{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:46:51Z","timestamp":1792630011277,"version":"4.5.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T00:00:00Z","timestamp":1655078400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T00:00:00Z","timestamp":1655078400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK47918 (to M.Bishr Omary)"],"award-info":[{"award-number":["DK47918 (to M.Bishr Omary)"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims:<\/jats:title>\n                    <jats:p>Hepatocyte keratin polypeptides 8\/18 (K8\/K18) are unique among intermediate filaments proteins (IFs) in that their mutation predisposes to, rather than causes, human disease. Mice that overexpress human K18 R90C manifest disrupted hepatocyte keratin filaments with hyperphosphorylated keratins and predisposition to Fas\u2010induced liver injury. We hypothesized that high\u2010throughput screening will identify compounds that protect the liver from mutation\u2010triggered predisposition to injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results:<\/jats:title>\n                    <jats:p>Using A549 cells transduced with a lentivirus K18 construct and high\u2010throughput screening, we identified the SRC\u2010family tyrosine kinases inhibitor, PP2, as a compound that reverses keratin filament disruption and protects from apoptotic cell death caused by K18 R90C mutation at this highly conserved arginine. PP2 also ameliorated Fas\u2010induced apoptosis and liver injury in male but not female K18 R90C mice. The PP2 male selectivity is due to its lower turnover in male versus female livers. Knockdown of SRC but not another kinase target of PP2, protein tyrosine kinase 6, in A549 cells abrogated the hepatoprotective effect of PP2. Phosphoproteomic analysis and validation showed that the protective effect of PP2 associates with Ser\/Thr but not Tyr keratin hypophosphorylation, and differs from the sex\u2010independent effect of the Ser\/Thr kinase inhibitor PKC412. Inhibition of RAF kinase, a downstream target of SRC, by vemurafenib had a similar protective effect to PP2 in A549 cells and male K18 R90C mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>PP2 protects, in a male\u2010selective manner, keratin mutation\u2010induced mouse liver injury by inhibiting SRC\u2010triggered downstream Ser\/Thr phosphorylation of K8\/K18, which is phenocopied by RAF kinase inhibitor vemurafenib. The PP2\/vemurafenib\u2010associated findings, and their unique mechanisms of action, further support the potential role of select kinase inhibition as therapeutic opportunities for keratin and other IF\u2010associated human diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.32574","type":"journal-article","created":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T03:59:27Z","timestamp":1652932767000},"page":"144-158","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":10,"title":["PP2 protects from keratin mutation\u2013associated liver injury and filament disruption via SRC kinase inhibition in male but not female mice"],"prefix":"10.1097","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1837-2753","authenticated-orcid":false,"given":"Pei","family":"Li","sequence":"first","affiliation":[{"name":"Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA"},{"name":"Center for Advanced Biotechnology & Medicine, Rutgers University, Piscataway, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8775-2963","authenticated-orcid":false,"given":"Dhiman","family":"Maitra","sequence":"additional","affiliation":[{"name":"Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA"},{"name":"Center for Advanced Biotechnology & Medicine, Rutgers University, Piscataway, New Jersey, USA"},{"name":"Early\u2010Stage Method Development & Characterization Unit, Bristol Myers Squibb, New Brunswick, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Kuo","sequence":"additional","affiliation":[{"name":"Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA"},{"name":"Center for Advanced Biotechnology & Medicine, Rutgers University, Piscataway, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Kwan","sequence":"additional","affiliation":[{"name":"Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA"},{"name":"Center for Advanced Biotechnology & Medicine, Rutgers University, Piscataway, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiliang","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2582-8803","authenticated-orcid":false,"given":"Qing","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Liu","sequence":"additional","affiliation":[{"name":"Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8624-2347","authenticated-orcid":false,"given":"M. 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