A network map of netrin receptor UNC5B-mediated signaling
- 294 Downloads
UNC-5 Homolog B (UNC5B) is a member of the dependence receptor family. This family of receptors 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 induces cell death in the absence of its ligand Netrin-1 and promotes cell survival in its presence. In addition, inhibition of Netrin-1 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. However, literature pertaining to UNC5B signaling is scarce and scattered. Considering the importance of UNC5B signaling, we developed a resource of signaling events mediated by UNC5B. Using data mined from published literature, we compiled an integrated pathway map consisting of 88 UNC5B-mediated signaling events and 55 proteins. These signaling events include 27 protein-protein interaction events, 33 catalytic events involving various post-translational modifications, 9 events of UNC5B-mediated protein activation/inhibition, 27 gene regulation events and 2 events of translocation. This pathway resource has been made available to the research community through NetPath (http://www.netpath.org/), a manually curated resource of signaling pathways (Database URL: http://www.netpath.org/pathways?path_id=NetPath_172). The current resource provides a foundation for the understanding of UNC5B-mediated cellular responses. The development of resource will serve researchers to explore the mechanisms of UNC-5B signaling in cancers.
KeywordsCarcinoma Tumorigenesis Netrin signaling pathway Gene set enrichment Molecular association Dependence receptors
UNC5 netrin receptor B
Protein Phosphate 2A
Deleted in colorectal cancer
Death-associated protein kinase
The work was supported by DST INSPIRE fellowship to Sameer Ahmed Bhat. We also thank Karnataka Biotechnology and Information Technology Services (KBITS), Government of Karnataka for the support to the Center for Systems Biology and Molecular Medicine at Yenepoya (Deemed to be University) under the Biotechnology Skill Enhancement Programme (BiSEP) in Multiomics Technology. We also thank the Department of Biotechnology, Government of India, for giving support to Dr. Shaida Andrabi through Ramalingaswami Fellowship.
Compliance with ethical standards
Declaration of interest
The authors report no declarations of interest.
- An XZ, Zhao ZG, Luo YX, Zhang R, Tang XQ, Hao D, Zhao X, Lv X, Liu D (2016) Netrin-1 suppresses the MEK/ERK pathway and ITGB4 in pancreatic cancer. Oncotarget 7:24719–24733Google Scholar
- Demir E, Cary MP, Paley S, Fukuda K, Lemer C, Vastrik I, Wu G, D'Eustachio P, Schaefer C, Luciano J, Schacherer F, Martinez-Flores I, Hu Z, Jimenez-Jacinto V, Joshi-Tope G, Kandasamy K, Lopez-Fuentes AC, Mi H, Pichler E, Rodchenkov I, Splendiani A, Tkachev S, Zucker J, Gopinath G, Rajasimha H, Ramakrishnan R, Shah I, Syed M, Anwar N, Babur O, Blinov M, Brauner E, Corwin D, Donaldson S, Gibbons F, Goldberg R, Hornbeck P, Luna A, Murray-Rust P, Neumann E, Ruebenacker O, Samwald M, van Iersel M, Wimalaratne S, Allen K, Braun B, Whirl-Carrillo M, Cheung KH, Dahlquist K, Finney A, Gillespie M, Glass E, Gong L, Haw R, Honig M, Hubaut O, Kane D, Krupa S, Kutmon M, Leonard J, Marks D, Merberg D, Petri V, Pico A, Ravenscroft D, Ren L, Shah N, Sunshine M, Tang R, Whaley R, Letovksy S, Buetow KH, Rzhetsky A, Schachter V, Sobral BS, Dogrusoz U, McWeeney S, Aladjem M, Birney E, Collado-Vides J, Goto S, Hucka M, Le Novere N, Maltsev N, Pandey A, Thomas P, Wingender E, Karp PD, Sander C, Bader GD (2010) The BioPAX community standard for pathway data sharing. Nat Biotechnol 28:935–942CrossRefGoogle Scholar
- 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 (2010) The dependence receptor UNC5H2/B triggers apoptosis via PP2A-mediated dephosphorylation of DAP kinase. Mol Cell 40:863–876CrossRefGoogle Scholar
