title: Wounding sheets of epithelial cells activates the epidermal growth factor receptor through distinct short- and long-range mechanisms.
abstract: Wounding epithelia induces activation of the epidermal growth factor receptor (EGFR), which is absolutely required for induction of motility. ATP is released from cells after wounding; it binds to purinergic receptors on the cell surface, and the EGFR is subsequently activated. Exogenous ATP activates phospholipase D, and we show here that ATP activates the EGFR through the phospholipase D2 isoform. The EGFR is activated in cells far (>0.3 cm) from wounds, which is mediated by diffusion of extracellular ATP because activation at a distance from wounds is abrogated by eliminating ATP in the medium with apyrase. In sharp contrast, activation of the EGFR near wounds is not sensitive to apyrase. Time-lapse microscopy revealed that cells exhibit increased motilities near edges of wounds; this increase in motility is not sensitive to apyrase, and apyrase does not detectably inhibit healing of wounds in epithelial sheets. This novel ATP/PLD2-independent pathway activates the EGFR by a transactivation process through ligand release, and it involves signaling by a member of the Src family of kinases. We conclude that wounding activates two distinct signaling pathways that induce EGFR activation and promote healing of wounds in epithelial cells. One pathway signals at a distance from wounds through release of ATP, and another pathway acts locally and is independent on ATP signaling.
authors.affiliation: Ophthalmology and Visual Sciences Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Ethan R
authors.initials: ER
authors.lastname: Block
authors.forename: Jes K
authors.initials: JK
authors.lastname: Klarlund
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D016850:Limbus Corneae / Q000166:cytology; D008954:Models, Biological; D010739:Phospholipase D / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D014945:Wound Healing; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D000255:Adenosine Triphosphate; D066246:ErbB Receptors; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C105606:phospholipase D2; D010739:Phospholipase D
references.citation: Biochem Cell Biol. 2004 Feb;82(1):225-53
references.pmid: 15052340
references.citation: Cell Mol Life Sci. 2007 Jun;64(12):1471-83
references.pmid: 17375261
references.citation: Cancer Res. 2004 Sep 1;64(17):6166-73
references.pmid: 15342401
references.citation: J Cell Sci. 2007 Mar 1;120(Pt 5):876-84
references.pmid: 17298977
references.citation: J Cell Biochem. 2004 Dec 15;93(6):1115-33
references.pmid: 15449317
references.citation: Kidney Int. 1995 Jul;48(1):85-92
references.pmid: 7564096
references.citation: Mol Cell Biol. 2003 May;23(9):3103-15
references.pmid: 12697812
references.citation: Invest Ophthalmol Vis Sci. 2004 Mar;45(3):813-20
references.pmid: 14985295
references.citation: Cornea. 2005 Jul;24(5):509-22
references.pmid: 15968154
references.citation: C R Biol. 2002 May;325(5):557-64
references.pmid: 12187641
references.citation: J Cell Sci. 2007 Mar 1;120(Pt 5):815-25
references.pmid: 17284517
references.citation: Am J Physiol Cell Physiol. 2006 Jul;291(1):C1-10
references.pmid: 16769815
references.citation: Biochem Soc Trans. 2003 Dec;31(Pt 6):1203-8
references.pmid: 14641026
references.citation: J Biol Chem. 2004 Apr 23;279(17):16918-26
references.pmid: 14761980
references.citation: Growth Factors. 2006 Jun;24(2):121-36
references.pmid: 16801132
references.citation: Cornea. 2005 Nov;24(8 Suppl):S2-S11
references.pmid: 16227819
references.citation: Endocrinology. 1990 Sep;127(3):1436-43
references.pmid: 1696885
references.citation: J Neurochem. 1999 Jul;73(1):334-43
references.pmid: 10386986
references.citation: Curr Opin Genet Dev. 2005 Aug;15(4):447-53
