title: Spatio-temporal modeling of signaling protein recruitment to EGFR.
abstract: BACKGROUND
  A stochastic simulator was implemented to study EGFR signal initiation in 3D with single molecule detail. The model considers previously unexplored contributions to receptor-adaptor coupling, such as receptor clustering and diffusive properties of both receptors and binding partners. The agent-based and rule-based approach permits consideration of combinatorial complexity, a problem associated with multiple phosphorylation sites and the potential for simultaneous binding of adaptors.
  
  
  RESULTS
  The model was used to simulate recruitment of four different signaling molecules (Grb2, PLCgamma1, Stat5, Shc) to the phosphorylated EGFR tail, with rules based on coarse-grained prediction of spatial constraints. Parameters were derived in part from quantitative immunoblotting, immunoprecipitation and electron microscopy data. Results demonstrate that receptor clustering increases the efficiency of individual adaptor retainment on activated EGFR, an effect that is overridden if crowding is imposed by receptor overexpression. Simultaneous docking of multiple proteins is highly dependent on receptor-adaptor stability and independent of clustering.
  
  
  CONCLUSIONS
  Overall, we propose that receptor density, reaction kinetics and membrane spatial organization all contribute to signaling efficiency and influence the carcinogenesis process.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Ming-yu
authors.initials: MY
authors.lastname: Hsieh
authors.forename: Shujie
authors.initials: S
authors.lastname: Yang
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Raymond-Stinz
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Edwards
authors.forename: Bridget S
authors.initials: BS
authors.lastname: Wilson
mesh_terms: D045744:Cell Line, Tumor; D016000:Cluster Analysis; D020650:Combinatorial Chemistry Techniques; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D003593:Cytoplasm / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D008962:Models, Theoretical; D010766:Phosphorylation; D015398:Signal Transduction; D013269:Stochastic Processes; D013347:Subcellular Fractions
chemical_list: D066246:ErbB Receptors
references.citation: Nat Biotechnol. 2002 Apr;20(4):370-5
references.pmid: 11923843
references.citation: Science. 1997 Sep 12;277(5332):1630-5
references.pmid: 9287210
references.citation: Mol Endocrinol. 1998 Apr;12(4):536-43
references.pmid: 9544989
references.citation: Nature. 2001 May 17;411(6835):355-65
references.pmid: 11357143
references.citation: J Biol Chem. 1990 Mar 5;265(7):3944-8
references.pmid: 1689311
references.citation: Biophys J. 2007 Aug 1;93(3):1021-31
references.pmid: 17496034
references.citation: Nature. 1993 May 6;363(6424):83-5
references.pmid: 8479540
references.citation: IET Syst Biol. 2008 Sep;2(5):256-72
references.pmid: 19045821
references.citation: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W363-7
references.pmid: 15980490
references.citation: J Biol Chem. 2002 Mar 8;277(10):8693-701
references.pmid: 11751923
references.citation: Mol Syst Biol. 2007;3:144
references.pmid: 18004277
references.citation: EMBO J. 2000 Jul 3;19(13):3159-67
references.pmid: 10880430
references.citation: J Biol Chem. 1992 Apr 25;267(12):8056-63
references.pmid: 1349015
references.citation: Cancer Res. 2003 Jul 15;63(14):3923-30
references.pmid: 12873986
references.citation: J Biol Chem. 1999 Sep 10;274(37):26091-7
references.pmid: 10473558
references.citation: Mol Syst Biol. 2005;1:2005.0008
references.pmid: 16729043
references.citation: J Mol Biol. 1991 Mar 5;218(1):183-94
references.pmid: 2002501
references.citation: Science. 1993 May 28;260(5112):1338-43
references.pmid: 8493579
references.citation: Trends Biochem Sci. 1996 Jul;21(7):257-61
references.pmid: 8755247
references.citation: Biophys J. 2003 Aug;85(2):730-43
references.pmid: 12885624
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18013-8
references.pmid: 17991782
references.citation: Biosystems. 2006 Feb-Mar;83(2-3):136-51
references.pmid: 16233948
references.citation: J Cell Sci. 2007 Aug 15;120(Pt 16):2763-73
references.pmid: 17652160
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):18992-7
