{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:09:24Z","timestamp":1790104164977,"version":"4.0.1"},"reference-count":44,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2017,6,1]],"date-time":"2017-06-01T00:00:00Z","timestamp":1496275200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["8218\/A18673"],"award-info":[{"award-number":["8218\/A18673"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2017,7]]},"abstract":"Abstract<\/jats:title>Focal adhesion kinase (FAK<\/jats:styled-content>) inhibitors have been developed as potential anticancer agents and are undergoing clinical trials. In vitro<\/jats:italic> activation of the FAK<\/jats:styled-content> kinase domain triggers autophosphorylation of Y397<\/jats:styled-content>, Src activation, and subsequent phosphorylation of other FAK<\/jats:styled-content> tyrosine residues. However, how FAK Y397<\/jats:styled-content> mutations affect FAK<\/jats:styled-content> kinase\u2010dead (KD<\/jats:styled-content>) phenotypes in tumour angiogenesis in vivo<\/jats:italic> is unknown. We developed three Pdgfb\u2010iCreert<\/jats:sup><\/jats:styled-content>\u2010driven endothelial cell (EC<\/jats:styled-content>)\u2010specific, tamoxifen\u2010inducible homozygous mutant mouse lines: FAK<\/jats:styled-content> wild\u2010type (WT<\/jats:styled-content>), FAK KD<\/jats:styled-content>, and FAK<\/jats:styled-content> double mutant (DM<\/jats:styled-content>), i.e. KD<\/jats:styled-content> with a putatively phosphomimetic Y397E<\/jats:styled-content> mutation. These ECCre<\/jats:styled-content>+;FAKWT<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>WT<\/jats:sup><\/jats:styled-content>, ECCre<\/jats:styled-content>+;FAKKD<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>KD<\/jats:sup><\/jats:styled-content> and ECCre<\/jats:styled-content>+;FAKDM<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>DM<\/jats:sup><\/jats:styled-content> mice were injected subcutaneously with syngeneic B16F0<\/jats:styled-content> melanoma cells. Tumour growth and tumour blood vessel functions were unchanged between ECCre<\/jats:styled-content>+;FAKWT<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>WT<\/jats:sup><\/jats:styled-content> and ECCre<\/jats:styled-content>\u2212;FAKWT<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>WT<\/jats:sup><\/jats:styled-content> control mice. In contrast, tumour growth and vessel density were decreased in ECCre<\/jats:styled-content>+;FAKKD<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>KD<\/jats:sup><\/jats:styled-content> and ECCre<\/jats:styled-content>+;FAKDM<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>DM<\/jats:sup><\/jats:styled-content> mice, as compared with Cre\u2009\u2212\u2009littermates. Despite no change in the percentage of perfused vessels or pericyte coverage in either genotype, tumour hypoxia was elevated in ECCre<\/jats:styled-content>+;FAKKD<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>KD<\/jats:sup><\/jats:styled-content> and ECCre<\/jats:styled-content>+;FAKDM<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>DM<\/jats:sup><\/jats:styled-content> mice. Furthermore, although ECCre<\/jats:styled-content>+;FAKKD<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>KD<\/jats:sup><\/jats:styled-content> mice showed reduced blood vessel leakage, ECCre<\/jats:styled-content>+;FAKDM<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>DM<\/jats:sup><\/jats:styled-content> and ECCre<\/jats:styled-content>\u2212;FAKDM<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>DM<\/jats:sup><\/jats:styled-content> mice showed no difference in leakage. Mechanistically, fibronectin\u2010stimulated Y397<\/jats:styled-content> autophosphorylation was reduced in Cre+;FAKKD<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>KD<\/jats:sup> ECs<\/jats:styled-content> as compared with Cre+;FAKWT<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>WT<\/jats:sup><\/jats:styled-content> cells, with no change in phosphorylation of the known Src targets FAK\u2010Y577<\/jats:styled-content>, FAK\u2010Y861<\/jats:styled-content>, FAK\u2010Y925<\/jats:styled-content>, paxillin\u2010Y118<\/jats:styled-content>, p130Cas\u2010Y410. Cre+;FAKDM<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>DM<\/jats:sup> ECs<\/jats:styled-content> showed decreased Src target phosphorylation levels, suggesting that the Y397E<\/jats:styled-content> substitution actually disrupted Src activation. Reduced VE<\/jats:styled-content>\u2010cadherin\u2010pY658<\/jats:styled-content> levels in Cre+;FAKKD<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>KD<\/jats:sup> ECs<\/jats:styled-content> were rescued in Cre+FAKDM<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>DM<\/jats:sup> ECs<\/jats:styled-content>, corresponding with the rescue in vessel leakage in the ECCre<\/jats:styled-content>+;FAKDM<\/jats:sup><\/jats:styled-content>\/<\/jats:sup>DM<\/jats:sup><\/jats:styled-content> mice. We show that EC<\/jats:styled-content>\u2010specific FAK<\/jats:styled-content> kinase activity is required for tumour growth, angiogenesis, and vascular permeability. The ECCre+;FAKDM\/DM<\/jats:sup> mice restored the KD\u2010dependent tumour vascular leakage observed in ECCre+;FAKKD\/KD<\/jats:sup> mice in vivo<\/jats:italic>. This study opens new fields in in vivo<\/jats:italic> FAK signalling. \u00a9 2017 The Authors. The Journal of Pathology<\/jats:italic> published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.4911","type":"journal-article","created":{"date-parts":[[2017,4,26]],"date-time":"2017-04-26T07:37:43Z","timestamp":1493192263000},"page":"358-370","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Focal Adhesion Kinase (FAK) tyrosine 397E mutation restores the vascular leakage defect in endothelium\u2010specific FAK\u2010kinase dead mice"],"prefix":"10.1002","volume":"242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9404-8133","authenticated-orcid":false,"given":"Annika N","family":"Alexopoulou","sequence":"first","affiliation":[{"name":"Department of Molecular Oncology, BSRC Alexander Fleming Athens 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