Netrin-1 signaling (Homo sapiens)

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5, 1614, 21615, 201012171, 43, 73, 8, 19112, 19, 211761, 4, 9, 12, 139, 13cytosolRGMA SRC-1 p-Y1420-DCC NTN1 DOCK1 NEO1 FYN GTP GDPFYN Netrin-1:NeogeninNEO1FYN NTN1 p-Y397-PTK2 UNC5A TRIO ATPNTN1 SIAH1SRC-1 NTN1 ABLIM1 FYN NTN1 PITPNAp-T567-EZR RAC1 Netrin-1:DCC:pUNC5CNEO1 TRPC6 TRIO UNC5B DCC&UNC5A:Netrin-4Netrin:DCC:PITPSRC-1 MYO10 DOCK1 NTN4 p-Y397-PTK2 RGMB SRC-1 NCK1 p-Y397-PTK2 NCK1 DCC Netrin:DCC:Nck:Cdc42-GTP:Active N-WASP:PIP2UNC5B ADPPIKE-L:UNC5BI(1,4,5)P3p-Y397-PTK2 UNC5D p-Y1420-DCC TRPC6 NTN1 Rho GEFs DOCK andTRIOUNC5A ABLIM1 NCK1 p-Y397-PTK2 TRPC3(1-848) DCC DCC p-Y146,Y354-EZR Netrin:DCC oligomerAGAP2 SIAH2 SLIT1 UNC5A NCK1 NTN1 RAC1 FYN GTPMyosin-X:DCC/NeogeninSIAH2 bound toDCC:Netrin-1GTP NTN1 ABLIM3 UNC5B DCC p-5Y-UNC5C SRC,FYNTRPC7 SIAH2FYN Netrin-1:pDCCdimer:pFAK:Src/Fynp-Y397-PTK2 p-Y397-PTK2 Netrin:DCColigomer:pFAK:Fyn:Nck-1:Rho GEFs DOCK/Triop-Y1420-DCC MYO10SRC-1 PI(4,5)P2AGAP2TRPC3(1-848) NTN4DCC:Ezrin complexNTN1 p-Y397-PTK2 ADPSLIT3 SLIT3 DCC/UNC5AABLIM2 UNC5D Netrin-1:DCC:UNC5CNTN1 H2OUNC-5:Netrin-1complexPI(4,5)P2 NTN1 GDP GDPp-Y146,Y354-EZRRGMA CDC42 p-Y-PLCG1 PI(4,5)P2p-Y1420-DCC DCC NTN1 p-5Y-UNC5C ABLIM2 UNC5C p-Y397-PTK2 SLIT2(31-1529) GTP DOCK1 SRC-1FYN PI(4,5)P2UNC5A RAC1:GDPSLIT2(31-1529) ATPSRC-1 SRC-1 ADPUNC5A SIAH1 bound toDCC:Netrin-1p-Y397-PTK2 SRC-1 NTN1 DCCUNC5BTRIO Active Cdc42 boundto Netrin:DCCcomplexp-Y1420-DCC TRPC5 SIAH1 TRIO p-Y1420-DCC ATPNEO1 DCC UNC-5 receptorsATPp-Y1420-DCC ROBO1 DOCK1 DOCK1 p-Y1420-DCC SRC-1 TRPC4 NTN1TRIO NTN1 TRPC channelsNCK1 TRIO DCC:Robo:SlitNetrin1:pUnc5C:DCC:Shp2UNC5C ROBO1 RGMB Robo:SlitNTN1 pPLCgamma:PIP2DCC RAC1 SLIT1 Activated TRPchannelsNeogenin:RGDPLCG1FYN PTPN11 CDC42 FAK1 N-WASPGDP TRPC5 CDC42 FYN SRC-1 SRC-1 TRPC4 HFE2 GTP p-Y397-PTK2 PI(4,5)P2ADPDCC ABLIMNTN1 DCC bound toUNC-5:Netrin-1TRPC1 DCC FYN FAK1DOCK1 DCC PI(4,5)P2 CDC42:GDPNetrin-1:DCC:pFyn:Nck:Rac1-GTP:AblimHFE2 DCC GTPNTN1 DCC PI(4,5)P2 SRC-1 NTN1 PI(4,5)P2 TRPC1 PTPN11DCC/Neogeninp-Y90,T538,S676,S695-PRKCQDAGsDCC DCC ATPNEO1 PI(4,5)P2 NCK1 Netrin1:DCColigomer:pFADK1:Fyn/srcFYN ADPUNC5C p-T567-EZR Active Rac1 bound toNetrin-1-DCCcomplexpEzrin:PIP2WASL FYN Netrin-1:pDCColigomer:pFAK:Fyn:NCK1FADK1:DCColigomer:NetrinABLIM3 DCC:Netrin-1NTN1 TRPC7 Netrin-1:DCColigomer:pFADK1NCK1UNC5B DCC NTN1 UNC5C RGDUNC5D p-Y397-PTK2 Ezrin:PIP2NTN1 p-Y1420-DCC p-Y1420-DCC PITPNA 18


Description

Netrins are secreted proteins that play a crucial role in neuronal migration and in axon guidance during the development of the nervous system. To date, several Netrins have been described in mouse and humans: Netrin-1, -3/NTL2, -4/h and G-Netrins. Netrin-1 is the most studied member of the family and has been shown to play a crucial role in neuronal navigation during nervous system development mainly through its interaction with its receptors DCC and UNC5. Members of the Deleted in colorectal cancer (DCC) family- which includes DCC and Neogenin in vertebrates- mediate netrin-induced axon attraction, whereas the C. elegans UNC5 receptor and its four vertebrate homologs Unc5a-Unc5d mediate repulsion. View original pathway at:Reactome.

