Netrin-UNC5B signaling pathway (WP4747)

UNC-5 Homolog B (UNC5B) is a member of the dependence receptor family. It can induce two opposite intracellular signaling cascades depending on the presence or absence of the ligand and is thus capable of driving two opposing processes. UNC5B signaling has been implicated in several cancers, where it promotes cell death in the absence of its ligand netrin-1 and increases cell survival in its presence. In addition, inhibition of the ligand has been reported to decrease invasiveness and angiogenesis in tumors. UNC5B signaling pathway has also been reported to be involved in several processes such as neural development, developmental angiogenesis and inflammatory processes. Interaction of UNC5B with netrins activates various signaling modules including ERK1/ERK2, p38 MAPK signaling and PI3k-AKT pathway modules
last edited


Subbannayya, Fehrhart, L Dupuis, Marvin M2, DeSl, and Eweitz

Cited In


Homo sapiens



Pathway Ontology: cancer pathway

Disease Ontology: cancer


Label Type Compact Identifier
Pancreatic ductal adenocarcinomatumorigenesis Pathway None
Protein Protein ncbigene:5894
Protein Protein ncbigene:5894
NTN1 GeneProduct ncbigene:9423
NTN3 GeneProduct ncbigene:4917
NTN4 GeneProduct ncbigene:59277
DAPK1 GeneProduct ncbigene:1612
PPP1CA GeneProduct ncbigene:5499
NEO1 GeneProduct ncbigene:4756
ARHGEF12 GeneProduct ncbigene:23365
RGMA GeneProduct ncbigene:56963
DCSTAMP GeneProduct ncbigene:81501
PRKCA GeneProduct ncbigene:5578
PPP2R1B GeneProduct ncbigene:5519
SRC GeneProduct ncbigene:6714
CIP2A GeneProduct ncbigene:57650
AGAP2 GeneProduct ncbigene:116986
FYN GeneProduct ncbigene:2534
YAP1 GeneProduct ncbigene:10413
INPP5D GeneProduct ncbigene:3635
PLEKHH1 GeneProduct ncbigene:57475
PTPN11 GeneProduct ncbigene:5781
AKT1 GeneProduct ncbigene:207
JUN GeneProduct ncbigene:3725
PTK2B GeneProduct ncbigene:2185
GSK3B GeneProduct ncbigene:4617
TP53 GeneProduct ncbigene:7157
PIK3CA GeneProduct ncbigene:5290
RAC1 GeneProduct ncbigene:5879
RHOA GeneProduct ncbigene:387
UNC5B GeneProduct ncbigene:219699
ITGB4 GeneProduct ncbigene:3691
RGMA GeneProduct ncbigene:56963
NEO1 GeneProduct ncbigene:4756
IL6 GeneProduct ncbigene:6018
CCL2 GeneProduct ncbigene:6347
PTK2 GeneProduct ncbigene:5747
RAF1 GeneProduct ncbigene:5894
MAP2K1 GeneProduct ncbigene:5604
MAP2K2 GeneProduct ncbigene:5605
MAPK1 GeneProduct ncbigene:5594
MAPK3 GeneProduct ncbigene:5595
JUN GeneProduct ncbigene:3725
NOS Pathway None
NO Pathway None
PPP2CA GeneProduct ncbigene:5499
PPP2CA GeneProduct ncbigene:5499
Promotes adhesion in vascular smooth muscle cells Pathway None
CTGF GeneProduct ncbigene:1490
Chondrocyte proliferation, differentiation and cell adhesion Pathway None
PTPA GeneProduct ncbigene:5524
Tumor supressor Pathway None
ARHGEF12 GeneProduct ncbigene:23365
Osteoclastdifferentiation Pathway None
Osteoclastdifferentiation Pathway None
Osteoclastdifferentiation Pathway None
Inflammation, B-cell maturation Pathway None
Chemotactic activity in monocytes and basophils Pathway None
TNF GeneProduct ncbigene:7124
Regulation of cell proliferation and differentiation Pathway None
IL1A GeneProduct ncbigene:3552
Immune responses,inflammationand hematopoiesis Pathway None
IL10 GeneProduct ncbigene:3586
B cell survivaland proliferation Pathway None
COL1A GeneProduct ncbigene:1277
Osteogenic differentiation Pathway None
ALPL GeneProduct ncbigene:249
Bone mineralization Pathway None
ICAM1 GeneProduct ncbigene:3383
Cell adhesion Pathway None
VCAM1 GeneProduct ncbigene:7412
Leukocyte-endothelial cell adhesion Pathway None
SELE GeneProduct ncbigene:6401
Cell adhesion Pathway None
MAPK14 GeneProduct ncbigene:1432
CASP3 GeneProduct ncbigene:836
YAP1 GeneProduct ncbigene:10413
UNC5B GeneProduct ncbigene:219699
UNC5B GeneProduct ncbigene:219699
ROBO4 GeneProduct ncbigene:54538
KDR GeneProduct ncbigene:3791
CDH5 GeneProduct ncbigene:1003