- Hermjakob H, Montecchi-Palazzi L, Bader G, Wojcik J, Salwinski L, Ceol A, Moore S, Orchard S, Sarkans U, von Mering C, Roechert B, Poux S, Jung E, Mersch H, Kersey P, Lappe M, Li Y, Zeng R, Rana D, Nikolski M, Husi H, Brun C, Shanker K, Grant SG, Sander C, Bork P, Zhu W, Pandey A, Brazma A, Jacq B, Vidal M, Sherman D, Legrain P, Cesareni G, Xenarios I, Eisenberg D, Steipe B, Hogue C, Apweiler R (2004) The HUPO PSI's molecular interaction format--a community standard for the representation of protein interaction data. Nat Biotechnol 22:177–183CrossRefGoogle Scholar
- Hucka M, Finney A, Sauro HM, Bolouri H, Doyle JC, Kitano H, Arkin AP, Bornstein BJ, Bray D, Cornish-Bowden A, Cuellar AA, Dronov S, Gilles ED, Ginkel M, Gor V, Goryanin II, Hedley WJ, Hodgman TC, Hofmeyr JH, Hunter PJ, Juty NS, Kasberger JL, Kremling A, Kummer U, Le Novere N, Loew LM, Lucio D, Mendes P, Minch E, Mjolsness ED, Nakayama Y, Nelson MR, Nielsen PF, Sakurada T, Schaff JC, Shapiro BE, Shimizu TS, Spence HD, Stelling J, Takahashi K, Tomita M, Wagner J, Wang J (2003) The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 19:524–531CrossRefGoogle Scholar
- Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GS, Venugopal AK, Telikicherla D, Navarro JD, Mathivanan S, Pecquet C, Gollapudi SK, Tattikota SG, Mohan S, Padhukasahasram H, Subbannayya Y, Goel R, Jacob HK, Zhong J, Sekhar R, Nanjappa V, Balakrishnan L, Subbaiah R, Ramachandra YL, Rahiman BA, Prasad TS, Lin JX, Houtman JC, Desiderio S, Renauld JC, Constantinescu SN, Ohara O, Hirano T, Kubo M, Singh S, Khatri P, Draghici S, Bader GD, Sander C, Leonard WJ, Pandey A (2010) NetPath: a public resource of curated signal transduction pathways. Genome Biol 11:R3CrossRefGoogle Scholar
- Keshava Prasad TS, Goel R, Kandasamy K, Keerthikumar S, Kumar S, Mathivanan S, Telikicherla D, Raju R, Shafreen B, Venugopal A, Balakrishnan L, Marimuthu A, Banerjee S, Somanathan DS, Sebastian A, Rani S, Ray S, Harrys Kishore CJ, Kanth S, Ahmed M, Kashyap MK, Mohmood R, Ramachandra YL, Krishna V, Rahiman BA, Mohan S, Ranganathan P, Ramabadran S, Chaerkady R, Pandey A (2009) Human protein reference database--2009 update. Nucleic Acids Res 37:D767–D772CrossRefGoogle Scholar
- Koch AW, Mathivet T, Larrivee B, Tong RK, Kowalski J, Pibouin-Fragner L, Bouvree K, Stawicki S, Nicholes K, Rathore N, Scales SJ, Luis E, del Toro R, Freitas C, Breant C, Michaud A, Corvol P, Thomas JL, Wu Y, Peale F, Watts RJ, Tessier-Lavigne M, Bagri A, Eichmann A (2011) Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B. Dev Cell 20:33–46CrossRefGoogle Scholar
- Larrivee B, Freitas C, Trombe M, Lv X, Delafarge B, Yuan L, Bouvree K, Breant C, Del Toro R, Brechot N, Germain S, Bono F, Dol F, Claes F, Fischer C, Autiero M, Thomas JL, Carmeliet P, Tessier-Lavigne M, Eichmann A (2007) Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis. Genes Dev 21:2433–2447CrossRefGoogle Scholar
- Lu X, Le Noble F, Yuan L, Jiang Q, De Lafarge B, Sugiyama D, Breant C, Claes F, De Smet F, Thomas JL, Autiero M, Carmeliet P, Tessier-Lavigne M, Eichmann A (2004) The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 432:179–186CrossRefGoogle Scholar
- Raju R, Balakrishnan L, Nanjappa V, Bhattacharjee M, Getnet D, Muthusamy B, Kurian Thomas J, Sharma J, Rahiman BA, Harsha HC, Shankar S, Prasad TS, Mohan SS, Bader GD, Wani MR, Pandey A (2011) A comprehensive manually curated reaction map of RANKL/RANK-signaling pathway. Database (Oxford) 2011:bar021Google Scholar
- Shimizu A, Nakayama H, Wang P, Konig C, Akino T, Sandlund J, Coma S, Italiano JE Jr, Mammoto A, Bielenberg DR, Klagsbrun M (2013) Netrin-1 promotes glioblastoma cell invasiveness and angiogenesis by multiple pathways including activation of RhoA, cathepsin B, and cAMP-response element-binding protein. J Biol Chem 288:2210–2222CrossRefGoogle Scholar