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Pathway is converted from Reactome id:

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Ontology Terms

 

Bibliography

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  1. Ren XR, Hong Y, Feng Z, Yang HM, Mei L, Xiong WC.; ''Tyrosine phosphorylation of netrin receptors in netrin-1 signaling.''; PubMed Europe PMC Scholia
  2. Stein E, Zou Y, Poo M, Tessier-Lavigne M.; ''Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation.''; PubMed Europe PMC Scholia
  3. Hu G, Fearon ER.; ''Siah-1 N-terminal RING domain is required for proteolysis function, and C-terminal sequences regulate oligomerization and binding to target proteins.''; PubMed Europe PMC Scholia
  4. Fuerst PG, Koizumi A, Masland RH, Burgess RW.; ''Neurite arborization and mosaic spacing in the mouse retina require DSCAM.''; PubMed Europe PMC Scholia
  5. Meyerhardt JA, Caca K, Eckstrand BC, Hu G, Lengauer C, Banavali S, Look AT, Fearon ER.; ''Netrin-1: interaction with deleted in colorectal cancer (DCC) and alterations in brain tumors and neuroblastomas.''; PubMed Europe PMC Scholia
  6. Li X, Meriane M, Triki I, Shekarabi M, Kennedy TE, Larose L, Lamarche-Vane N.; ''The adaptor protein Nck-1 couples the netrin-1 receptor DCC (deleted in colorectal cancer) to the activation of the small GTPase Rac1 through an atypical mechanism.''; PubMed Europe PMC Scholia
  7. Agarwala KL, Nakamura S, Tsutsumi Y, Yamakawa K.; ''Down syndrome cell adhesion molecule DSCAM mediates homophilic intercellular adhesion.''; PubMed Europe PMC Scholia
  8. Yamagata M, Sanes JR.; ''Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina.''; PubMed Europe PMC Scholia
  9. Millard TH, Sharp SJ, Machesky LM.; ''Signalling to actin assembly via the WASP (Wiskott-Aldrich syndrome protein)-family proteins and the Arp2/3 complex.''; PubMed Europe PMC Scholia
  10. Meriane M, Tcherkezian J, Webber CA, Danek EI, Triki I, McFarlane S, Bloch-Gallego E, Lamarche-Vane N.; ''Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance.''; PubMed Europe PMC Scholia
  11. Agarwala KL, Ganesh S, Tsutsumi Y, Suzuki T, Amano K, Yamakawa K.; ''Cloning and functional characterization of DSCAML1, a novel DSCAM-like cell adhesion molecule that mediates homophilic intercellular adhesion.''; PubMed Europe PMC Scholia
  12. Bretscher A, Edwards K, Fehon RG.; ''ERM proteins and merlin: integrators at the cell cortex.''; PubMed Europe PMC Scholia
  13. Li W, Guan KL.; ''The Down syndrome cell adhesion molecule (DSCAM) interacts with and activates Pak.''; PubMed Europe PMC Scholia
  14. Barallobre MJ, Pascual M, Del Río JA, Soriano E.; ''The Netrin family of guidance factors: emphasis on Netrin-1 signalling.''; PubMed Europe PMC Scholia
  15. Martín M, Simon-Assmann P, Kedinger M, Martin M, Mangeat P, Real FX, Fabre M.; ''DCC regulates cell adhesion in human colon cancer derived HT-29 cells and associates with ezrin.''; PubMed Europe PMC Scholia
  16. Briançon-Marjollet A, Ghogha A, Nawabi H, Triki I, Auziol C, Fromont S, Piché C, Enslen H, Chebli K, Cloutier JF, Castellani V, Debant A, Lamarche-Vane N.; ''Trio mediates netrin-1-induced Rac1 activation in axon outgrowth and guidance.''; PubMed Europe PMC Scholia
  17. Li X, Gao X, Liu G, Xiong W, Wu J, Rao Y.; ''Netrin signal transduction and the guanine nucleotide exchange factor DOCK180 in attractive signaling.''; PubMed Europe PMC Scholia
  18. Shekarabi M, Kennedy TE.; ''The netrin-1 receptor DCC promotes filopodia formation and cell spreading by activating Cdc42 and Rac1.''; PubMed Europe PMC Scholia
