title: A new scheme to discover functional associations and regulatory networks of E3 ubiquitin ligases.
abstract: BACKGROUND
  Protein ubiquitination catalyzed by E3 ubiquitin ligases play important modulatory roles in various biological processes. With the emergence of high-throughput mass spectrometry technology, the proteomics research community embraced the development of numerous experimental methods for the determination of ubiquitination sites. The result is an accumulation of ubiquitinome data, coupled with a lack of available resources for investigating the regulatory networks among E3 ligases and ubiquitinated proteins. In this study, by integrating existing ubiquitinome data, experimentally validated E3 ligases and established protein-protein interactions, we have devised a strategy to construct a comprehensive map of protein ubiquitination networks.
  
  
  RESULTS
  In total, 41,392 experimentally verified ubiquitination sites from 12,786 ubiquitinated proteins of humans have been obtained for this study. Additional 494 E3 ligases along with 1220 functional annotations and 28588 protein domains were manually curated. To characterize the regulatory networks among E3 ligases and ubiquitinated proteins, a well-established network viewer was utilized for the exploration of ubiquitination networks from 40892 protein-protein interactions. The effectiveness of the proposed approach was demonstrated in a case study examining E3 ligases involved in the ubiquitination of tumor suppressor p53. In addition to Mdm2, a known regulator of p53, the investigation also revealed other potential E3 ligases that may participate in the ubiquitination of p53.
  
  
  CONCLUSIONS
  Aside from the ability to facilitate comprehensive investigations of protein ubiquitination networks, by integrating information regarding protein-protein interactions and substrate specificities, the proposed method could discover potential E3 ligases for ubiquitinated proteins. Our strategy presents an efficient means for the preliminary screen of ubiquitination networks and overcomes the challenge as a result of limited knowledge about E3 ligase-regulated ubiquitination.
authors.affiliation: Department of Computer Science and Engineering, Yuan Ze University, Taoyuan, 320, Taiwan. kaiyao.tw@gmail.com.
authors.forename: Kai-Yao
authors.initials: KY
authors.lastname: Huang
authors.affiliation: Department of Computer Science and Engineering, Yuan Ze University, Taoyuan, 320, Taiwan. julweng@saturn.yzu.edu.tw.|Innovation Center for Big Data and Digital Convergence, Yuan Ze University, Taoyuan, 320, Taiwan. julweng@saturn.yzu.edu.tw.
authors.forename: Julia Tzu-Ya
authors.initials: JT
authors.lastname: Weng
authors.affiliation: Department of Computer Science and Engineering, Yuan Ze University, Taoyuan, 320, Taiwan. francis@saturn.yzu.edu.tw.|Innovation Center for Big Data and Digital Convergence, Yuan Ze University, Taoyuan, 320, Taiwan. francis@saturn.yzu.edu.tw.
authors.forename: Tzong-Yi
authors.initials: TY
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Hsinchu Mackay Memorial Hospital, Hsin-Chu, 300, Taiwan. 4467@mmh.org.tw.|Mackay Junior College of Medicine, Nursing and Management, Taipei, 112, Taiwan. 4467@mmh.org.tw.|Department of Medicine, Mackay Medical College, New Taipei City, 252, Taiwan. 4467@mmh.org.tw.
authors.forename: Shun-Long
authors.initials: SL
authors.lastname: Weng
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D066289:Data Curation; D030562:Databases, Protein; D006801:Humans; D013058:Mass Spectrometry; D000072417:Protein Domains; D060066:Protein Interaction Maps; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D044767:Ubiquitin-Protein Ligases
references.citation: Nucleic Acids Res. 2007 Jul;35(Web Server issue):W588-94
references.pmid: 17517770
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15280-2
references.pmid: 16230621
references.citation: J Biol Chem. 2000 Mar 24;275(12 ):8945-51
references.pmid: 10722742
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D445-51
references.pmid: 23172288
references.citation: BMC Bioinformatics. 2013;14 Suppl 16:S2
references.pmid: 24564522
references.citation: Annu Rev Biochem. 1998;67:425-79
references.pmid: 9759494
references.citation: Bioinformatics. 2012 Sep 1;28(17):2293-5
references.pmid: 22782549
references.citation: Cancer Biol Ther. 2003 Nov-Dec;2(6):623-9
references.pmid: 14688465
references.citation: Immunol Rev. 2005 Oct;207:145-57
references.pmid: 16181333
references.citation: PLoS One. 2012;7(7):e40694
references.pmid: 22844408
references.citation: Mol Cell Proteomics. 2012 Apr;11(4):O111.014076
references.pmid: 22199232
references.citation: Genes Dev. 2010 Aug 1;24(15):1580-9
references.pmid: 20679392
references.citation: Proc Natl Acad Sci U S A. 1995 May 23;92 (11):5249
references.pmid: 7761480
references.citation: Oncogene. 2000 Mar 9;19(11):1473-6
references.pmid: 10723139
references.citation: Biochem J. 2006 Nov 1;399(3):361-72
references.pmid: 17034365
references.citation: Biochim Biophys Acta. 2014 Apr;1845(2):277-93
references.pmid: 24569229
