Construction of a large scale integrated map of macrophage pathogen recognition and effector systems.
BACKGROUND
In an effort to better understand the molecular networks that underpin macrophage activation we have been assembling a map of relevant pathways. Manual curation of the published literature was carried out in order to define the components of these pathways and the interactions between them. This information has been assembled into a large integrated directional network and represented graphically using the modified Edinburgh Pathway Notation (mEPN) scheme.


RESULTS
The diagram includes detailed views of the toll-like receptor (TLR) pathways, other pathogen recognition systems, NF-kappa-B, apoptosis, interferon signalling, MAP-kinase cascades, MHC antigen presentation and proteasome assembly, as well as selected views of the transcriptional networks they regulate. The integrated pathway includes a total of 496 unique proteins, the complexes formed between them and the processes in which they are involved. This produces a network of 2,170 nodes connected by 2,553 edges.


CONCLUSIONS
The pathway diagram is a navigable visual aid for displaying a consensus view of the pathway information available for these systems. It is also a valuable resource for computational modelling and aid in the interpretation of functional genomics data. We envisage that this work will be of value to those interested in macrophage biology and also contribute to the ongoing Systems Biology community effort to develop a standard notation scheme for the graphical representation of biological pathways.
Raza
Sobia
S
Division of Pathway Medicine, University of Edinburgh, The Chancellor's Building, College of Medicine, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
McDerment
Neil
N
Lacaze
Paul A
PA
Robertson
Kevin
K
Watterson
Steven
S
Chen
Ying
Y
Chisholm
Michael
M
Eleftheriadis
George
G
Monk
Stephanie
S
O'Sullivan
Maire
M
Turnbull
Arran
A
Roy
Douglas
D
Theocharidis
Athanasios
A
Ghazal
Peter
P
Freeman
Tom C
TC
D001296:Audiovisual Aids; D053263:Gene Regulatory Networks / Q000276:immunology*; D007372:Interferons / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008262:Macrophage Activation / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025941:Protein Interaction Mapping / Q000379:methods*; D051193:Toll-Like Receptors / Q000378:metabolism
D016328:NF-kappa B; D051193:Toll-Like Receptors; D007372:Interferons; D046988:Proteasome Endopeptidase Complex
Genome Res. 2003 Jun;13(6B):1389-94
12819137
Prog Biophys Mol Biol. 2004 Jun-Jul;85(2-3):433-50
15142756
Genome Res. 2003 Nov;13(11):2498-504
14597658
J Immunol. 2001 Oct 1;167(7):3555-8
11564765
J Biol Chem. 2000 Nov 3;275(44):34035-40
10952994
Nat Immunol. 2009 Mar;10(3):266-72
19158679
Nat Protoc. 2009;4(10):1535-50
19798086
BMC Genomics. 2009 Aug 10;10:372
19664281
Mol Syst Biol. 2006;2:2006.0022
16738567
Mol Biol Cell. 1999 Aug;10(8):2703-34
10436023
Ann N Y Acad Sci. 2006 Oct;1082:31-43
17145922
PLoS Comput Biol. 2007 Oct;3(10):2032-42
17967053
Biochem Biophys Res Commun. 2003 Jul 11;306(4):860-6
12821121
Eur J Immunol. 2007 Nov;37 Suppl 1:S9-17
17972350
Int J Antimicrob Agents. 2008 Nov;32 Suppl 1:S44-50
18849152
EMBO J. 2004 Nov 10;23(22):4384-93
15510218
Science. 2003 Jun 6;300(5625):1524-5
12791976
J Cell Sci. 2009 Aug 15;122(Pt 16):2793-800
19657015
Mol Cell Biol. 2008 May;28(10):3139-50
18299388
Nature. 2009 Mar 26;458(7237):509-13
19158676
Mol Cell Biol. 1998 May;18(5):2640-9
9566883
N Engl J Med. 1997 Apr 10;336(15):1066-71
9091804
Hum Genet. 2008 Jul;123(6):557-98
18512079
Eur J Immunol. 2007 Feb;37(2):306-9
17273997