  19. Qin S, Yu L, Gao Y, Zhou R, Zhang C.; ''Characterization of the receptors for axon guidance factor netrin-4 and identification of the binding domains.''; PubMed Europe PMC Scholia
  20. Li W, Lee J, Vikis HG, Lee SH, Liu G, Aurandt J, Shen TL, Fearon ER, Guan JL, Han M, Rao Y, Hong K, Guan KL.; ''Activation of FAK and Src are receptor-proximal events required for netrin signaling.''; PubMed Europe PMC Scholia
  21. Strübing C, Krapivinsky G, Krapivinsky L, Clapham DE.; ''Formation of novel TRPC channels by complex subunit interactions in embryonic brain.''; PubMed Europe PMC Scholia
  22. Liu G, Beggs H, Jürgensen C, Park HT, Tang H, Gorski J, Jones KR, Reichardt LF, Wu J, Rao Y.; ''Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction.''; PubMed Europe PMC Scholia
  23. Rohatgi R, Ho HY, Kirschner MW.; ''Mechanism of N-WASP activation by CDC42 and phosphatidylinositol 4, 5-bisphosphate.''; PubMed Europe PMC Scholia
  24. Rouer E.; ''[Neuronal isoforms of Src, Fyn and Lck tyrosine kinases: A specific role for p56lckN in neuron protection].''; PubMed Europe PMC Scholia
  25. Cooper HM, Gad JM, Keeling SL.; ''The Deleted in Colorectal Cancer netrin guidance system: a molecular strategy for neuronal navigation.''; PubMed Europe PMC Scholia
  26. Moore SW, Tessier-Lavigne M, Kennedy TE.; ''Netrins and their receptors.''; PubMed Europe PMC Scholia
  27. Shekarabi M, Moore SW, Tritsch NX, Morris SJ, Bouchard JF, Kennedy TE.; ''Deleted in colorectal cancer binding netrin-1 mediates cell substrate adhesion and recruits Cdc42, Rac1, Pak1, and N-WASP into an intracellular signaling complex that promotes growth cone expansion.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
101460view11:32, 1 November 2018ReactomeTeamreactome version 66
100998view21:11, 31 October 2018ReactomeTeamreactome version 65
100534view19:45, 31 October 2018ReactomeTeamreactome version 64
100081view16:30, 31 October 2018ReactomeTeamreactome version 63
99632view15:02, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99238view12:44, 31 October 2018ReactomeTeamreactome version 62
93774view13:35, 16 August 2017ReactomeTeamreactome version 61
93301view11:19, 9 August 2017ReactomeTeamreactome version 61
88041view13:37, 25 July 2016RyanmillerOntology Term : 'signaling pathway pertinent to the brain and nervous system' added !
88040view13:37, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86384view09:16, 11 July 2016ReactomeTeamreactome version 56
83269view10:36, 18 November 2015ReactomeTeamVersion54
81379view12:54, 21 August 2015ReactomeTeamVersion53
76847view08:07, 17 July 2014ReactomeTeamFixed remaining interactions
76551view11:53, 16 July 2014ReactomeTeamFixed remaining interactions
75884view09:54, 11 June 2014ReactomeTeamRe-fixing comment source
75584view10:42, 10 June 2014ReactomeTeamReactome 48 Update
74939view13:46, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74583view08:37, 30 April 2014ReactomeTeamReactome46
42086view21:55, 4 March 2011MaintBotAutomatic update
39894view05:55, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ABLIM1 ProteinO14639 (Uniprot-TrEMBL)
ABLIM2 ProteinQ6H8Q1 (Uniprot-TrEMBL)
ABLIM3 ProteinO94929 (Uniprot-TrEMBL)
ABLIMComplexR-HSA-418808 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AGAP2 ProteinQ99490 (Uniprot-TrEMBL)
AGAP2ProteinQ99490 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated TRP channelsComplexR-HSA-622374 (Reactome)
Active Cdc42 bound