references.citation: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W226-9
references.pmid: 15980458
references.citation: Database (Oxford). 2011 Nov 30;2011:bar055
references.pmid: 22134927
references.citation: Proteins. 1997 Jul;28(3):405-20
references.pmid: 9223186
references.citation: Nature. 1997 May 15;387(6630):299-303
references.pmid: 9153396
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D295-305
references.pmid: 23193290
references.citation: Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W416-22
references.pmid: 18483079
references.citation: BMC Bioinformatics. 2014;15 Suppl 16:S1
references.pmid: 25521204
references.citation: Curr Genomics. 2006;7(8):509-22
references.pmid: 18369404
references.citation: J Cell Sci. 2004 Oct 15;117(Pt 22):5191-4
references.pmid: 15483315
references.citation: Cancer Res. 2014 Sep 1;74(17 ):4783-95
references.pmid: 24994714
references.citation: PLoS One. 2011;6(7):e21849
references.pmid: 21789187
references.citation: Biomed Res Int. 2014;2014:918183
references.pmid: 24868554
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D537-45
references.pmid: 24302577
references.citation: Bioinformatics. 2006 Jun 15;22(12):1536-7
references.pmid: 16632492
references.citation: Genome Res. 2004 Jun;14(6):1188-90
references.pmid: 15173120
references.citation: Bioinformatics. 2011 Jul 1;27(13):1780-7
references.pmid: 21551145
references.citation: Nature. 1997 May 15;387(6630):296-9
references.pmid: 9153395
references.citation: Biochem J. 2014 Mar 15;458(3):421-37
references.pmid: 24576094
references.citation: PLoS One. 2008 Jan 23;3(1):e1487
references.pmid: 18213395
references.citation: BMC Biochem. 2007 Nov 22;8 Suppl 1:S6
references.pmid: 18047743
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D777-87
references.pmid: 21037261
references.citation: FEBS Lett. 1997 Dec 22;420(1):25-7
references.pmid: 9450543
references.citation: Nucleic Acids Res. 2003 Jan 1;31(1):258-61
references.pmid: 12519996
references.citation: Science. 2007 Jan 12;315(5809):201-5
references.pmid: 17218518
references.citation: Front Plant Sci. 2014 Feb 13;5:42
references.pmid: 24592270
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D306-12
references.pmid: 22096229
references.citation: Biochem Soc Trans. 2010 Feb;38(Pt 1):65-71
references.pmid: 20074037
references.citation: PLoS One. 2015 Apr 07;10(4):e0118752
references.pmid: 25849935
references.citation: Cell. 2000 Aug 18;102(4):533-9
references.pmid: 10966114
references.citation: J Cell Sci. 2012 Feb 1;125(Pt 3):531-7
references.pmid: 22389392
references.citation: World J Clin Oncol. 2013 Aug 10;4(3):58-69
references.pmid: 23936758
references.citation: Bioinformatics. 2014 Aug 15;30(16):2386-8
references.pmid: 24790154
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D622-7
references.pmid: 16381945
references.citation: J Biol Chem. 2003 Sep 19;278(38):35857-60
references.pmid: 12860974
references.citation: Nature. 2012 Sep 6;489(7414):115-20
references.pmid: 22842904
references.citation: Methods Mol Biol. 2011;696:291-303
references.pmid: 21063955
references.citation: Nucleic Acids Res. 1998 Jan 1;26(1):323-6
references.pmid: 9399865
references.citation: Nat Rev Mol Cell Biol. 2009 Jun;10 (6):398-409
references.pmid: 19436320
references.citation: Mol Cell Proteomics. 2011 Oct;10 (10 ):M111.013284
references.pmid: 21890473
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D530-5
references.pmid: 23161678
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D109-14
references.pmid: 22080510
references.citation: Cell Death Differ. 2010 Jan;17 (1):86-92
references.pmid: 19543236
references.citation: Nucleic Acids Res. 1991 Apr 25;19 Suppl:2241-5
references.pmid: 2041810
references.citation: PLoS One. 2011 Mar 09;6(3):e17331
references.pmid: 21408064
references.citation: Nat Rev Mol Cell Biol. 2005 Aug;6(8):610-21
references.pmid: 16064137
references.citation: Nucleic Acids Res. 2015 Jan;43(Database issue):D503-11
references.pmid: 25399423
references.citation: Nat Biotechnol. 2003 Aug;21(8):921-6
references.pmid: 12872131
references.citation: Methods Mol Biol. 2013;960:109-25
references.pmid: 23329482
references.citation: Nucleic Acids Res. 1990 Oct 25;18(20):6097-100
references.pmid: 2172928
references.citation: J Cell Sci. 2006 Jun 15;119(Pt 12):2401-4
references.pmid: 16763193
references.citation: BMC Bioinformatics. 2015 ;16 Suppl 1:S1
references.pmid: 25707307
references.citation: BMC Bioinformatics. 2011 Jun 26;12:261
references.pmid: 21703007
references.citation: Physiol Rev. 2002 Apr;82(2):373-428
references.pmid: 11917093
references.citation: Nucleic Acids Res. 1999 Jan 1;27(1):29-34
references.pmid: 9847135
references.citation: Nucleic Acids Res. 2003 Jan 1;31(1):365-70
references.pmid: 12520024
references.citation: Nucleic Acids Res. 1994 Sep;22(17):3590-6
references.pmid: 7937065
references.citation: Database (Oxford). 2014 Apr 25;2014(0):bau034
references.pmid: 24771658
references.citation: Cancer Cell. 2008 Jul 8;14 (1):10-21
references.pmid: 18598940
references.citation: Nat Struct Mol Biol. 2014 Apr;21(4):301-7
references.pmid: 24699078