Netrin-UNC5B signaling Pathway (Homo sapiens)

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Netrins1-30Netrin-UNC5B signalingPancreatic ductal adenocarcinomatumorigenesisCYNUProteinmRNALigandAuto catalysisTranslocationRegulation of gene expressionLeads to through unknown mechanismInduced catalysisProtein-protein interactionLEGENDPhosphorylationProteinNucleusCytoplasmCYNUInduced activationProteinReceptorInhibitionNTN1NTN3NTN4DAPK1S308PPP1CANEO1ARHGEF12RGMAPDCSTAMPPRKCAPPP2R1BSRCPCIP2APAGAP2YFYNS472PYAP1INPP5DS397S127PLEKHH1PTPN11AKT1S473JUNS73PTK2BGSK3BTP53PIK3CARAC1RHOAUNC5BITGB4RGMANEO1IL6CCL2PTK2Y576Y397RAF1PMAP2K1Y222Y218MAP2K2Y226T394Y222DephosphorylationMAPK1MAPK3PT185Y187T202PY204JUNNOSNOPPP2CAY307PPP2CAPromotes adhesion in vascular smooth muscle cellsCTGFChondrocyte proliferation, differentiation and cell adhesionPTPATumor supressorARHGEF12OsteoclastdifferentiationOsteoclastdifferentiationOsteoclastdifferentiationInflammation, B-cell maturationChemotactic activity in monocytes and basophilsTNFRegulation of cell proliferation and differentiationIL1AImmune responses,inflammationand hematopoiesis IL10B cell survivaland proliferation COL1AOsteogenic differentiationALPLBone mineralizationICAM1Cell adhesionVCAM1Leukocyte-endothelial cell adhesionSELECell adhesionMAPK14PCASP3YAP1CYNUNucleusUNC5BPUNC5BROBO4KDRY951CytoplasmPlasma membraneCDH529