to Netrin:DCC

complex
ComplexR-HSA-418820 (Reactome)
Active Rac1 bound to

Netrin-1-DCC

complex
ComplexR-HSA-418826 (Reactome)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CDC42:GDPComplexR-HSA-418830 (Reactome)
DAGsMetaboliteCHEBI:18035 (ChEBI)
DCC ProteinP43146 (Uniprot-TrEMBL)
DCC bound to UNC-5:Netrin-1ComplexR-HSA-373654 (Reactome)
DCC&UNC5A:Netrin-4ComplexR-HSA-593689 (Reactome)
DCC/NeogeninComplexR-HSA-593676 (Reactome)
DCC/UNC5AComplexR-HSA-593684 (Reactome)
DCC:Ezrin complexComplexR-HSA-374565 (Reactome)
DCC:Netrin-1ComplexR-HSA-373667 (Reactome)
DCC:Robo:SlitComplexR-HSA-373666 (Reactome)
DCCProteinP43146 (Uniprot-TrEMBL)
DOCK1 ProteinQ14185 (Uniprot-TrEMBL)
Ezrin:PIP2ComplexR-HSA-374570 (Reactome)
FADK1:DCC oligomer:NetrinComplexR-HSA-373662 (Reactome)
FAK1 ProteinQ05397 (Uniprot-TrEMBL)
FAK1ProteinQ05397 (Uniprot-TrEMBL)
FYN ProteinP06241 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HFE2 ProteinQ6ZVN8 (Uniprot-TrEMBL)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
MYO10 ProteinQ9HD67 (Uniprot-TrEMBL)
MYO10ProteinQ9HD67 (Uniprot-TrEMBL)
Myosin-X:DCC/NeogeninComplexR-HSA-593674 (Reactome)
N-WASPProteinO00401 (Uniprot-TrEMBL)
NCK1 ProteinP16333 (Uniprot-TrEMBL)
NCK1ProteinP16333 (Uniprot-TrEMBL)
NEO1 ProteinQ92859 (Uniprot-TrEMBL)
NEO1ProteinQ92859 (Uniprot-TrEMBL)
NTN1 ProteinO95631 (Uniprot-TrEMBL)
NTN1ProteinO95631 (Uniprot-TrEMBL)
NTN4 ProteinQ9HB63 (Uniprot-TrEMBL)
NTN4ProteinQ9HB63 (Uniprot-TrEMBL)
Neogenin:RGDComplexR-HSA-374583 (Reactome)
Netrin-1:DCC oligomer:pFADK1ComplexR-HSA-418822 (Reactome)
Netrin-1:DCC:UNC5CComplexR-HSA-418818 (Reactome)
Netrin-1:DCC:pFyn:Nck:Rac1-GTP:AblimComplexR-HSA-418814 (Reactome)
Netrin-1:DCC:pUNC5CComplexR-HSA-418827 (Reactome)
Netrin-1:NeogeninComplexR-HSA-374592 (Reactome)
Netrin-1:pDCC dimer:pFAK:Src/FynComplexR-HSA-374551 (Reactome)
Netrin-1:pDCC oligomer:pFAK:Fyn:NCK1ComplexR-HSA-373663 (Reactome)
Netrin1:DCC oligomer:pFADK1:Fyn/srcComplexR-HSA-418815 (Reactome)
Netrin1:pUnc5C:DCC:Shp2ComplexR-HSA-418825 (Reactome)
Netrin:DCC oligomer:pFAK:Fyn:Nck-1:Rho GEFs DOCK/TrioComplexR-HSA-418829 (Reactome)
Netrin:DCC oligomerComplexR-HSA-373678 (Reactome)
Netrin:DCC:Nck:Cdc42-GTP:Active N-WASP:PIP2ComplexR-HSA-418834 (Reactome)
Netrin:DCC:PITPComplexR-HSA-418843 (Reactome)
PI(4,5)P2 MetaboliteCHEBI:18348 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PIKE-L:UNC5BComplexR-HSA-622358 (Reactome)
PITPNA ProteinQ00169 (Uniprot-TrEMBL)
