title: Delayed skin wound repair in proline-rich protein tyrosine kinase 2 knockout mice.
abstract: Proline-rich protein tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family. We used Pyk2 knockout (Pyk2-KO) mice to study the role of Pyk2 in cutaneous wound repair. We report that the rate of wound closure was delayed in Pyk2-KO compared with control mice. To examine whether impaired wound healing of Pyk2-KO mice was caused by a keratinocyte cell-autonomous defect, the capacities of primary keratinocytes from Pyk2-KO and wild-type (WT) littermates to heal scratch wounds in vitro were compared. The rate of scratch wound repair was decreased in Pyk2-KO keratinocytes compared with WT cells. Moreover, cultured human epidermal keratinocytes overexpressing the dominant-negative mutant of Pyk2 failed to heal scratch wounds. Conversely, stimulation of Pyk2-dependent signaling via WT Pyk2 overexpression induced accelerated scratch wound closure and was associated with increased expression of matrix metalloproteinase (MMP)-1, MMP-9, and MMP-10. The Pyk2-stimulated increase in the rate of scratch wound repair was abolished by coexpression of the dominant-negative mutant of PKCδ and by GM-6001, a broad-spectrum inhibitor of MMP activity. These results suggest that Pyk2 is essential for skin wound reepithelialization in vivo and in vitro and that it regulates epidermal keratinocyte migration via a pathway that requires PKCδ and MMP functions.
authors.affiliation: Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; and.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Koppel
authors.affiliation: Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; and.
authors.forename: Alexi
authors.initials: A
authors.lastname: Kiss
authors.affiliation: Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; and.
authors.forename: Anna
authors.initials: A
authors.lastname: Hindes
authors.affiliation: Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; and.
authors.forename: Carole J
authors.initials: CJ
authors.lastname: Burns
authors.affiliation: Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; and.
authors.forename: Barry L
authors.initials: BL
authors.lastname: Marmer
authors.affiliation: Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; and.
authors.forename: Gregory
authors.initials: G
authors.lastname: Goldberg
authors.affiliation: R. O. Perelman Department of Dermatology, NYU Langone Medical Center, New York, New York.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Blumenberg
authors.affiliation: Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; and tefimova@dom.wustl.edu.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Efimova
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2 / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D053506:Matrix Metalloproteinase 10 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D062326:Re-Epithelialization / Q000235:genetics*; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*
chemical_list: D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse; D051745:Protein Kinase C-delta; D053506:Matrix Metalloproteinase 10; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1
keywords: epidermis; knockout mice; nonreceptor tyrosine kinase; proline-rich protein tyrosine kinase 2; wound healing