROBO3.1 in response to NTN1 is not known (Zelina et al. 2014). The biological significance of SRC-mediated phosphorylation of ROBO3.1 is not known.
R-HSA-9011289 (Reactome) Based on studies in C. elegans and with recombinant human and mouse proteins, ZSWIM8 and its C. elegans orthologue EBAX-1 are predicted to be an E3 ubiquitin ligase component of the CUL2 ubiquitin ligase complex. ZSWIM8 co-immunoprecipitates with the CUL2 ubiquitin ligase complex components Elongin-B (ELOB) and Elongin-C (ELOC). The BC-box and Cul2-box of ZSWIM8 are needed for interaction with ELOB and ELOC, implying the presence of other CUL2 complex components in the complex of ZSWIM8, ELOB and ELOC. ZSWIM8 binds to wild-type ROBO3.1, but preferentially associates with misfolded or mutant ROBO3.1 proteins, suggesting that it is involved in the quality control of ROBO3.1 (Wang et al. 2013).
R-HSA-9011300 (Reactome) Based on studies with C. elegans proteins, ZSWIM8 (orthologue of C. elegans EBAX-1) promotes ubiquitination of ROBO3.1 (orthologue of C. elegans SAX-3) (Wang et al. 2013).
R-HSA-9011313 (Reactome) Based on studies using recombinant C. elegans proteins expressed in human 293T cells, ZSWIM8-mediated ubiquitination of ROBO3.1 targets ROBO3.1 for proteasome-mediated degradation (Wang et al. 2013).
R-HSA-9011346 (Reactome) Based on studies in mice, MSI1, and RNA-binding protein, binds to ROBO3.1 mRNA (Kuwako et al. 2010).
R-HSA-9011347 (Reactome) Based on studies in mice, binding of MSI1 to ROBO3.1 mRNA positively regulates ROBO3.1 mRNA translation, resulting in increased levels of ROBO3.1 protein. Similar to Robo3 knockout mice, Msi1 knockout mice also show sever abnormalities in axonal midline crossing and migration of precerebellar neurons (Kuwako et al. 2010).
R-HSA-9014587 (Reactome) Based on studies in mice, a transcript variant ROBO3.2 is produced from nascent ROBO3 mRNA by alternative splicing. Existence of this splicing isoform is predicted to be conserved in humans and rats. The alternative splicing results in retention of the intronic sequence between exons 26 and 27, which creates a premature stop codon. While Robo3.1 mouse mRNA is expressed in the pre-crossing and crossing commissural axons, Robo3.2 mRNA is expressed after midline crossing and thought to block midline re-crossing (Chen et al. 2008).
R-HSA-9014610 (Reactome) Based on studies in mice, ROBO3.2 mRNA, which contains a premature stop codon, is recognized by components of the nonsense mediated decay (NMD) machinery during translation. Association of ROBO3.2 mRNA with UPF2 and UPF1 was directly demonstrated in mouse cells, and presence of other translation and NMD components is assumed (Colak et al. 2013). In this step, we only show association of ROBO3.2 mRNA with the UPF2-containing exon junction complex. For detailed representation of UPF2 and UPF1 in NMD, please refer to the Reactome pathway 'Nonsense Mediated Decay (NMD)'.
R-HSA-9014652 (Reactome) Based on studies in mice, translation of ROBO3.2 mRNA in commissural axons at the floor plate is negatively regulated by nonsense mediated decay (NMD). Deficiency of NMD components results in aberrant axonal trajectories after crossing the midline (Colak et al. 2013).
R-HSA-9014812 (Reactome) ROBO receptors ROBO1 and ROBO2 interact with keratan sulfate through their extracellular regions (Conrad et al. 2010).
R-HSA-9014834 (Reactome) Based on studies in mice, SLIT3 can bind to both ROBO1 and ROBO2 receptors (Mommersteeg et al. 2013). The interaction between SLIT3 and ROBO2 contributes to targeting of axons of olfactory sensory neurons (Cho et al. 2012).
RAC1:GDPArrowR-HSA-428522 (Reactome)
RAC1:GDPR-HSA-428535 (Reactome)
RAC1:GTPArrowR-HSA-428535 (Reactome)
RAC1:GTPR-HSA-428522 (Reactome)
RHOA:GDPArrowR-HSA-8985594 (Reactome)
RHOA:GTPR-HSA-8985594 (Reactome)
ROBO1 geneR-HSA-9011074 (Reactome)
ROBO1 geneR-HSA-9011083 (Reactome)
ROBO1,ROBO2:Keratan sulfateArrowR-HSA-9014812 (Reactome)
ROBO1,ROBO2R-HSA-8985799 (Reactome)
ROBO1,ROBO2R-HSA-9014812 (Reactome)
ROBO1,ROBO2R-HSA-9014834 (Reactome)
ROBO1:NRP1ArrowR-HSA-9010951 (Reactome)
ROBO1:SLIT2:ARHGAP39ArrowR-HSA-428536 (Reactome)
ROBO1:SLIT2:ARHGAP39mim-catalysisR-HSA-428522 (Reactome)
ROBO1:SLIT2ArrowR-HSA-204364 (Reactome)
ROBO1:SLIT2R-HSA-376140 (Reactome)