references.pmid: 15950458
references.citation: Oncogene. 2007 May 14;26(22):3113-21
references.pmid: 17496910
references.citation: Biochem Biophys Res Commun. 1989 Nov 30;165(1):319-26
references.pmid: 2556140
references.citation: Eur J Clin Invest. 1998 Jul;28(7):554-61
references.pmid: 9726036
references.citation: Front Biosci. 2007 May 01;12:2849-68
references.pmid: 17485264
references.citation: Curr Biol. 2000 Jul 13;10(14):831-8
references.pmid: 10899000
references.citation: Am J Physiol. 1992 Apr;262(4 Pt 1):C941-9
references.pmid: 1314492
references.citation: Biochem J. 1992 Jul 1;285 ( Pt 1):235-40
references.pmid: 1637305
references.citation: Biochem J. 2007 Dec 15;408(3):297-315
references.pmid: 17850214
references.citation: Invest Ophthalmol Vis Sci. 2003 Jun;44(6):2496-506
references.pmid: 12766048
references.citation: J Cell Sci. 2005 Jan 1;118(Pt 1):51-63
references.pmid: 15585576
references.citation: FEBS Lett. 2002 Oct 30;531(1):58-61
references.pmid: 12401203
references.citation: Physiol Rev. 2007 Apr;87(2):659-797
references.pmid: 17429044
references.citation: J Biol Chem. 2007 Feb 2;282(5):3213-20
references.pmid: 17135261
references.citation: Biochem Biophys Res Commun. 2005 May 27;331(1):1-14
references.pmid: 15845350
references.citation: J Biol Chem. 1992 Nov 25;267(33):23664-73
references.pmid: 1331096
references.citation: Nat Cell Biol. 2001 May;3(5):E117-23
references.pmid: 11331897
references.citation: J Cell Sci. 2001 Dec;114(Pt 23):4185-95
references.pmid: 11739651
references.citation: Novartis Found Symp. 2006;276:26-48; discussion 48-57, 275-81
references.pmid: 16805422
references.citation: Proc Natl Acad Sci U S A. 2006 May 2;103(18):6901-6
references.pmid: 16641105
references.citation: Invest Ophthalmol Vis Sci. 2000 May;41(6):1346-55
references.pmid: 10798649
references.citation: Biochem J. 1996 Jan 15;313 ( Pt 2):529-35
references.pmid: 8573088
references.citation: J Cell Biochem. 2004 Apr 1;91(5):938-50
references.pmid: 15034929
references.citation: J Mammary Gland Biol Neoplasia. 2007 Sep;12(2-3):103-14
references.pmid: 17549611
references.citation: J Immunol. 2000 Jan 1;164(1):379-88
references.pmid: 10605033
references.citation: Mol Biotechnol. 2005 Oct;31(2):151-74
references.pmid: 16170216
references.citation: J Invest Dermatol. 2004 Nov;123(5):982-9
references.pmid: 15482488
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 May;290(5):L849-55
references.pmid: 16361356
references.citation: Biochim Biophys Acta. 2007 Aug;1773(8):1161-76
references.pmid: 17306385
references.citation: Pharmacol Ther. 2006 Nov;112(2):358-404
references.pmid: 16784779
references.citation: Invest Ophthalmol Vis Sci. 2006 Jul;47(7):2832-9
references.pmid: 16799022
references.citation: J Pharmacol Exp Ther. 2005 Mar;312(3):1043-54
references.pmid: 15525798
references.citation: Exp Eye Res. 2007 Jul;85(1):130-41
references.pmid: 17490650
references.citation: IUBMB Life. 2006 Aug;58(8):457-61
references.pmid: 16916782
references.citation: Dermatol Clin. 2007 Oct;25(4):477-85, vii
references.pmid: 17903607
references.citation: Am J Pathol. 1997 Jun;150(6):1959-75
references.pmid: 9176390
references.citation: Cell Signal. 2003 Oct;15(10):927-35
references.pmid: 12873706
references.citation: J Cell Sci. 2006 Apr 15;119(Pt 8):1645-54
references.pmid: 16569667
references.citation: J Biol Chem. 2004 Jun 4;279(23):24307-12
references.pmid: 15039441
references.citation: J Lipid Res. 2002 Aug;43(8):1244-55
references.pmid: 12177168
references.citation: J Mol Biol. 1990 Oct 5;215(3):403-10
references.pmid: 2231712
references.citation: Biochim Biophys Acta. 2005 Aug 1;1751(1):110-7
references.pmid: 16054021
references.citation: Cell Mol Life Sci. 2005 Oct;62(19-20):2305-16
references.pmid: 16143829