Delayed skin wound repair in proline-rich protein tyrosine kinase 2 knockout mice
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 impa...
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Veröffentlicht in: | American Journal of Physiology: Cell Physiology 2014-05, Vol.306 (10), p.C899-C909 |
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description | 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. |
doi_str_mv | 10.1152/ajpcell.00331.2013 |
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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.</description><identifier>ISSN: 0363-6143</identifier><identifier>EISSN: 1522-1563</identifier><identifier>DOI: 10.1152/ajpcell.00331.2013</identifier><identifier>PMID: 24598361</identifier><identifier>CODEN: AJPCDD</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Animals ; Cell Movement - drug effects ; Cells ; Cells, Cultured ; Dipeptides - pharmacology ; Focal Adhesion Kinase 2 - deficiency ; Focal Adhesion Kinase 2 - genetics ; Gene Expression Regulation ; Genes, Dominant ; Humans ; Keratinocytes - cytology ; Keratinocytes - drug effects ; Keratinocytes - metabolism ; Kinases ; Male ; Matrix Metalloproteinase 1 - genetics ; Matrix Metalloproteinase 1 - metabolism ; Matrix Metalloproteinase 10 - genetics ; Matrix Metalloproteinase 10 - metabolism ; Matrix Metalloproteinase 9 - genetics ; Matrix Metalloproteinase 9 - metabolism ; Matrix Metalloproteinase Inhibitors - pharmacology ; Mice ; Mice, Knockout ; Protein expression ; Protein Kinase C-delta - genetics ; Protein Kinase C-delta - metabolism ; Re-Epithelialization - genetics ; Rodents ; Signal Transduction ; Skin ; Skin - drug effects ; Skin - injuries ; Skin - metabolism ; Wound healing</subject><ispartof>American Journal of Physiology: Cell Physiology, 2014-05, Vol.306 (10), p.C899-C909</ispartof><rights>Copyright © 2014 the American Physiological Society.</rights><rights>Copyright American Physiological Society May 15, 2014</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c331t-b1f762d51b9114eeaa4ca6db7c9ee0e5825fae0dcdf4740e91cbf190d1f64f4b3</citedby><cites>FETCH-LOGICAL-c331t-b1f762d51b9114eeaa4ca6db7c9ee0e5825fae0dcdf4740e91cbf190d1f64f4b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3026,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24598361$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Koppel, Aaron C</creatorcontrib><creatorcontrib>Kiss, Alexi</creatorcontrib><creatorcontrib>Hindes, Anna</creatorcontrib><creatorcontrib>Burns, Carole J</creatorcontrib><creatorcontrib>Marmer, Barry L</creatorcontrib><creatorcontrib>Goldberg, Gregory</creatorcontrib><creatorcontrib>Blumenberg, Miroslav</creatorcontrib><creatorcontrib>Efimova, Tatiana</creatorcontrib><title>Delayed skin wound repair in proline-rich protein tyrosine kinase 2 knockout mice</title><title>American Journal of Physiology: Cell Physiology</title><addtitle>Am J Physiol Cell Physiol</addtitle><description>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.</description><subject>Animals</subject><subject>Cell Movement - drug effects</subject><subject>Cells</subject><subject>Cells, Cultured</subject><subject>Dipeptides - pharmacology</subject><subject>Focal Adhesion Kinase 2 - deficiency</subject><subject>Focal Adhesion Kinase 2 - genetics</subject><subject>Gene Expression Regulation</subject><subject>Genes, Dominant</subject><subject>Humans</subject><subject>Keratinocytes - cytology</subject><subject>Keratinocytes - drug effects</subject><subject>Keratinocytes - metabolism</subject><subject>Kinases</subject><subject>Male</subject><subject>Matrix Metalloproteinase 1 - genetics</subject><subject>Matrix Metalloproteinase 1 - metabolism</subject><subject>Matrix Metalloproteinase 10 - genetics</subject><subject>Matrix Metalloproteinase 10 - metabolism</subject><subject>Matrix Metalloproteinase 9 - genetics</subject><subject>Matrix Metalloproteinase 9 - metabolism</subject><subject>Matrix Metalloproteinase Inhibitors - pharmacology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Protein expression</subject><subject>Protein Kinase C-delta - genetics</subject><subject>Protein Kinase C-delta - metabolism</subject><subject>Re-Epithelialization - genetics</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Skin</subject><subject>Skin - drug effects</subject><subject>Skin - injuries</subject><subject>Skin - metabolism</subject><subject>Wound healing</subject><issn>0363-6143</issn><issn>1522-1563</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkE1Lw0AQhhdRbK3-AQ-y4MVL6s5-JTmK31AQQc9hs5lg2ny5myD9925s9eBpmJn3Hd55CDkHtgRQ_Nqse4t1vWRMCFhyBuKAzMOCR6C0OCRzJrSINEgxIyferxljkuv0mMy4VGkiNMzJ6x3WZosF9ZuqpV_d2BbUYW8qR0Pfu66uWoxcZT-mZsAwHLau82FKg8N4pJxu2s5uunGgTWXxlByVpvZ4tq8L8v5w_3b7FK1eHp9vb1aRDWmHKIcy1rxQkKcAEtEYaY0u8timiAxVwlVpkBW2KGUsGaZg8xJSVkCpZSlzsSBXu7sh1-eIfsiayk88TIvd6LMAQsU6iSEJ0st_0nU3ujakCyrBJNNKsaDiO5UN_3mHZda7qjFumwHLJuDZHnj2AzybgAfTxf70mDdY_Fl-CYtvBl5-Bg</recordid><startdate>20140515</startdate><enddate>20140515</enddate><creator>Koppel, Aaron