title: Structure of the EGF receptor transactivation circuit integrates multiple signals with cell context.
abstract: Transactivation of the epidermal growth factor receptor (EGFR) is thought to be a process by which a variety of cellular inputs can be integrated into a single signaling pathway through either stimulated proteolysis (shedding) of membrane-anchored EGFR ligands or by modification of the activity of the EGFR. As a first step towards building a predictive model of the EGFR transactivation circuit, we quantitatively defined how signals from multiple agonists were integrated both upstream and downstream of the EGFR to regulate extracellular signal regulated kinase (ERK) activity in human mammary epithelial cells. By using a "non-binding" reporter of ligand shedding, we found that transactivation triggers a positive feedback loop from ERK back to the EGFR such that ligand shedding drives EGFR-stimulated ERK that in turn drives further ligand shedding. Importantly, activated Ras and ERK levels were nearly linear functions of ligand shedding and the effect of multiple, sub-saturating inputs was additive. Simulations showed that ERK-mediated feedback through ligand shedding resulted in a stable steady-state level of activated ERK, but also showed that the extracellular environment can modulate the level of feedback. Our results suggest that the transactivation circuit acts as a context-dependent integrator and amplifier of multiple extracellular signals and that signal integration can effectively occur at multiple points in the EGFR pathway.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Joslin
authors.forename: Harish
authors.initials: H
authors.lastname: Shankaran
authors.forename: Lee K
authors.initials: LK
authors.lastname: Opresko
authors.forename: Nikki
authors.initials: N
authors.lastname: Bollinger
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.forename: H Steven
authors.initials: HS
authors.lastname: Wiley
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D000077156:Gefitinib; D053263:Gene Regulatory Networks / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008024:Ligands; D008246:Lysophospholipids / Q000494:pharmacology; D042361:Mammary Glands, Human / Q000166:cytology; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects; D016211:Transforming Growth Factor alpha / Q000494:pharmacology
chemical_list: D005419:Flavonoids; D007093:Imidazoles; D008024:Ligands; D008246:Lysophospholipids; D011725:Pyridines; D011799:Quinazolines; D016211:Transforming Growth Factor alpha; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; C093642:SB 203580; C032881:lysophosphatidic acid; D000077156:Gefitinib; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
references.citation: J Clin Invest. 2008 Nov;118(11):3574-81
references.pmid: 18982164
references.citation: Nat Cell Biol. 2007 Aug;9(8):905-14
references.pmid: 17618274
references.citation: J Biol Chem. 2000 Jul 21;275(29):22583-9
references.pmid: 10807918
references.citation: Nat Rev Mol Cell Biol. 2006 Jul;7(7):505-16
references.pmid: 16829981
references.citation: Biophys J. 2003 Jun;84(6):3624-35
references.pmid: 12770871
references.citation: Exp Cell Res. 2004 Jul 1;297(1):224-34
references.pmid: 15194438
references.citation: Am J Physiol Cell Physiol. 2002 Mar;282(3):C545-59
references.pmid: 11832340
references.citation: J Cell Sci. 2001 Jun;114(Pt 12):2301-13
references.pmid: 11493669
references.citation: J Biol Chem. 2008 Nov 14;283(46):31477-87
references.pmid: 18782770
references.citation: Exp Cell Res. 2005 Aug 15;308(2):439-45
references.pmid: 15950968
references.citation: Trends Pharmacol Sci. 1999 Oct;20(10):408-12
references.pmid: 10577253
references.citation: Science. 2008 Oct 17;322(5900):390-5
references.pmid: 18927383
references.citation: J Biol Chem. 1996 Feb 9;271(6):3279-84
references.pmid: 8621731
references.citation: Nat Cell Biol. 2006 Nov;8(11):1195-203
references.pmid: 17060902
references.citation: Proc Natl Acad Sci U S A. 1999 May 25;96(11):6235-40
references.pmid: 10339571
references.citation: Cell. 2006 Mar 24;124(6):1225-39
references.pmid: 16564013
references.citation: Tissue Eng. 1995 Spring;1(1):81-94
references.pmid: 19877917
references.citation: J Biol Chem. 1999 Oct 1;274(40):28828-35
references.pmid: 10497257
references.citation: Biochem Soc Trans. 2003 Dec;31(Pt 6):1203-8
references.pmid: 14641026
references.citation: J Biol Chem. 1999 Nov 26;274(48):34350-60
references.pmid: 10567412
references.citation: Nat Cell Biol. 2007 Mar;9(3):324-30
references.pmid: 17310240
references.citation: J Biol Chem. 1994 Dec 23;269(51):32621-5
references.pmid: 7798267
references.citation: J Cell Sci. 2005 Jun 1;118(Pt 11):2371-80
references.pmid: 15923650
references.citation: Exp Cell Res. 2003 Mar 10;284(1):2-13
references.pmid: 12648462
references.citation: Oncogene. 1997 Feb 6;14(5):623-5
references.pmid: 9053862
references.citation: J Cell Sci. 2007 Oct 15;120(Pt 20):3688-99
references.pmid: 17895366
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Sep;291(3):L407-16
references.pmid: 16632517
references.citation: J Biol Chem. 2001 Aug 10;276(32):30475-82
references.pmid: 11402047
references.citation: Cell Signal. 2005 Oct;17(10):1183-93
references.pmid: 15982853
references.citation: Exp Cell Res. 1993 Sep;208(1):175-88
references.pmid: 7689475
references.citation: Sci STKE. 2000 Jan 18;2000(15):pe1
references.pmid: 11865189
references.citation: Mol Cell Biol. 2000 Nov;20(22):8513-25
references.pmid: 11046147
references.citation: Endocr Relat Cancer. 2001 Mar;8(1):11-31
references.pmid: 11350724
references.citation: J Proteome Res. 2008 Feb;7(2):558-69
references.pmid: 18166007
references.citation: Front Biosci. 2008 Jan 01;13:1857-65
references.pmid: 17981673
references.citation: J Cell Physiol. 2007 Dec;213(3):589-602
references.pmid: 17786953
references.citation: Biochem J. 1992 Dec 1;288 ( Pt 2):351-5
references.pmid: 1334404
references.citation: Science. 2002 May 31;296(5573):1648-9
references.pmid: 12040181
references.citation: Proc Natl Acad Sci U S A. 1989 Feb;86(4):1249-53
references.pmid: 2919173
references.citation: EMBO J. 1999 Dec 15;18(24):6962-72
references.pmid: 10601018
references.citation: Hepatology. 2008 Jul;48(1):276-88
references.pmid: 18536058
references.citation: J Cell Biol. 1998 Nov 30;143(5):1317-28
references.pmid: 9832559
references.citation: Protein Eng. 1996 Sep;9(9):781-8
references.pmid: 8888144
references.citation: J Mol Cell Cardiol. 2008 May;44(5):831-54
references.pmid: 18430438