PITPNAProteinQ00169 (Uniprot-TrEMBL)
PLCG1ProteinP19174 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GDPComplexR-HSA-445010 (Reactome)
RGDComplexR-HSA-374581 (Reactome)
RGMA ProteinQ96B86 (Uniprot-TrEMBL)
RGMB ProteinQ6NW40 (Uniprot-TrEMBL)
ROBO1 ProteinQ9Y6N7 (Uniprot-TrEMBL)
Rho GEFs DOCK and TRIOComplexR-HSA-418807 (Reactome)
Robo:SlitComplexR-HSA-204367 (Reactome)
SIAH1 ProteinQ8IUQ4 (Uniprot-TrEMBL)
SIAH1 bound to DCC:Netrin-1ComplexR-HSA-374593 (Reactome)
SIAH1ProteinQ8IUQ4 (Uniprot-TrEMBL)
SIAH2 ProteinO43255 (Uniprot-TrEMBL)
SIAH2 bound to DCC:Netrin-1ComplexR-HSA-374590 (Reactome)
SIAH2ProteinO43255 (Uniprot-TrEMBL)
SLIT1 ProteinO75093 (Uniprot-TrEMBL)
SLIT2(31-1529) ProteinO94813 (Uniprot-TrEMBL)
SLIT3 ProteinO75094 (Uniprot-TrEMBL)
SRC,FYNComplexR-HSA-418805 (Reactome)
SRC-1 ProteinP12931-1 (Uniprot-TrEMBL)
SRC-1ProteinP12931-1 (Uniprot-TrEMBL)
TRIO ProteinO75962 (Uniprot-TrEMBL)
TRPC channelsComplexR-HSA-622392 (Reactome)
TRPC1 ProteinP48995 (Uniprot-TrEMBL)
TRPC3(1-848) ProteinQ13507 (Uniprot-TrEMBL)
TRPC4 ProteinQ9UBN4 (Uniprot-TrEMBL)
TRPC5 ProteinQ9UL62 (Uniprot-TrEMBL)
TRPC6 ProteinQ9Y210 (Uniprot-TrEMBL)
TRPC7 ProteinQ9HCX4 (Uniprot-TrEMBL)
UNC-5 receptorsComplexR-HSA-373650 (Reactome)
UNC-5:Netrin-1 complexComplexR-HSA-373660 (Reactome)
UNC5A ProteinQ6ZN44 (Uniprot-TrEMBL)
UNC5B ProteinQ8IZJ1 (Uniprot-TrEMBL)
UNC5BProteinQ8IZJ1 (Uniprot-TrEMBL)
UNC5C ProteinO95185 (Uniprot-TrEMBL)
UNC5D ProteinQ6UXZ4 (Uniprot-TrEMBL)
WASL ProteinO00401 (Uniprot-TrEMBL)
p-5Y-UNC5C ProteinO95185 (Uniprot-TrEMBL)
p-T567-EZR ProteinP15311 (Uniprot-TrEMBL)
p-Y-PLCG1 ProteinP19174 (Uniprot-TrEMBL)
p-Y1420-DCC ProteinP43146 (Uniprot-TrEMBL)
p-Y146,Y354-EZR ProteinP15311 (Uniprot-TrEMBL)
p-Y146,Y354-EZRProteinP15311 (Uniprot-TrEMBL)
p-Y397-PTK2 ProteinQ05397 (Uniprot-TrEMBL)
p-Y90,T538,S676,S695-PRKCQProteinQ04759 (Uniprot-TrEMBL)
pEzrin:PIP2ComplexR-HSA-374558 (Reactome)
pPLCgamma:PIP2ComplexR-HSA-622379 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ABLIMR-HSA-418865 (Reactome)
ADPArrowR-HSA-374664 (Reactome)
ADPArrowR-HSA-374701 (Reactome)
ADPArrowR-HSA-418859 (Reactome)
ADPArrowR-HSA-418872 (Reactome)
ADPArrowR-HSA-593690 (Reactome)
AGAP2R-HSA-622357 (Reactome)
ATPR-HSA-374664 (Reactome)
ATPR-HSA-374701 (Reactome)
ATPR-HSA-418859 (Reactome)
ATPR-HSA-418872 (Reactome)
ATPR-HSA-593690 (Reactome)
Activated TRP channelsArrowR-HSA-622390 (Reactome)
Active Cdc42 bound