C</creator><creator>Kiss, Alexi</creator><creator>Hindes, Anna</creator><creator>Burns, Carole J</creator><creator>Marmer, Barry L</creator><creator>Goldberg, Gregory</creator><creator>Blumenberg, Miroslav</creator><creator>Efimova, Tatiana</creator><general>American Physiological Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TS</scope><scope>7X8</scope></search><sort><creationdate>20140515</creationdate><title>Delayed skin wound repair in proline-rich protein tyrosine kinase 2 knockout mice</title><author>Koppel, Aaron C ; Kiss, Alexi ; Hindes, Anna ; Burns, Carole J ; Marmer, Barry L ; Goldberg, Gregory ; Blumenberg, Miroslav ; Efimova, Tatiana</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c331t-b1f762d51b9114eeaa4ca6db7c9ee0e5825fae0dcdf4740e91cbf190d1f64f4b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Cell Movement - drug effects</topic><topic>Cells</topic><topic>Cells, Cultured</topic><topic>Dipeptides - pharmacology</topic><topic>Focal Adhesion Kinase 2 - deficiency</topic><topic>Focal Adhesion Kinase 2 - genetics</topic><topic>Gene Expression Regulation</topic><topic>Genes, Dominant</topic><topic>Humans</topic><topic>Keratinocytes - cytology</topic><topic>Keratinocytes - drug effects</topic><topic>Keratinocytes - metabolism</topic><topic>Kinases</topic><topic>Male</topic><topic>Matrix Metalloproteinase 1 - genetics</topic><topic>Matrix Metalloproteinase 1 - metabolism</topic><topic>Matrix Metalloproteinase 10 - genetics</topic><topic>Matrix Metalloproteinase 10 - metabolism</topic><topic>Matrix Metalloproteinase 9 - genetics</topic><topic>Matrix Metalloproteinase 9 - metabolism</topic><topic>Matrix Metalloproteinase Inhibitors - pharmacology</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Protein expression</topic><topic>Protein Kinase C-delta - genetics</topic><topic>Protein Kinase C-delta - metabolism</topic><topic>Re-Epithelialization - genetics</topic><topic>Rodents</topic><topic>Signal Transduction</topic><topic>Skin</topic><topic>Skin - drug effects</topic><topic>Skin - injuries</topic><topic>Skin - metabolism</topic><topic>Wound healing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Koppel, Aaron C</creatorcontrib><creatorcontrib>Kiss, Alexi</creatorcontrib><creatorcontrib>Hindes, Anna</creatorcontrib><creatorcontrib>Burns, Carole J</creatorcontrib><creatorcontrib>Marmer, Barry L</creatorcontrib><creatorcontrib>Goldberg, Gregory</creatorcontrib><creatorcontrib>Blumenberg, Miroslav</creatorcontrib><creatorcontrib>Efimova, Tatiana</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Physical Education Index</collection><collection>MEDLINE - Academic</collection><jtitle>American Journal of Physiology: Cell Physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Koppel, Aaron C</au><au>Kiss, Alexi</au><au>Hindes, Anna</au><au>Burns, Carole J</au><au>Marmer, Barry L</au><au>Goldberg, Gregory</au><au>Blumenberg, Miroslav</au><au>Efimova, Tatiana</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Delayed skin wound repair in proline-rich protein tyrosine kinase 2 knockout mice</atitle><jtitle>American Journal of Physiology: Cell Physiology</jtitle><addtitle>Am J Physiol Cell Physiol</addtitle><date>2014-05-15</date><risdate>2014</risdate><volume>306</volume><issue>10</issue><spage>C899</spage><epage>C909</epage><pages>C899-C909</pages><issn>0363-6143</issn><eissn>1522-1563</eissn><coden>AJPCDD</coden><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.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>24598361</pmid><doi>10.1152/ajpcell.00331.2013</doi></addata></record> |
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subjects | Animals Cell Movement - drug effects Cells Cells, Cultured Dipeptides - pharmacology Focal Adhesion Kinase 2 - deficiency Focal Adhesion Kinase 2 - genetics Gene Expression Regulation Genes, Dominant Humans Keratinocytes - cytology Keratinocytes - drug effects Keratinocytes - metabolism Kinases Male Matrix Metalloproteinase 1 - genetics Matrix Metalloproteinase 1 - metabolism Matrix Metalloproteinase 10 - genetics Matrix Metalloproteinase 10 - metabolism Matrix Metalloproteinase 9 - genetics Matrix Metalloproteinase 9 - metabolism Matrix Metalloproteinase Inhibitors - pharmacology Mice Mice, Knockout Protein expression Protein Kinase C-delta - genetics Protein Kinase C-delta - metabolism Re-Epithelialization - genetics Rodents Signal Transduction Skin Skin - drug effects Skin - injuries Skin - metabolism Wound healing |
title | Delayed skin wound repair in proline-rich protein tyrosine kinase 2 knockout mice |
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