references.pmid: 17146050
references.citation: Bioessays. 1991 Mar;13(3):107-13
references.pmid: 1651708
references.citation: Biochem Biophys Res Commun. 2008 Jun 27;371(2):220-4
references.pmid: 18424261
references.citation: Proteins. 2001;Suppl 5:2-7
references.pmid: 11835476
references.citation: Nature. 2006 Jan 12;439(7073):168-74
references.pmid: 16273093
references.citation: Oncogene. 2000 May 15;19(21):2474-88
references.pmid: 10851046
references.citation: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references.pmid: 11252954
references.citation: J Biol Chem. 1994 Dec 16;269(50):31653-8
references.pmid: 7527391
references.citation: Cell. 2006 Jun 16;125(6):1137-49
references.pmid: 16777603
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references.pmid: 10592235
references.citation: BMC Bioinformatics. 2008 Jan 23;9:40
references.pmid: 18215316
references.citation: Mol Cell Biol. 1993 Mar;13(3):1449-55
references.pmid: 7680095
references.citation: J Biol Chem. 2003 Jun 27;278(26):23343-51
references.pmid: 12686539
references.citation: Mol Cell Biol. 1994 Aug;14(8):5192-201
references.pmid: 7518560
references.citation: J Biol Chem. 1996 Mar 1;271(9):4770-5
references.pmid: 8617744
references.citation: J Cell Biol. 1994 Nov;127(3):847-57
references.pmid: 7962064
references.citation: Biophys J. 1999 Jun;76(6):3331-44
references.pmid: 10354459
references.citation: Nature. 1992 Dec 17;360(6405):689-92
references.pmid: 1465135
references.citation: Cell. 1992 Aug 7;70(3):431-42
references.pmid: 1322798
references.citation: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W72-6
references.pmid: 15980571
references.citation: Protein Sci. 2005 Nov;14(11):2793-803
references.pmid: 16199664
references.citation: Cell. 2002 Sep 20;110(6):669-72
references.pmid: 12297041
references.citation: J Cell Biol. 1988 Aug;107(2):801-10
references.pmid: 3262110
references.citation: Biochem Soc Trans. 2003 Oct;31(Pt 5):1020-7
references.pmid: 14505472
references.citation: Biochemistry. 1987 Mar 10;26(5):1443-51
references.pmid: 3494473
references.citation: Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3199-203
references.pmid: 7536927
references.citation: Clin Exp Metastasis. 2003;20(4):285-90
references.pmid: 12856715
references.citation: Antisense Nucleic Acid Drug Dev. 1997 Dec;7(6):539-48
references.pmid: 9450911
references.citation: Biochemistry. 1994 May 3;33(17):5070-6
references.pmid: 7513553
references.citation: Bioinformatics. 2008 Sep 15;24(18):2037-43
references.pmid: 18614583
references.citation: J Biol Chem. 1980 Sep 25;255(18):8363-5
references.pmid: 6157683
references.citation: Biophys J. 2002 May;82(5):2415-27
references.pmid: 11964230
references.citation: Nat Struct Biol. 2002 Oct;9(10):750-5
references.pmid: 12244297
references.citation: Nat Cell Biol. 2000 Mar;2(3):168-72
references.pmid: 10707088
references.citation: J Biol Chem. 1996 Mar 1;271(9):5265-9
references.pmid: 8617812
references.citation: Mol Biol Cell. 2004 Jun;15(6):2580-92
references.pmid: 15034144
references.citation: Micron. 2006;37(1):14-34
references.pmid: 16081296
references.citation: Curr Opin Struct Biol. 2005 Jun;15(3):285-9
references.pmid: 15939584
references.citation: J Biol Chem. 2005 Feb 4;280(5):3832-7
references.pmid: 15546878
references.citation: J Cell Sci. 2004 Aug 1;117(Pt 17):3785-95
references.pmid: 15252117
references.citation: EMBO J. 1998 Mar 16;17(6):1740-9
references.pmid: 9501095
references.citation: Cancer Res. 2003 Sep 1;63(17):5629-35
references.pmid: 14500405
references.citation: Biophys J. 2004 Jun;86(6):4075-93
references.pmid: 15189902
references.citation: Nature. 1978 Nov 23;276(5686):409-10
references.pmid: 309559
references.citation: J Biol Chem. 1999 Oct 15;274(42):30169-81
references.pmid: 10514507
references.citation: Biophys J. 2007 Jul 15;93(2):684-98
references.pmid: 17468161
references.citation: Mol Biol Cell. 2002 Jul;13(7):2547-57
references.pmid: 12134089
references.citation: Trends Cell Biol. 2003 Jan;13(1):43-50
references.pmid: 12480339
references.citation: J Biol Chem. 1996 Nov 29;271(48):30472-8
references.pmid: 8940013
references.citation: Biophys J. 2006 Jun 1;90(11):3993-4009
references.pmid: 16533841