Netrin-1 signaling (Homo sapiens)

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1, 216, 17198, 1012, 1311-1519201814, 154, 55-77-9181121extracellular regioncytosolRGDSIAH1 bound to DCC:Netrin-1Ezrin:PIP2ADPADPPhospholipase C gamma 1Netrin-1:DCC:UNC5CNetrin-1:pDCC dimer:pFAK:Src/FynNCK1Netrin-1:DCC:pUNC5CDCC/UNC5ATRPC channelsADPNeogenin:RGDNetrin1:pUnc5C:DCC:Shp21D-myo-Inositol 1,4,5-trisphosphateDCC:Ezrin complexPhosphatidylinositol-4,5-bisphosphateActive phosphorylated PKC thetaATPNetrin-1:DCC:pFyn:Nck:Rac1-GTP:AblimCDC42-GDPSRCFADK1:DCC oligomer:NetrinActive Rac1 bound to Netrin-1-DCC complexpPLCgamma:PIP2Myosin-XSIAH2 bound to DCC:Netrin-1Netrin:DCC:PITPDCC:Robo:SlitATPEzrinActivated TRP channelsADPNetrin1:DCC oligomer:pFADK1:Fyn/srcSHP2N-WASPDCC:Netrin-1UNC-5 receptorsPITPalphaPhosphatidylinositol-4,5-bisphosphatepEzrin:PIP2PIKE-LATPMyosin-X:DCC/NeogeninDCC&UNC5A:Netrin-4SIAH2E3 ubiquitin-protein ligase SIAH1Robo:SlitFADK1DCCNetrin-4Active Cdc42 bound to Netrin:DCC complexNetrin-1DCCGDPUNC-5:Netrin-1 complexPIKE-L:UNC5BADPdiacylglycerolsNetrin:DCC oligomer:pFAK:Fyn:Nck-1:Rho GEFs DOCK/TrioPhosphatidylinositol-4,5-bisphosphateGTPNetrin:DCC:Nck:Cdc42-GTP:Active N-WASP:PIP2UNC5BNterin-1:pDCC oligomer:pFAK:Fyn:NCK1ATPSrc/FynH2ORho GEFs DOCK and TrioNeogenin1D-myo-Inositol 1,4,5-trisphosphateNetrin:DCC oligomerGDPNetrin-1:NeogenindiacylglycerolsDCC bound to UNC-5:Netrin-1ATPABLIMDCC/Neogenin1-Phosphatidyl-D-myo-inositol 4,5-bisphosphateGTPRAC1-GDPNterin-1:DCC oligomer:pFADK13


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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  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


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External references


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NameTypeDatabase referenceComment

myo-inositol 4,5- bisphosphate

Unknown18348 (ChEBI)


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


ComplexREACT_22774 (Reactome)

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-


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)


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


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


ComplexREACT_22611 (Reactome)


ComplexREACT_22595 (Reactome)

Nck:Rac1-GTP: Ablim

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


ComplexREACT_23053 (Reactome)
Netrin-4 ProteinQ9HB63 (UniProt)

oligomer:pFADK1: Fyn/src

ComplexREACT_22915 (Reactome)


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

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

ComplexREACT_23304 (Reactome)

Cdc42-GTP:Active N-WASP:PIP2

ComplexREACT_22730 (Reactome)
Netrin:DCC:PITP ComplexREACT_23076 (Reactome)


ComplexREACT_23005 (Reactome)

oligomer:pFAK:Fyn: NCK1

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


Metabolite18348 (ChEBI)
Phospholipase C

gamma 1

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


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


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


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


ComplexREACT_22951 (Reactome)
UNC-5 receptors ProteinREACT_22907 (Reactome)


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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