ROBO1:SLIT2R-HSA-376141 (Reactome)
ROBO1:SLIT2R-HSA-376145 (Reactome)
ROBO1:SLIT2R-HSA-428511 (Reactome)
ROBO1:SLIT2R-HSA-428536 (Reactome)
ROBO1:SLIT2R-HSA-8985591 (Reactome)
ROBO1:SLIT2R-HSA-8986258 (Reactome)
ROBO1:SLITR-HSA-373715 (Reactome)
ROBO1ArrowR-HSA-8986083 (Reactome)
ROBO1ArrowR-HSA-9011083 (Reactome)
ROBO1R-HSA-204364 (Reactome)
ROBO1R-HSA-9010951 (Reactome)
ROBO2 geneR-HSA-9010503 (Reactome)
ROBO2 geneR-HSA-9010523 (Reactome)
ROBO2 geneR-HSA-9011077 (Reactome)
ROBO2,(ROBO1):ROBO3.1ArrowR-HSA-428510 (Reactome)
ROBO2,(ROBO1)R-HSA-428510 (Reactome)
ROBO2:AKAP5:PPP3CBArrowR-HSA-9010645 (Reactome)
ROBO2:AKAP5:PRKAR2A-PKA type IIArrowR-HSA-9010641 (Reactome)
ROBO2:AKAP5:p-T497,T638,S657-PRKCAArrowR-HSA-9010643 (Reactome)
ROBO2:AKAP5ArrowR-HSA-9010648 (Reactome)
ROBO2:AKAP5R-HSA-9010641 (Reactome)
ROBO2:AKAP5R-HSA-9010643 (Reactome)
ROBO2:AKAP5R-HSA-9010645 (Reactome)
ROBO2:SLIT2ArrowR-HSA-9010898 (Reactome)
ROBO2ArrowR-HSA-9010523 (Reactome)
ROBO2R-HSA-9010648 (Reactome)
ROBO2R-HSA-9010898 (Reactome)
ROBO3 geneR-HSA-9011143 (Reactome)
ROBO3 geneR-HSA-9011145 (Reactome)
ROBO3 geneR-HSA-9014587 (Reactome)
ROBO3.1 mRNA:MSI1ArrowR-HSA-9011346 (Reactome)
ROBO3.1 mRNA:MSI1ArrowR-HSA-9011347 (Reactome)
ROBO3.1 mRNAArrowR-HSA-9011143 (Reactome)
ROBO3.1 mRNAR-HSA-9011346 (Reactome)
ROBO3.1 mRNAR-HSA-9011347 (Reactome)
ROBO3.1:AKAP5:p-T497,T638,S657-PRKCAArrowR-HSA-9010646 (Reactome)
ROBO3.1:AKAP5:p-T497,T638,S657-PRKCAR-HSA-9010681 (Reactome)
ROBO3.1:AKAP5:p-T497,T638,S657-PRKCAmim-catalysisR-HSA-9010681 (Reactome)
ROBO3.1:AKAP5ArrowR-HSA-9010647 (Reactome)
ROBO3.1:AKAP5R-HSA-9010646 (Reactome)
ROBO3.1:DCC:NTN1ArrowR-HSA-9011224 (Reactome)
ROBO3.1:DCC:NTN1R-HSA-9011241 (Reactome)
ROBO3.1:ZSWIM8-CUL2ArrowR-HSA-9011289 (Reactome)
ROBO3.1:ZSWIM8-CUL2R-HSA-9011300 (Reactome)
ROBO3.1:ZSWIM8-CUL2mim-catalysisR-HSA-9011300 (Reactome)
ROBO3.1ArrowR-HSA-9011347 (Reactome)
ROBO3.1R-HSA-428510 (Reactome)
ROBO3.1R-HSA-9010647 (Reactome)
ROBO3.1R-HSA-9011224 (Reactome)
ROBO3.1R-HSA-9011289 (Reactome)
ROBO3.2 mRNAArrowR-HSA-9014587 (Reactome)
ROBO3.2 mRNAR-HSA-9014610 (Reactome)
ROBO3.2 mRNAR-HSA-9014652 (Reactome)
ROBO3.2ArrowR-HSA-9014652 (Reactome)
ROBO3R-HSA-9010190 (Reactome)
SLIT1:COL4A5ArrowR-HSA-9010396 (Reactome)
SLIT1:ROBO1,ROBO2:NCK2ArrowR-HSA-8985812 (Reactome)
SLIT1:ROBO1,ROBO2ArrowR-HSA-8985799 (Reactome)
SLIT1:ROBO1,ROBO2R-HSA-8985812 (Reactome)
SLIT1:ROBO1:FLRT3ArrowR-HSA-9010231 (Reactome)
SLIT1:ROBO1R-HSA-9010231 (Reactome)
SLIT1R-HSA-8985799 (Reactome)
SLIT1R-HSA-9010396 (Reactome)
SLIT2 geneR-HSA-9010539 (Reactome)
SLIT2 geneR-HSA-9010541 (Reactome)
SLIT2(1122-1529)ArrowR-HSA-376149 (Reactome)
SLIT2(31-1121)ArrowR-HSA-376149 (Reactome)
SLIT2,(SLIT3):Keratan sulfateArrowR-HSA-9010815 (Reactome)
SLIT2,(SLIT3)R-HSA-9010815 (Reactome)
SLIT2,SLIT2 cleavage fragments:GPC1:HSPGArrowR-HSA-428518 (Reactome)
SLIT2,SLIT2 cleavage fragmentsR-HSA-428518 (Reactome)
SLIT2:DystroglycanArrowR-HSA-9010872 (Reactome)
SLIT2:ROBO1:ABL:CAPArrowR-HSA-428883 (Reactome)
SLIT2:ROBO1:ABL:CLASPArrowR-HSA-428885 (Reactome)
SLIT2:ROBO1:ABLArrowR-HSA-376141 (Reactome)
SLIT2:ROBO1:ABLR-HSA-428883 (Reactome)
SLIT2:ROBO1:ABLR-HSA-428885 (Reactome)
SLIT2:ROBO1:ABLR-HSA-428888 (Reactome)
SLIT2:ROBO1:ABLmim-catalysisR-HSA-428888 (Reactome)
SLIT2:ROBO1:Ena/VASP proteinsArrowR-HSA-376140 (Reactome)
SLIT2:ROBO1:Ena/VASP proteinsR-HSA-428534 (Reactome)
SLIT2:ROBO1:Ena/VASP:PFNArrowR-HSA-428534 (Reactome)
SLIT2:ROBO1:MYO9BArrowR-HSA-8985591 (Reactome)
SLIT2:ROBO1:MYO9BTBarR-HSA-8985594 (Reactome)
SLIT2:ROBO1:NCK:PAKArrowR-HSA-428531 (Reactome)
SLIT2:ROBO1:NCK:SOSArrowR-HSA-428515 (Reactome)
SLIT2:ROBO1:NCK:SOSmim-catalysisR-HSA-428535 (Reactome)
SLIT2:ROBO1:NCKArrowR-HSA-428511 (Reactome)
SLIT2:ROBO1:NCKR-HSA-428515 (Reactome)
SLIT2:ROBO1:NCKR-HSA-428531 (Reactome)
SLIT2:ROBO1:SRGAPArrowR-HSA-376145 (Reactome)
SLIT2:ROBO1:SRGAPmim-catalysisR-HSA-428533 (Reactome)
SLIT2:p-Y1073-ROBO1:ABLArrowR-HSA-428888 (Reactome)
SLIT2ArrowR-HSA-9010539 (Reactome)
SLIT2R-HSA-204364 (Reactome)
SLIT2R-HSA-376149 (Reactome)
SLIT2R-HSA-9010872 (Reactome)
SLIT2R-HSA-9010898 (Reactome)
SLIT3:ROBO1,ROBO2ArrowR-HSA-9014834 (Reactome)
SLIT3R-HSA-9014834 (Reactome)
SOSR-HSA-428515 (Reactome)
SRGAPR-HSA-376145 (Reactome)
Translated ROBO3.2