  1. Wang H, Copeland NG, Gilbert DJ, Jenkins NA, Tessier-Lavigne M. Netrin-3, a mouse homolog of human NTN2L, is highly expressed in sensory ganglia and shows differential binding to netrin receptors. J Neurosci. 1999 Jun 15;19(12):4938–47. PubMed Europe PMC Scholia
  2. Llambi F, Causeret F, Bloch-Gallego E, Mehlen P. Netrin-1 acts as a survival factor via its receptors UNC5H and DCC. EMBO J. 2001 Jun 1;20(11):2715–22. PubMed Europe PMC Scholia
  3. Huang X, Cheng HJ, Tessier-Lavigne M, Jin Y. MAX-1, a novel PH/MyTH4/FERM domain cytoplasmic protein implicated in netrin-mediated axon repulsion. Neuron. 2002 May 16;34(4):563–76. PubMed Europe PMC Scholia
  4. Tomizawa K, Iga N, Lu Y-F, Moriwaki A, Matsushita M, Li S-T, et al. Oxytocin improves long-lasting spatial memory during motherhood through MAP kinase cascade. Nat Neurosci. 2003 Apr;6(4):384–90. PubMed Europe PMC Scholia
  5. Tanikawa C, Matsuda K, Fukuda S, Nakamura Y, Arakawa H. p53RDL1 regulates p53-dependent apoptosis. Nat Cell Biol. 2003 Mar;5(3):216–23. PubMed Europe PMC Scholia
  6. Llambi F, Lourenço FC, Gozuacik D, Guix C, Pays L, Del Rio G, et al. The dependence receptor UNC5H2 mediates apoptosis through DAP-kinase. EMBO J. 2005 Mar 23;24(6):1192–201. PubMed Europe PMC Scholia
  7. Wang W, Reeves WB, Ramesh G. Netrin-1 and kidney injury. I. Netrin-1 protects against ischemia-reperfusion injury of the kidney. Am J Physiol Renal Physiol. 2008 Apr;294(4):F739-47. PubMed Europe PMC Scholia
  8. Ren X-R, Hong Y, Feng Z, Yang H-M, Mei L, Xiong W-C. Tyrosine phosphorylation of netrin receptors in netrin-1 signaling. Neurosignals. 2008;16(2–3):235–45. PubMed Europe PMC Scholia
  9. Tang X, Jang S-W, Okada M, Chan C-B, Feng Y, Liu Y, et al. Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B. Nat Cell Biol. 2008 Jun;10(6):698–706. PubMed Europe PMC Scholia
  10. Lejmi E, Leconte L, Pédron-Mazoyer S, Ropert S, Raoul W, Lavalette S, et al. Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B. Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12491–6. PubMed Europe PMC Scholia
  11. Wang W, Reeves WB, Ramesh G. Netrin-1 increases proliferation and migration of renal proximal tubular epithelial cells via the UNC5B receptor. Am J Physiol Renal Physiol. 2009 Apr;296(4):F723-9. PubMed Europe PMC Scholia
  12. Hata K, Kaibuchi K, Inagaki S, Yamashita T. Unc5B associates with LARG to mediate the action of repulsive guidance molecule. J Cell Biol. 2009 Mar 9;184(5):737–50. PubMed Europe PMC Scholia
  13. Mille F, Llambi F, Guix C, Delloye-Bourgeois C, Guenebeaud C, Castro-Obregon S, et al. Interfering with multimerization of netrin-1 receptors triggers tumor cell death. Cell Death Differ. 2009 Oct;16(10):1344–51. PubMed Europe PMC Scholia
  14. Tadagavadi RK, Wang W, Ramesh G. Netrin-1 regulates Th1/Th2/Th17 cytokine production and inflammation through UNC5B receptor and protects kidney against ischemia-reperfusion injury. J Immunol. 2010 Sep 15;185(6):3750–8. PubMed Europe PMC Scholia
  15. Guenebeaud C, Goldschneider D, Castets M, Guix C, Chazot G, Delloye-Bourgeois C, et al. The dependence receptor UNC5H2/B triggers apoptosis via PP2A-mediated dephosphorylation of DAP kinase. Mol Cell. 2010 Dec 22;40(6):863–76. PubMed Europe PMC Scholia