to Netrin:DCC

complex
ArrowR-HSA-418850 (Reactome)
Active Cdc42 bound

to Netrin:DCC

complex
R-HSA-418874 (Reactome)
Active Rac1 bound to

Netrin-1-DCC

complex
ArrowR-HSA-418856 (Reactome)
Active Rac1 bound to

Netrin-1-DCC

complex
R-HSA-418865 (Reactome)
CDC42:GDPR-HSA-418850 (Reactome)
DAGsArrowR-HSA-622382 (Reactome)
DAGsArrowR-HSA-622390 (Reactome)
DCC bound to UNC-5:Netrin-1ArrowR-HSA-373713 (Reactome)
DCC&UNC5A:Netrin-4ArrowR-HSA-593685 (Reactome)
DCC/NeogeninR-HSA-593672 (Reactome)
DCC/UNC5AR-HSA-593685 (Reactome)
DCC:Ezrin complexArrowR-HSA-374663 (Reactome)
DCC:Netrin-1ArrowR-HSA-373711 (Reactome)
DCC:Netrin-1R-HSA-373707 (Reactome)
DCC:Netrin-1R-HSA-374665 (Reactome)
DCC:Netrin-1R-HSA-374667 (Reactome)
DCC:Robo:SlitArrowR-HSA-373715 (Reactome)
DCCR-HSA-373707 (Reactome)
DCCR-HSA-373711 (Reactome)
DCCR-HSA-373713 (Reactome)
DCCR-HSA-373715 (Reactome)
DCCR-HSA-374663 (Reactome)
Ezrin:PIP2ArrowR-HSA-374662 (Reactome)
Ezrin:PIP2R-HSA-374664 (Reactome)
FADK1:DCC oligomer:NetrinArrowR-HSA-373720 (Reactome)
FADK1:DCC oligomer:NetrinR-HSA-418872 (Reactome)
FADK1:DCC oligomer:Netrinmim-catalysisR-HSA-418872 (Reactome)
FAK1R-HSA-373720 (Reactome)
GDPArrowR-HSA-418850 (Reactome)
GDPArrowR-HSA-418856 (Reactome)
GTPR-HSA-418850 (Reactome)
GTPR-HSA-418856 (Reactome)
H2OR-HSA-622382 (Reactome)
I(1,4,5)P3ArrowR-HSA-622382 (Reactome)
MYO10R-HSA-593672 (Reactome)
Myosin-X:DCC/NeogeninArrowR-HSA-593672 (Reactome)
N-WASPR-HSA-418874 (Reactome)
NCK1R-HSA-373716 (Reactome)
NEO1R-HSA-374689 (Reactome)
NEO1R-HSA-374692 (Reactome)
NTN1R-HSA-373711 (Reactome)
NTN1R-HSA-373751 (Reactome)
NTN1R-HSA-374689 (Reactome)
NTN4R-HSA-593685 (Reactome)
Neogenin:RGDArrowR-HSA-374692 (Reactome)
Netrin-1:DCC oligomer:pFADK1ArrowR-HSA-418872 (Reactome)
Netrin-1:DCC oligomer:pFADK1R-HSA-418868 (Reactome)
Netrin-1:DCC:UNC5CR-HSA-418859 (Reactome)
Netrin-1:DCC:pFyn:Nck:Rac1-GTP:AblimArrowR-HSA-418865 (Reactome)
Netrin-1:DCC:pUNC5CArrowR-HSA-418859 (Reactome)
Netrin-1:DCC:pUNC5CR-HSA-418863 (Reactome)
Netrin-1:NeogeninArrowR-HSA-374689 (Reactome)
Netrin-1:pDCC dimer:pFAK:Src/FynArrowR-HSA-374701 (Reactome)
Netrin-1:pDCC dimer:pFAK:Src/FynR-HSA-373716 (Reactome)
Netrin-1:pDCC oligomer:pFAK:Fyn:NCK1ArrowR-HSA-373716 (Reactome)
Netrin-1:pDCC oligomer:pFAK:Fyn:NCK1R-HSA-418858 (Reactome)
Netrin1:DCC oligomer:pFADK1:Fyn/srcArrowR-HSA-418868 (Reactome)
Netrin1:DCC oligomer:pFADK1:Fyn/srcR-HSA-374701 (Reactome)
Netrin1:DCC oligomer:pFADK1:Fyn/srcmim-catalysisR-HSA-374701 (Reactome)
Netrin1:pUnc5C:DCC:Shp2ArrowR-HSA-418863 (Reactome)
Netrin:DCC oligomer:pFAK:Fyn:Nck-1:Rho GEFs DOCK/TrioArrowR-HSA-418858 (Reactome)
Netrin:DCC oligomer:pFAK:Fyn:Nck-1:Rho GEFs DOCK/TrioR-HSA-418850 (Reactome)
Netrin:DCC oligomer:pFAK:Fyn:Nck-1:Rho GEFs DOCK/TrioR-HSA-418856 (Reactome)
Netrin:DCC oligomer:pFAK:Fyn:Nck-1:Rho GEFs DOCK/Triomim-catalysisR-HSA-418850 (Reactome)
Netrin:DCC oligomer:pFAK:Fyn:Nck-1:Rho GEFs DOCK/Triomim-catalysisR-HSA-418856 (Reactome)
Netrin:DCC oligomerArrowR-HSA-373707 (Reactome)
Netrin:DCC oligomerR-HSA-373720 (Reactome)
Netrin:DCC oligomerR-HSA-418866 (Reactome)
Netrin:DCC:Nck:Cdc42-GTP:Active N-WASP:PIP2ArrowR-HSA-418874 (Reactome)
Netrin:DCC:PITPArrowR-HSA-418866 (Reactome)
Netrin:DCC:PITPArrowR-HSA-593690 (Reactome)
PI(4,5)P2R-HSA-374662 (Reactome)
PI(4,5)P2R-HSA-418874 (Reactome)
PI(4,5)P2R-HSA-593690 (Reactome)
PI(4,5)P2R-HSA-622382 (Reactome)
PIKE-L:UNC5BArrowR-HSA-622357 (Reactome)
PITPNAR-HSA-418866 (Reactome)
PLCG1R-HSA-593690 (Reactome)
PTPN11R-HSA-418863 (Reactome)
R-HSA-373707 (Reactome) Netrin binding to DCC causes DCC clustering via its P3 domain in the cytoplasmic region and mediates attractive signaling.
R-HSA-373711 (Reactome) Netrin-1 promotes attraction of the commissural neurons to midline cells. It is secreted in the ventral midline (also known as the floor plate). The transmembrane DCC receptor is a Netrin-1 receptor, involved in the attractive effects of Netrin-1. Contact-dependent mechanisms promote extension of growth cones across the floor plate to the contralateral side, whereupon growth cones acquire sensitivity to the midline repellent Slit and grow away from the midline.
Netrin-1 binds directly to the fifth Fibronectin III motif of DCC, thereby inducing DCC clustering through the association between the DCC P3 domains, a process required for an attractive response.
R-HSA-373713 (Reactome) UNC-5 uses DCC as a co-receptor and binds to the DCC P1 domain with its DB domain to repel axons at low netrin concentration. It is generally thought that UNC5 receptor alone transduces short range signals whereas DCC-Unc5 complex transduces long range signals important for neuron migration, neurite growth and axon repulsion.
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 receptors it was deduced that Robo repulsion on its own is sufficient to prevent commissural axons from recrossing the midline, and that Netrin DCC is not the only source of attraction at the midline.

