title: Src promotes cutaneous wound healing by regulating MMP-2 through the ERK pathway.
abstract: Wound healing is a highly orchestrated, multistep process, and delayed wound healing is a significant symptomatic clinical problem. Keratinocyte migration and re-epithelialization play the most important roles in wound healing, as they determine the rate of wound healing. In our previous study, we found that Src, one of the oldest proto‑oncogenes encoding a membrane-associated, non-receptor protein tyrosine kinase, promotes keratinocyte migration. We therefore hypothesized that Src promotes wound healing through enhanced keratinocyte migration. In order to test this hypothesis, vectors for overexpressing Src and small interfering RNAs (siRNAs) for silencing of Src were used in the present study. We found that the overexpression of Src accelerated keratinocyte migration in vitro and promoted wound healing in vivo without exerting a marked effect on cell proliferation. The extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways play important roles in Src-accelerated keratinocyte migration. Further experiments demonstrated that Src induced the protein expression of matrix metalloproteinase-2 (MMP-2) and decreased the protein expression of E-cadherin. We suggest that ERK signaling is involved in the Src-mediated regulation of MMP-2 expression. The present study provided evidence that Src promotes keratinocyte migration and cutaneous wound healing, in which the regulation of MMP-2 through the ERK pathway plays an important role, and thus we also demonstrated a potential therapeutic role for Src in cutaneous wound healing.
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Longlong
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Shichao
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Chaowu
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Su
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Dahai
authors.initials: D
authors.lastname: Hu
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014945:Wound Healing / Q000235:genetics / Q000502:physiology
chemical_list: D016392:Proto-Oncogene Proteins pp60(c-src); D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2
references.citation: Arch Dermatol Res. 1999 Nov;291(11):583-90
references.pmid: 10638331
references.citation: J Cell Sci. 2005 Aug 1;118(Pt 15):3471-85
references.pmid: 16079289
references.citation: Cell. 2000 Oct 27;103(3):481-90
references.pmid: 11081634
references.citation: Mol Cell Biol. 2002 Apr;22(8):2427-40
references.pmid: 11909938
references.citation: J Biol Chem. 2002 May 24;277(21):18640-8
references.pmid: 11901145
references.citation: J Biol Chem. 2002 Jun 14;277(24):21237-45
references.pmid: 11940567
references.citation: J Biol Chem. 2002 Jul 5;277(27):24252-7
references.pmid: 11983694
references.citation: Cell. 2003 Feb 21;112(4):535-48
references.pmid: 12600316
references.citation: J Med Chem. 2003 Jul 31;46(16):3514-25
references.pmid: 12877590
references.citation: Surgery. 2003 Aug;134(2):242-6
references.pmid: 12947324
references.citation: Curr Biol. 2004 Apr 20;14(8):731-5
references.pmid: 15084290
references.citation: Mol Biol Cell. 2004 Jun;15(6):2794-803
references.pmid: 15075377
references.citation: Surgery. 2004 Aug;136(2):483-8
references.pmid: 15300219
references.citation: J Cell Sci. 2004 Aug 15;117(Pt 18):4089-98
references.pmid: 15280426
references.citation: Exp Cell Res. 2004 Oct 1;299(2):465-75
references.pmid: 15350544
references.citation: Cancer Cell. 2004 Sep;6(3):209-14
references.pmid: 15380511
references.citation: Science. 1991 Mar 22;251(5000):1451-5
references.pmid: 2006419
references.citation: Cell. 1991 May 17;65(4):663-75
references.pmid: 2032290
references.citation: Science. 1997 Apr 4;276(5309):75-81
references.pmid: 9082989
references.citation: J Cell Biol. 1997 Jun 16;137(6):1445-57
references.pmid: 9182674
references.citation: J Biol Chem. 1997 Aug 29;272(35):22103-10
references.pmid: 9268353
references.citation: Annu Rev Cell Dev Biol. 1997;13:513-609
references.pmid: 9442882
references.citation: Exp Dermatol. 1997 Oct;6(5):199-213
references.pmid: 9450622
references.citation: Exp Cell Res. 1998 Jul 10;242(1):201-10
references.pmid: 9665817
references.citation: Arch Dermatol Res. 1998 Jul;290 Suppl:S47-54
references.pmid: 9710383
references.citation: Expert Opin Ther Targets. 2006 Feb;10(1):143-55
references.pmid: 16441234
references.citation: J Biol Chem. 2006 Jul 28;281(30):20851-64
references.pmid: 16728403
references.citation: J Invest Dermatol. 2006 Dec;126(12):2697-706
references.pmid: 16810296
references.citation: Front Biosci. 2007;12:2849-68
references.pmid: 17485264
references.citation: J Cell Physiol. 2008 May;215(2):292-308
references.pmid: 18247374
references.citation: Development. 2008 Apr;135(7):1355-64
references.pmid: 18305002
references.citation: Cell Mol Life Sci. 2008 Nov;65(23):3756-88
references.pmid: 18726070
references.citation: Br J Dermatol. 2010 Apr;162(4):717-23
references.pmid: 19995368
references.citation: Br J Pharmacol. 2011 Dec;164(7):1883-98
references.pmid: 21518338
references.citation: Nat Cell Biol. 2012 May;14(5):526-34
references.pmid: 22446736
references.citation: Acta Pharmacol Sin. 2012 May;33(5):606-14
references.pmid: 22465949
references.citation: J Cell Biol. 2012 Oct 15;199(2):225-34
references.pmid: 23045550
references.citation: J Cell Sci. 2012 Dec 15;125(Pt 24):5984-97
references.pmid: 23038780
references.citation: Front Biosci (Landmark Ed). 2013;18:852-61
references.pmid: 23747852
references.citation: PLoS One. 2013;8(11):e80883
references.pmid: 24278338
references.citation: J Cell Sci. 2014 Apr 15;127(Pt 8):1829-39
references.pmid: 24522188
references.citation: Oncol Rep. 2014 Jul;32(1):45-9
references.pmid: 24841138
references.citation: Am J Physiol Cell Physiol. 2014 Nov 1;307(9):C893-9
references.pmid: 25163517
references.citation: Oncotarget. 2015 Apr 10;6(10):7570-83
references.pmid: 25779657
references.citation: Am J Pathol. 2016 Jan;186(1):101-8
references.pmid: 26597882
references.citation: J Biol Chem. 1999 Apr 9;274(15):10372-81
references.pmid: 10187826
references.citation: Ann N Y Acad Sci. 1999 Jun 30;878:12-24
references.pmid: 10415717
references.citation: N Engl J Med. 1999 Sep 2;341(10):738-46
references.pmid: 10471461
references.citation: Exp Cell Res. 2005 Mar 10;304(1):274-86
references.pmid: 15707592
references.citation: J Pharmacol Exp Ther. 2005 Apr;313(1):325-32
references.pmid: 15626722
references.citation: Hypertension. 2005 Apr;45(4):773-9
references.pmid: 15699470
references.citation: Int J Mol Med. 2000 Oct;6(4):391-407
references.pmid: 10998429