  16. Koch AW, Mathivet T, Larrivée B, Tong RK, Kowalski J, Pibouin-Fragner L, et al. Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B. Dev Cell. 2011 Jan 18;20(1):33–46. PubMed Europe PMC Scholia
  17. He K, Jang S-W, Joshi J, Yoo M-H, Ye K. Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner. Mol Biol Cell. 2011 Jun 1;22(11):1943–54. PubMed Europe PMC Scholia
  18. van Gils JM, Derby MC, Fernandes LR, Ramkhelawon B, Ray TD, Rayner KJ, et al. The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat Immunol. 2012 Jan 8;13(2):136–43. PubMed Europe PMC Scholia
  19. Lejmi E, Bouras I, Camelo S, Roumieux M, Minet N, Leré-Déan C, et al. Netrin-4 promotes mural cell adhesion and recruitment to endothelial cells. Vasc Cell. 2014 Jan 28;6(1):1. PubMed Europe PMC Scholia
  20. Liu J, Kong C, Gong D, Zhang Z, Zhu Y. PKC α regulates netrin-1/UNC5B-mediated survival pathway in bladder cancer. BMC Cancer. 2014 Feb 15;14:93. PubMed Europe PMC Scholia
  21. Hayano Y, Sasaki K, Ohmura N, Takemoto M, Maeda Y, Yamashita T, et al. Netrin-4 regulates thalamocortical axon branching in an activity-dependent fashion. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15226–31. PubMed Europe PMC Scholia
  22. Mediero A, Ramkhelawon B, Perez-Aso M, Moore KJ, Cronstein BN. Netrin-1 is a critical autocrine/paracrine factor for osteoclast differentiation. J Bone Miner Res. 2015 May;30(5):837–54. PubMed Europe PMC Scholia
  23. Qi Q, Li DY, Luo HR, Guan K-L, Ye K. Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability. Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):7255–60. PubMed Europe PMC Scholia
  24. Lv J, Sun X, Ma J, Ma X, Zhang Y, Li F, et al. Netrin-1 induces the migration of Schwann cells via p38 MAPK and PI3K-Akt signaling pathway mediated by the UNC5B receptor. Biochem Biophys Res Commun. 2015 Aug 14;464(1):263–8. PubMed Europe PMC Scholia
  25. An X-Z, Zhao Z-G, Luo Y-X, Zhang R, Tang X-Q, Hao D-L, et al. Netrin-1 suppresses the MEK/ERK pathway and ITGB4 in pancreatic cancer. Oncotarget. 2016 Apr 26;7(17):24719–33. PubMed Europe PMC Scholia
  26. Hayano Y, Takasu K, Koyama Y, Yamada M, Ogawa K, Minami K, et al. Dorsal horn interneuron-derived Netrin-4 contributes to spinal sensitization in chronic pain via Unc5B. J Exp Med. 2016 Dec 12;213(13):2949–66. PubMed Europe PMC Scholia
  27. Zhang F, Prahst C, Mathivet T, Pibouin-Fragner L, Zhang J, Genet G, et al. The Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization. Nat Commun. 2016 Nov 24;7:13517. PubMed Europe PMC Scholia
  28. Sato T, Kokabu S, Enoki Y, Hayashi N, Matsumoto M, Nakahira M, et al. Functional Roles of Netrin-1 in Osteoblast Differentiation. In Vivo. 2017;31(3):321–8. PubMed Europe PMC Scholia
  29. Wang J, Zhai W, Yu Z, Sun L, Li H, Shen H, et al. Neuroprotection Exerted by Netrin-1 and Kinesin Motor KIF1A in Secondary Brain Injury following Experimental Intracerebral Hemorrhage in Rats. Front Cell Neurosci. 2018 Jan 11;11:432. PubMed Europe PMC Scholia
  30. Bhat SA, Gurtoo S, Deolankar SC, Fazili KM, Advani J, Shetty R, et al. A network map of netrin receptor UNC5B-mediated signaling. J Cell Commun Signal. 2019 Mar;13(1):121–7. PubMed Europe PMC Scholia