R-HSA-373716 (Reactome) DCC interacts with the SH3/SH2 adaptor NCK1 in commissural neurons. This interaction is direct and requires the SH3 but not SH2 domains of NCK1. NCK1 can recruit Rac, Cdc42 and their effectors Pak and N-WASP to the activated receptor, thereby providing a direct link between DCC, Rho GTPases and numerous downstream signaling components that regulate the actin cytoskeleton.
R-HSA-373720 (Reactome) The carboxy (C) terminal domain of FADK1 interacts with the C-terminal P3 domain of DCC. This FADK1-DCC interaction is required for Netrin-1 to stimulate tyrosine phosphorylation and activation of FADK1.
R-HSA-373751 (Reactome) UNC-5 receptors interact with netrins and mediate the short-range repulsion signal. The extracellular Ig domains of Unc5 bind netrin.
R-HSA-374662 (Reactome) Ezrin is a member of the ezrin/radixin/moesin (ERM) family that acts as a linker between the plasma membrane and the actin cytoskeleton. Ezrin exists in a dormant, monomeric form in which its FERM/NERMAD and C-ERMAD domains are associated, masking membrane and F-actin binding regions. On production of PIP2, ezrin binds it, is recruited to the plasma membrane, and undergoes conformational changes unmasking the two binding sites.
R-HSA-374663 (Reactome) Phosphorylated Ezrin can link in microfilaments to the plasma membrane by direct association with transmembrane proteins such as the cytoplasmic domain of DCC.
R-HSA-374664 (Reactome) PIP2 places Ezrin at the membrane in a location to be phosphorylated, and thereby activated, by protein kinase-C theta.
R-HSA-374665 (Reactome) Siah-1 binds DCC and promotes its proteolysis via the ubiquitin-proteasome pathway. Siah-1 contains an N-terminal RING domain that is involved in proteolysis function and a C-terminal sequence that is involved in its oligomerization and binding to target proteins, such as DCC.
R-HSA-374667 (Reactome) Siah-2 binds to the DCC protein and promote its proteolysis via the ubiquitin-proteasome pathway.
R-HSA-374689 (Reactome) Netrin-1 is not only involved as an axon guidance cue during the development of nervous system but is also involved in the morphogenesis of the mammary glands. Netrin-1 acts as a short-range attractant and has an adhesive, rather than a guidance, function during mammary gland morphogenesis. In the developing mammary gland, netrin-1 acts locally through neogenin to maintain close apposition of cap cells and prelumenal cells at the leading edge of the TEB (Terminal end bud).
R-HSA-374692 (Reactome) Among netrin1 receptors neogenin is the only protein to interact with the repulsive guidance molecules (RGM). RGMs are membrane bound proteins involved in axon guidance in the visual system. Neogenin is the dependence receptor and cleaved by activated caspase-3 to trigger apoptotic cell death. RGM binding blocks the cleavage of neogenin so RGM functions as a cell survival factor.
R-HSA-374701 (Reactome) Netrin-1 stimulates phosphorylation of DCC on serine, threonine, and tyrosine residues. The experimental data suggest that tyrosine phosphorylation of DCC is a prerequisite step for DCC phosphorylation on serine and threonine residues. Fyn initiates the phosphorylation of the tyrosine residue 1420 in the DCC cytoplasmic domain. This phosphorylation of DCC in turn facilitates the DCC-Fyn interaction, forming a positive reinforcement cycle.
R-HSA-418850 (Reactome) RhoGEF complexed with Netrin-1-DCC induces guanine nucleotide exchange by Cdc42, activating it. Activated Cdc42 activates N-WASP, which promotes the nucleation of F-actin via the Arp2/3 complex. Netrin-1, via DCC, influences cellular motility by regulating actin-based membrane extension through the activation of Cdc42.
R-HSA-418856 (Reactome) Rho GEF's DOCK180 and Trio directly associate with DCC, activate Rac-1 on DCC stimulation and cause cell spreading.
R-HSA-418858 (Reactome) When Netrin-1 binds to the DCC-NCK1 complex, a conformational change in NCK1 promotes interaction between the SH2 domain proteins, leading to recruitment and activation of RhoGEFs DOCK180 and Trio. These GEFs mediate Netrin-1 signaling in axon outgrowth and guidance through their ability to activate Rac1 and Cdc42.
R-HSA-418859 (Reactome) Multiple sites on Unc5c are phosphorylated after netrin-1 stimulation. An activated Src tyrosine kinase induces phosphorylation of Unc5c at multiple cytoplasmic tyrosine residues including highly-conserved residues 449, 454, 568, 649 and 667. Phosphorylation of these residues creates potential binding sites for cytoplasmic signaling proteins.
R-HSA-418863 (Reactome) Shp2 is recruited to the phosphorylated Unc5C receptor after netrin stimulation, in a fashion that requires binding of the Shp2 SH2 domains to the Tyr568 phosphorylated motif. The functional significance of the Unc5C-shp2 interaction has not been reported .Shp2 might negatively regulate tyrosine phosphorylation of Unc5C receptor, facilitating resensitization of the receptor to the netrin signal.
