title: Simultaneous deactivation of FAK and Src improves the pathology of hypertrophic scar.
abstract: Hypertrophic scar (HS) is a serious fibrotic skin condition with currently no satisfactory therapy due to undefined molecular mechanism. FAK and Src are two important non-receptor tyrosine kinases that have been indicated in HS pathogenesis. Here we found both FAK and Src were activated in HS vs. normal skin (NS), NS fibroblasts treated with TGF-β1 also exhibited FAK/Src activation. Co-immunoprecipitation and dual-labelled immunofluorescence revealed an enhanced FAK-Src association and co-localization in HS vs. NS. To examine effects of FAK/Src activation and their interplay on HS pathogenesis, site-directed mutagenesis followed by gene overexpression was conducted. Results showed only simultaneous overexpression of non-phosphorylatable mutant FAK Y407F and phosphomimetic mutant Src Y529E remarkably down-regulated the expression of Col I, Col III and α-SMA in cultured HS fibroblasts, alleviated extracellular matrix deposition and made collagen fibers more orderly in HS tissue vs. the effect from single transfection with wild-type or mutational FAK/Src. Glabridin, a chemical found to block FAK-Src complex formation in cancers, exhibited therapeutic effects on HS pathology probably through co-deactivation of FAK/Src which further resulted in FAK-Src de-association. This study suggests FAK-Src complex could serve as a potential molecular target, and FAK/Src double deactivation might be a novel strategy for HS therapy.
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Su
authors.affiliation: Department of Burns and Plastic Surgery, General Hospital of Lanzhou Petrochemical Company, Lanzhou, Gansu 730060, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Surgery, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Hui
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710032, 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, 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, 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, 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, China.
authors.forename: Huayu
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Dahai
authors.initials: D
authors.lastname: Hu
mesh_terms: D000199:Actins / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D017439:Cicatrix, Hypertrophic / Q000235:genetics / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology; D010766:Phosphorylation / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012867:Skin / Q000473:pathology*; D055815:Young Adult
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D024042:Collagen Type I; D024061:Collagen Type III; D007529:Isoflavones; D010636:Phenols; D051417:Focal Adhesion Kinase 1; D015688:Oncogene Protein pp60(v-src); C496050:PTK2 protein, human; C107601:glabridin