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

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  1. Hata K, Kaibuchi K, Inagaki S, Yamashita T; ''Unc5B associates with LARG to mediate the action of repulsive guidance molecule.''; J Cell Biol, 2009 PubMed Europe PMC Scholia
  2. van Gils JM, Derby MC, Fernandes LR, Ramkhelawon B, Ray TD, Rayner KJ, Parathath S, Distel E, Feig JL, Alvarez-Leite JI, Rayner AJ, McDonald TO, O'Brien KD, Stuart LM, Fisher EA, Lacy-Hulbert A, Moore KJ; ''The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques.''; Nat Immunol, 2012 PubMed Europe PMC Scholia
  3. Guenebeaud C, Goldschneider D, Castets M, Guix C, Chazot G, Delloye-Bourgeois C, Eisenberg-Lerner A, Shohat G, Zhang M, Laudet V, Kimchi A, Bernet A, Mehlen P; ''The dependence receptor UNC5H2/B triggers apoptosis via PP2A-mediated dephosphorylation of DAP kinase.''; Mol Cell, 2010 PubMed Europe PMC Scholia
  4. Wang J, Zhai W, Yu Z, Sun L, Li H, Shen H, Li X, Liu C, Chen G; ''Neuroprotection Exerted by Netrin-1 and Kinesin Motor KIF1A in Secondary Brain Injury following Experimental Intracerebral Hemorrhage in Rats.''; Front Cell Neurosci, 2017 PubMed Europe PMC Scholia
  5. 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 PubMed Europe PMC Scholia
  6. Mille F, Llambi F, Guix C, Delloye-Bourgeois C, Guenebeaud C, Castro-Obregon S, Bredesen DE, Thibert C, Mehlen P; ''Interfering with multimerization of netrin-1 receptors triggers tumor cell death.''; Cell Death Differ, 2009 PubMed Europe PMC Scholia
  7. Sato T, Kokabu S, Enoki Y, Hayashi N, Matsumoto M, Nakahira M, Sugasawa M, Yoda T; ''Functional Roles of Netrin-1 in Osteoblast Differentiation.''; In Vivo, 2017 PubMed Europe PMC Scholia
  8. Bhat SA, Gurtoo S, Deolankar SC, Fazili KM, Advani J, Shetty R, Prasad TSK, Andrabi S, Subbannayya Y; ''A network map of netrin receptor UNC5B-mediated signaling.''; J Cell Commun Signal, 2019 PubMed Europe PMC Scholia
  9. Lv J, Sun X, Ma J, Ma X, Zhang Y, Li F, Li Y, Zhao Z; ''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 PubMed Europe PMC Scholia
  10. Tang X, Jang SW, Okada M, Chan CB, Feng Y, Liu Y, Luo SW, Hong Y, Rama N, Xiong WC, Mehlen P, Ye K; ''Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B.''; Nat Cell Biol, 2008 PubMed Europe PMC Scholia
  11. He K, Jang SW, Joshi J, Yoo MH, Ye K; ''Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner.''; Mol Biol Cell, 2011 PubMed Europe PMC Scholia
  12. Ren XR, Hong Y, Feng Z, Yang HM, Mei L, Xiong WC; ''Tyrosine phosphorylation of netrin receptors in netrin-1 signaling.''; Neurosignals, 2008 PubMed Europe PMC Scholia
  13. Hayano Y, Takasu K, Koyama Y, Yamada M, Ogawa K, Minami K, Asaki T, Kitada K, Kuwabara S, Yamashita T; ''Dorsal horn interneuron-derived Netrin-4 contributes to spinal sensitization in chronic pain via Unc5B.''; J Exp Med, 2016 PubMed Europe PMC Scholia
  14. Liu J, Kong CZ, Gong DX, Zhang Z, Zhu YY; ''PKC α regulates netrin-1/UNC5B-mediated survival pathway in bladder cancer.''; BMC Cancer, 2014 PubMed Europe PMC Scholia
  15. Qi Q, Li DY, Luo HR, Guan KL, Ye K; ''Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability.''; Proc Natl Acad Sci U S A, 2015 PubMed Europe PMC Scholia
  16. Lejmi E, Leconte L, Pédron-Mazoyer S, Ropert S, Raoul W, Lavalette S, Bouras I, Feron JG, Maitre-Boube M, Assayag F, Feumi C, Alemany M, Jie TX, Merkulova T, Poupon MF, Ruchoux MM, Tobelem G, Sennlaub F, Plouët J; ''Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B.''; Proc Natl Acad Sci U S A, 2008 PubMed Europe PMC Scholia
  17. Tanikawa C, Matsuda K, Fukuda S, Nakamura Y, Arakawa H; ''p53RDL1 regulates p53-dependent apoptosis.''; Nat Cell Biol, 2003 PubMed Europe PMC Scholia
  18. Lejmi E, Bouras I, Camelo S, Roumieux M, Minet N, Leré-Déan C, Merkulova-Rainon T, Autret G, Vayssettes C, Clement O, Plouët J, Leconte L; ''Netrin-4 promotes mural cell adhesion and recruitment to endothelial cells.''; Vasc Cell, 2014 PubMed Europe PMC Scholia
  19. 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 PubMed Europe PMC Scholia
  20. 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 PubMed Europe PMC Scholia
  21. Zhang F, Prahst C, Mathivet T, Pibouin-Fragner L, Zhang J, Genet G, Tong R, Dubrac A, Eichmann A; ''The Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization.''; Nat Commun, 2016 PubMed Europe PMC Scholia
  22. Tomizawa K, Iga N, Lu YF, Moriwaki A, Matsushita M, Li ST, Miyamoto O, Itano T, Matsui H; ''Oxytocin improves long-lasting spatial memory during motherhood through MAP kinase cascade.''; Nat Neurosci, 2003 PubMed Europe PMC Scholia
  23. 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 PubMed Europe PMC Scholia
  24. Koch AW, Mathivet T, Larrivée B, Tong RK, Kowalski J, Pibouin-Fragner L, Bouvrée K, Stawicki S, Nicholes K, Rathore N, Scales SJ, Luis E, del Toro R, Freitas C, Bréant C, Michaud A, Corvol P, Thomas JL, Wu Y, Peale F, Watts RJ, Tessier-Lavigne M, Bagri A, Eichmann A; ''Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B.''; Dev Cell, 2011 PubMed Europe PMC Scholia
  25. Hayano Y, Sasaki K, Ohmura N, Takemoto M, Maeda Y, Yamashita T, Hata Y, Kitada K, Yamamoto N; ''Netrin-4 regulates thalamocortical axon branching in an activity-dependent fashion.''; Proc Natl Acad Sci U S A, 2014 PubMed Europe PMC Scholia
  26. Llambi F, Lourenço FC, Gozuacik D, Guix C, Pays L, Del Rio G, Kimchi A, Mehlen P; ''The dependence receptor UNC5H2 mediates apoptosis through DAP-kinase.''; EMBO J, 2005 PubMed Europe PMC Scholia
  27. An XZ, Zhao ZG, Luo YX, Zhang R, Tang XQ, Hao D, Zhao X, Lv X, Liu D; ''Netrin-1 suppresses the MEK/ERK pathway and ITGB4 in pancreatic cancer.''; Oncotarget, 2016 PubMed Europe PMC Scholia
  28. 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 PubMed Europe PMC Scholia
  29. 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 PubMed Europe PMC Scholia
  30. 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 PubMed Europe PMC Scholia


