Netrin-1 signaling (Homo sapiens)

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1, 212, 13198, 101816, 1711-151921181114, 154, 5205-77-9extracellular regioncytosolFADK1:DCC oligomer:NetrinUNC-5 receptorsEzrinNetrin:DCC oligomerDCC&UNC5A:Netrin-4Netrin:DCC oligomer:pFAK:Fyn:Nck-1:Rho GEFs DOCK/TrioPhospholipase C gamma 1pEzrin:PIP2Netrin-1:DCC:pFyn:Nck:Rac1-GTP:AblimCDC42-GDPEzrin:PIP2PITPalphaSRCActivated TRP channels1D-myo-Inositol 1,4,5-trisphosphateNetrin:DCC:PITPPIKE-L:UNC5BDCC bound to UNC-5:Netrin-1Rho GEFs DOCK and TrioUNC5BDCC/NeogeninPhosphatidylinositol-4,5-bisphosphateNeogeninNeogenin:RGDGTPE3 ubiquitin-protein ligase SIAH1Netrin1:pUnc5C:DCC:Shp2GTPDCC:Robo:SlitdiacylglycerolsADPUNC-5:Netrin-1 complexATPDCCPhosphatidylinositol-4,5-bisphosphateH2OATPATPADPDCC:Ezrin complexNetrin-1:pDCC dimer:pFAK:Src/FynNterin-1:pDCC oligomer:pFAK:Fyn:NCK1Netrin:DCC:Nck:Cdc42-GTP:Active N-WASP:PIP2Netrin1:DCC oligomer:pFADK1:Fyn/srcDCCPIKE-LGDPSIAH2 bound to DCC:Netrin-1Nterin-1:DCC oligomer:pFADK1Myosin-XADPSIAH1 bound to DCC:Netrin-1pPLCgamma:PIP2SIAH2Robo:SlitGDPActive phosphorylated PKC thetaADPABLIMdiacylglycerolsNetrin-4N-WASPRGDDCC:Netrin-1Myosin-X:DCC/NeogeninATPNetrin-1:DCC:UNC5CATPDCC/UNC5ANetrin-1Phosphatidylinositol-4,5-bisphosphateTRPC channelsNetrin-1:DCC:pUNC5CActive Cdc42 bound to Netrin:DCC complexActive Rac1 bound to Netrin-1-DCC complexSrc/FynADPFADK11-Phosphatidyl-D-myo-inositol 4,5-bisphosphateRAC1-GDPNetrin-1:NeogeninSHP2NCK11D-myo-Inositol 1,4,5-trisphosphate3


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.

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Bibliography

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  1. 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
  2. Barallobre MJ, Pascual M, Del Río JA, Soriano E.; ''The Netrin family of guidance factors: emphasis on Netrin-1 signalling.''; PubMed Europe PMC Scholia
  3. 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
  4. 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
  5. 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
  6. Fuerst PG, Koizumi A, Masland RH, Burgess RW.; ''Neurite arborization and mosaic spacing in the mouse retina require DSCAM.''; PubMed Europe PMC Scholia
  7. Strübing C, Krapivinsky G, Krapivinsky L, Clapham DE.; ''Formation of novel TRPC channels by complex subunit interactions in embryonic brain.''; PubMed Europe PMC Scholia
  8. 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
  9. Shekarabi M, Kennedy TE.; ''The netrin-1 receptor DCC promotes filopodia formation and cell spreading by activating Cdc42 and Rac1.''; PubMed Europe PMC Scholia
  10. Bretscher A, Edwards K, Fehon RG.; ''ERM proteins and merlin: integrators at the cell cortex.''; PubMed Europe PMC Scholia
  11. Moore SW, Tessier-Lavigne M, Kennedy TE.; ''Netrins and their receptors.''; PubMed Europe PMC Scholia
  12. Cooper HM, Gad JM, Keeling SL.; ''The Deleted in Colorectal Cancer netrin guidance system: a molecular strategy for neuronal navigation.''; PubMed Europe PMC Scholia
  13. Yamagata M, Sanes JR.; ''Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina.''; PubMed Europe PMC Scholia
  14. 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
  15. Li W, Guan KL.; ''The Down syndrome cell adhesion molecule (DSCAM) interacts with and activates Pak.''; PubMed Europe PMC Scholia
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. Agarwala KL, Nakamura S, Tsutsumi Y, Yamakawa K.; ''Down syndrome cell adhesion molecule DSCAM mediates homophilic intercellular adhesion.''; PubMed Europe PMC Scholia
  25. Rouer E.; ''[Neuronal isoforms of Src, Fyn and Lck tyrosine kinases: A specific role for p56lckN in neuron protection].''; PubMed Europe PMC Scholia
  26. Rohatgi R, Ho HY, Kirschner MW.; ''Mechanism of N-WASP activation by CDC42 and phosphatidylinositol 4, 5-bisphosphate.''; PubMed Europe PMC Scholia
  27. 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

History

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CompareRevisionActionTimeUserComment
114889view16:40, 25 January 2021ReactomeTeamReactome version 75
113335view11:40, 2 November 2020ReactomeTeamReactome version 74
112546view15:51, 9 October 2020ReactomeTeamReactome version 73
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