mRNA in complex with NMD-initiating

UPF2
ArrowR-HSA-9014610 (Reactome)
Translated ROBO3.2

mRNA in complex with NMD-initiating

UPF2
TBarR-HSA-9014652 (Reactome)
USP33mim-catalysisR-HSA-8986083 (Reactome)
Ub-ROBO3.1:ZSWIM8-CUL2ArrowR-HSA-9011300 (Reactome)
Ub-ROBO3.1:ZSWIM8-CUL2R-HSA-9011313 (Reactome)
UbArrowR-HSA-8986083 (Reactome)
UbArrowR-HSA-9011313 (Reactome)
UbR-HSA-9011300 (Reactome)
Unidentified proteasemim-catalysisR-HSA-376149 (Reactome)
ZSWIM8-CUL2 E3 ubiquitin ligaseArrowR-HSA-9011313 (Reactome)
ZSWIM8-CUL2 E3 ubiquitin ligaseR-HSA-9011289 (Reactome)
eRF3:GDPR-HSA-9014610 (Reactome)
p-S1330-ROBO3.1:AKAP5:p-T497,T638,S657-PRKCAArrowR-HSA-9010681 (Reactome)
p-T497,T638,S657-PRKCAR-HSA-9010643 (Reactome)
p-T497,T638,S657-PRKCAR-HSA-9010646 (Reactome)
p-Y1019-ROBO3.1:DCC:NTN1ArrowR-HSA-9011241 (Reactome)
tRNAR-HSA-9014610 (Reactome)

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