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108877view09:48, 4 February 2020DeSlChanged /ncbigene/5524 to correct format.
108362view14:52, 12 December 2019Marvin M2Connected line
108259view14:38, 3 December 2019L DupuisConcerted interactions to graphical lines in the legend
108141view10:33, 29 November 2019FehrhartOntology Term : 'cancer pathway' added !
107976view13:48, 18 November 2019Subbannayyaupdated gene symbols
107970view09:57, 18 November 2019SubbannayyaOntology Term : 'cancer' added !
107969view09:55, 18 November 2019SubbannayyaModified description
107968view09:52, 18 November 2019SubbannayyaNew pathway

External references


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NameTypeDatabase referenceComment
AGAP2GeneProduct116986 (Entrez Gene)
AKT1GeneProduct207 (Entrez Gene)
ALPLGeneProduct249 (Entrez Gene)
ARHGEF12GeneProduct23365 (Entrez Gene)
B cell survival and proliferation Pathway
Bone mineralizationPathway
CASP3GeneProduct836 (Entrez Gene)
CCL2GeneProduct6347 (Entrez Gene)
CDH5GeneProduct1003 (Entrez Gene)
CIP2AGeneProduct57650 (Entrez Gene)
COL1AGeneProduct1277 (Entrez Gene)
CTGF GeneProduct1490 (Entrez Gene)
Cell adhesionPathway
Chemotactic activity in monocytes and basophilsPathway
Chondrocyte proliferation,

differentiation and

cell adhesion
DAPK1GeneProduct1612 (Entrez Gene)
DCSTAMPGeneProduct81501 (Entrez Gene)
FYNGeneProduct2534 (Entrez Gene)
GSK3BGeneProduct4617 (Entrez Gene)
ICAM1GeneProduct3383 (Entrez Gene)
IL10GeneProduct3586 (Entrez Gene)
IL1AGeneProduct3552 (Entrez Gene)
IL6GeneProduct6018 (Entrez Gene)
INPP5DGeneProduct3635 (Entrez Gene)
ITGB4GeneProduct3691 (Entrez Gene)
Immune responses,


and hematopoiesis
Inflammation, B-cell maturationPathway
JUN GeneProduct3725 (Entrez Gene)
KDRGeneProduct3791 (Entrez Gene)
Leukocyte-endothelial cell adhesionPathway
MAP2K1GeneProduct5604 (Entrez Gene)
MAP2K2GeneProduct5605 (Entrez Gene)
MAPK14GeneProduct1432 (Entrez Gene)
MAPK1GeneProduct5594 (Entrez Gene)
MAPK3GeneProduct5595 (Entrez Gene)
NEO1GeneProduct4756 (Entrez Gene)
NTN1GeneProduct9423 (Entrez Gene)
NTN3GeneProduct4917 (Entrez Gene)
NTN4GeneProduct59277 (Entrez Gene)
Osteoclast differentiationPathway
Osteogenic differentiationPathway
PIK3CAGeneProduct5290 (Entrez Gene)
PLEKHH1GeneProduct57475 (Entrez Gene)
PPP1CAGeneProduct5499 (Entrez Gene)
PPP2CAGeneProduct5499 (Entrez Gene)
PPP2R1BGeneProduct5519 (Entrez Gene)
PRKCAGeneProduct5578 (Entrez Gene)
PTK2GeneProduct5747 (Entrez Gene)
PTK2BGeneProduct2185 (Entrez Gene)
PTPA GeneProduct5524 (Entrez Gene)
PTPN11GeneProduct5781 (Entrez Gene)
Pancreatic ductal
Promotes adhesion
in vascular smooth
muscle cells
ProteinProtein5894 (Entrez Gene)
RAC1GeneProduct5879 (Entrez Gene)
RAF1GeneProduct5894 (Entrez Gene)
RGMAGeneProduct56963 (Entrez Gene)
RHOAGeneProduct387 (Entrez Gene)
ROBO4GeneProduct54538 (Entrez Gene)
Regulation of

cell proliferation

and differentiation
SELEGeneProduct6401 (Entrez Gene)
SRCGeneProduct6714 (Entrez Gene)
TNFGeneProduct7124 (Entrez Gene)
TP53GeneProduct7157 (Entrez Gene)
Tumor supressorPathway
UNC5B GeneProduct219699 (Entrez Gene)
UNC5BGeneProduct219699 (Entrez Gene)
VCAM1GeneProduct7412 (Entrez Gene)
YAP1GeneProduct10413 (Entrez Gene)

Annotated Interactions

No annotated interactions

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