R-HSA-418865 (Reactome) Unc-115/AbLIM is a key regulator of lamellipodia and filopodia in the growth cone during axon pathfinding and acts downstream of Rac GTPase signaling. It acts as a scaffold to recruit other actin-modulating complexes involved in lamellipodia and filopodia. Unc-115/AbLIM is locally recruited to the plasma membrane by activated Rac1 and subsequently dephosphorylated on serine 617. Dephosphorylated Unc-115/AbLIM then might interact with other molecules at the plasma membrane to induce formation of lamellipodia and filopodia by reorganization of the actin cytoskeleton.
R-HSA-418866 (Reactome) DCC interacts directly with PITPalpha and this interaction is enhanced in the presence of Netrin-1. The interaction of DCC with PITPalpha requires the carboxy-terminal dmain of both the proteins. PITPalpha signaling pathway is important for netrin-1 mediated axon outgrowth. Netrin-1 activates PITPalpha to regulate local phosphoinositide (PI) synthesis, which is important for PI3K dependent neurite elongation.
R-HSA-418868 (Reactome) Activated (phosphorylated) FADK1 acts as a scaffold and recruits src tyrosine kinases Src and Fyn to DCC. These tyrosine kinases phosphorylate DCC which is critical for Netrin-1 signaling.
R-HSA-418872 (Reactome) FADK1 interacts with the C-terminal P3 domain of DCC complexed with Netrin-1, and undergoes tyrosine phosphorylation and activation. Netrin-1-DCC binding thus leads to the autophosphorylation of tyrosine 393 in FADK1.
R-HSA-418874 (Reactome) The adaptor protein Nck-1 binds to DCC and recruits Rac-1, Cdc42 and their effectors PAK-1 and N-WASP to the activated receptor. Both Cdc42 and Nck-1 are activators of N-WASP. Cdc42 in its active GTP bound form binds to the CRIB domain of N-WASP and this interaction along with PIP2 results in the activation of N-WASP. Nck-1 activate N-WASP via binding of its SH3 domain to the proline rich domain of N-WASP. Nck-1 also possess an SH2 domain that associates directly with activated tyrosine kinase receptors which can phosphorylate N-WASP.
R-HSA-593672 (Reactome) Myosin-X, an unconventional myosin implicated in cell adhesion and filopodia elongation interacts with DCC and Neogenin and helps in their distribution in neurites. Myosin-X functions to transfer cargo proteins into filopodia and its hypothesized that Myosin-X may deliver DCC to filopodia on Netrin-1 stimulation.
R-HSA-593685 (Reactome) DCC and UNC5A, are also receptors for Netrin-4. The LNT domain of Netrin-4 is the key domain for this specific binding. Netrin-4 might also mediate attractive action through DCC and repulsive action through UNC5A.
R-HSA-593690 (Reactome) Netrin-1-DCC mediated signaling rapidly phosphorylates PLCgamma. Netrin-1 mediated PLC activation depends on recruitment of PITPalpha to DCC. Stimulation of PLC signaling and hydrolysis of PIP2 by netrin-1 in neurons is time-dependent, with a maximal activity observed within 15 min of netrin-1 stimulation.
R-HSA-622357 (Reactome) PIKE-L a brain-specific GTPase selectively associates with UNC5B but not with other family members of UNC5. Netrin-1 enhances this interaction and this interaction triggers the activation of PI3K kinase signalling, prevents UNC5B's pro-apoptotic activity and enhances neuronal survival.
R-HSA-622382 (Reactome) PIP2 hydrolysis appers to be an important mechanism for netrin-1 mediated neurite elongation. Netrin-1 alone could not elicit hydrolysis of PIP2 but depends on the stimulation of DCC and PLCgamma.
R-HSA-622390 (Reactome) Netrin-1, through its activation of DCC, triggers TRPC channel mediating the Ca+2 influx that is required for the growth cone turning. The effect of netrin-1 on TRP currents in the neurons is studied in Xenopus. In cultured Xenopus spinal neurons, Netrin-1 evoked Ca+2 influx and a depolarizing, TRPC-like current in both soma and growth cones. Inhibition of the Xenopus homologue of mammalian TRPC1 (XTRPC1) prevented Ca+2 influx, TRPC-like current activation and the chemotropic turning of the growth cone in response to a gradient of Netrin-1.
Netrin-1 receptor signalling to TRPC channels is mediated via hydrolysis of PIP2 by PLCgamma which then activates TRPC channel activity through IP3 and DAG.
RAC1:GDPR-HSA-418856 (Reactome)
RGDR-HSA-374692 (Reactome)
Rho GEFs DOCK and TRIOR-HSA-418858 (Reactome)
Robo:SlitR-HSA-373715 (Reactome)
SIAH1 bound to DCC:Netrin-1ArrowR-HSA-374665 (Reactome)
SIAH1R-HSA-374665 (Reactome)
SIAH2 bound to DCC:Netrin-1ArrowR-HSA-374667 (Reactome)
SIAH2R-HSA-374667 (Reactome)
SRC,FYNR-HSA-418868 (Reactome)
SRC-1mim-catalysisR-HSA-418859 (Reactome)
TRPC channelsR-HSA-622390 (Reactome)
UNC-5 receptorsR-HSA-373751 (Reactome)
UNC-5:Netrin-1 complexArrowR-HSA-373751 (Reactome)
UNC-5:Netrin-1 complexR-HSA-373713 (Reactome)
UNC5BR-HSA-622357 (Reactome)
p-Y146,Y354-EZRR-HSA-374662 (Reactome)
p-Y90,T538,S676,S695-PRKCQmim-catalysisR-HSA-374664 (Reactome)
pEzrin:PIP2ArrowR-HSA-374664 (Reactome)
pEzrin:PIP2R-HSA-374663 (Reactome)
pPLCgamma:PIP2ArrowR-HSA-593690 (Reactome)
pPLCgamma:PIP2mim-catalysisR-HSA-622382 (Reactome)
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