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NameTypeDatabase referenceComment
1-Phosphatidyl-D-

myo-inositol 4,5- bisphosphate

Unknown18348 (ChEBI)
1D-myo-Inositol

1,4,5-trisphosphate

Metabolite16595 (ChEBI)
ABLIM ProteinREACT_22492 (Reactome)
ADP Metabolite16761 (ChEBI)
ATP Metabolite15422 (ChEBI)
Activated TRP

channels

ComplexREACT_22774 (Reactome)
Active

phosphorylated PKC theta

ProteinQ04759 (UniProt)
Active Cdc42 bound

to Netrin:DCC complex

ComplexREACT_22825 (Reactome)
Active Rac1 bound

to Netrin-1-DCC complex

ComplexREACT_22845 (Reactome)
CDC42-GDP ComplexREACT_20401 (Reactome)
DCC ProteinP43146 (UniProt)
DCC bound to UNC-

5:Netrin-1

ComplexREACT_22490 (Reactome)
DCC&UNC5A:Netrin-4 ComplexREACT_23166 (Reactome)
DCC/Neogenin ProteinREACT_22539 (Reactome)
DCC/UNC5A ProteinREACT_23092 (Reactome)
DCC:Ezrin complex ComplexREACT_22661 (Reactome)
DCC:Netrin-1 ComplexREACT_22821 (Reactome)
DCC:Robo:Slit ComplexREACT_23020 (Reactome)
E3 ubiquitin-protein

ligase SIAH1

ProteinQ8IUQ4 (UniProt)
Ezrin ProteinP15311 (UniProt)
Ezrin:PIP2 ComplexREACT_23169 (Reactome)
FADK1 ProteinQ05397 (UniProt)
FADK1:DCC

oligomer:Netrin

ComplexREACT_22770 (Reactome)
GDP Metabolite17552 (ChEBI)
GTP Metabolite15996 (ChEBI)
H2O Metabolite15377 (ChEBI)
Myosin-X ProteinQ9HD67 (UniProt)
Myosin-X:

DCC/Neogenin

ComplexREACT_23119 (Reactome)
N-WASP ProteinO00401 (UniProt)
NCK1 ProteinP16333 (UniProt)
Neogenin ProteinQ92859 (UniProt)
Neogenin:RGD ComplexREACT_23351 (Reactome)
Netrin-1 ProteinO95631 (UniProt)
Netrin-1:DCC:

UNC5C

ComplexREACT_22611 (Reactome)
Netrin-1:DCC:

pUNC5C

ComplexREACT_22595 (Reactome)
Netrin-1:DCC:pFyn:

Nck:Rac1-GTP: Ablim

ComplexREACT_23105 (Reactome)
Netrin-1:Neogenin ComplexREACT_23329 (Reactome)
Netrin-1:pDCC

dimer:pFAK:Src/Fyn

ComplexREACT_23053 (Reactome)
Netrin-4 ProteinQ9HB63 (UniProt)
Netrin1:DCC

oligomer:pFADK1: Fyn/src

ComplexREACT_22915 (Reactome)
Netrin1:pUnc5C:

DCC:Shp2

ComplexREACT_23193 (Reactome)
Netrin:DCC oligomer ComplexREACT_23248 (Reactome)
Netrin:DCC oligomer:

pFAK:Fyn:Nck-1:Rho GEFs DOCK/Trio

ComplexREACT_23304 (Reactome)
Netrin:DCC:Nck:

Cdc42-GTP:Active N-WASP:PIP2

ComplexREACT_22730 (Reactome)
Netrin:DCC:PITP ComplexREACT_23076 (Reactome)
Nterin-1:DCC

oligomer:pFADK1

ComplexREACT_23005 (Reactome)
Nterin-1:pDCC

oligomer:pFAK:Fyn: NCK1

ComplexREACT_23303 (Reactome)
PIKE-L ProteinQ99490 (UniProt)
PIKE-L:UNC5B ComplexREACT_22961 (Reactome)
PITPalpha ProteinQ00169 (UniProt)
Phosphatidylinositol-

4,5-bisphosphate

Metabolite18348 (ChEBI)
Phospholipase C

gamma 1

ProteinP19174 (UniProt)
RAC1-GDP ComplexREACT_22018 (Reactome)
RGD ProteinREACT_22662 (Reactome)
Rho GEFs DOCK and

Trio

ProteinREACT_22958 (Reactome)
Robo:Slit ComplexREACT_22837 (Reactome)
SHP2 ProteinQ06124 (UniProt)
SIAH1 bound to

DCC:Netrin-1

ComplexREACT_23235 (Reactome)
SIAH2 ProteinO43255 (UniProt)
SIAH2 bound to

DCC:Netrin-1

ComplexREACT_22880 (Reactome)
SRC ProteinP12931-1 (UniProt)
Src/Fyn ProteinREACT_22877 (Reactome)
TRPC

channels

ComplexREACT_22951 (Reactome)
UNC-5 receptors ProteinREACT_22907 (Reactome)
UNC-5:Netrin-1

complex

ComplexREACT_22538 (Reactome)
UNC5B ProteinQ8IZJ1 (UniProt)
diacylglycerols Metabolite18035 (ChEBI)
pEzrin:PIP2 ComplexREACT_22690 (Reactome)
pPLCgamma:PIP2 ComplexREACT_22512 (Reactome)

Annotated Interactions

No annotated interactions

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