Semin Immunopathol. 2007 Sep;29(3):213-29
17703304
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D452-5
14681455
Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13108-13
10557281
Nature. 2007 Jul 26;448(7152):501-5
17618271
Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3274-9
16484370
BMC Biochem. 2008 Oct 21;9 Suppl 1:S7
19007437
Nat Rev Mol Cell Biol. 2009 Feb;10(2):104-15
19165213
Nucleic Acids Res. 2005 Jan 1;33(Database issue):D418-24
15608229
Nature. 2001 Oct 18;413(6857):732-8
11607032
Nature. 2001 Apr 26;410(6832):1099-103
11323673
Cell. 2007 Jun 15;129(6):1111-23
17574024
J Mol Biol. 2008 Dec 12;384(2):335-48
18823997
Nat Genet. 2002 May;31(1):19-20
11984561
Brief Bioinform. 2006 Dec;7(4):364-74
17107967
Annu Rev Immunol. 2009;27:693-733
19302050
PLoS Biol. 2008 Jul 22;6(7):e184
18651794
Annu Rev Med. 2008;59:343-59
17845139
Nat Cell Biol. 2009 May;11(5):521-6
19404331
Biol Cell. 2004 Jun;96(5):355-62
15207904
Nat Rev Mol Cell Biol. 2003 Feb;4(2):95-104
12563287
Nat Immunol. 2002 Mar;3(3):221-7
11875461
J Immunol. 2005 Feb 1;174(3):1566-73
15661917
Bioinformatics. 2009 Oct 1;25(19):2617-8
19654116
Bioinformatics. 2001 Sep;17(9):853-4
11590107
J Hepatol. 2005 Mar;42(3):431-3
15710232
Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12487-92
16891416
BMC Syst Biol. 2009 Mar 17;3:34
19292901
Nature. 2009 Mar 26;458(7237):514-8
19158675
In Silico Biol. 2005;5(4):419-23
16268787
Nucleic Acids Res. 2009 Jan;37(Database issue):D674-9
18832364
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5598-603
15034168
Nat Immunol. 2005 Oct;6(10):981-8
16127453
Cell Death Differ. 2007 Jan;14(1):10-22
16977329
Immunity. 2005 Oct;23(4):347-50
16226500
Drug Discov Today. 2008 May;13(9-10):447-56
18468563
Science. 2009 Feb 20;323(5917):1057-60
19131592
Genome Biol. 2007;8(3):R39
17367534
Proc Jpn Acad Ser B Phys Biol Sci. 2009;85(1):12-36
19145068
J Biol Chem. 2004 Apr 30;279(18):19008-17
14976215
Conf Proc IEEE Eng Med Biol Soc. 2006;2006:2009-12
17945690
Curr Opin Immunol. 2006 Feb;18(1):49-53
16338128
BMC Syst Biol. 2010 May 17;4:65
20478018
Methods Mol Biol. 2007;356:319-50
16988414
Clin Microbiol Rev. 2008 Oct;21(4):686-703
18854487
Drug Discov Today. 2005 May 15;10(10):727-34
15896686
Oncogene. 1996 Oct 3;13(7):1367-78
8875974
Adv Drug Deliv Rev. 2008 Apr 29;60(7):847-57
18280611
Genome Biol. 2008;9(12):R179
19094223
Bioinformatics. 2004 Sep 1;20(13):2156-8
15145817
J Endotoxin Res. 2002;8(6):459-63
12697090
Mol Syst Biol. 2008;4:173
18319725
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D411-4
16381900
Nat Biotechnol. 2009 Aug;27(8):735-41
19668183
Immunity. 2002 Sep;17(3):251-63
12354379
Nat Genet. 2000 Jun;25(2):187-91
10835634
Dev Biol. 2002 Jun 1;246(1):86-102
12027436
Nucleic Acids Res. 2008 Jan;36(Database issue):D480-4
18077471
Proteomics. 2008 Jun;8(11):2196-8
18452226
Trends Biochem Sci. 2007 Jul;32(7):311-9
17561400
Syst Synth Biol. 2007 Aug;1(3):145-60
19003449
Mol Syst Biol. 2005;1:2005.0010
16729045
Annu Rev Immunol. 2002;20:55-72
11861597
PLoS Comput Biol. 2008 Feb 29;4(2):e1000005
18463702
BMC Syst Biol. 2009 Jun 30;3:67
19566957
BMC Bioinformatics. 2006 Aug 18;7:386
16916470
Mol Syst Biol. 2006;2:2006.0015
16738560
Bioinformatics. 2003 Mar 1;19(4):524-31
12611808
Trends Biotechnol. 2004 Sep;22(9):446-50
15331224
Nat Biotechnol. 2005 Aug;23(8):961-6
16082367
Drug Discov Today. 2005 Jul 1;10(13):937-42
15993813
BMC Syst Biol. 2008 Apr 23;2:36
18433497
Nat Rev Immunol. 2008 Dec;8(12):911-22
18989317
J Leukoc Biol. 2005 Jul;78(1):9-13
15774547
Mol Biol Cell. 1992 Dec;3(12):1339-52
1493333
Nucleic Acids Res. 2009 Jan;37(Database issue):D412-6
18940858