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Hepatic kinome atlas: An in‐depth identification of kinase pathways in liver fibrosis of humans and rodents
Author(s) -
Creeden Justin F.,
Kipp Zachary A.,
Xu Mei,
Flight Robert M.,
Moseley Hunter N. B.,
Martinez Genesee J.,
Lee WangHsin,
Alganem Khaled,
Imami Ali S.,
McMullen Megan R.,
Roychowdhury Sanjoy,
Nawabi Atta M.,
Hipp Jennifer A.,
Softic Samir,
Weinman Steven A.,
McCullumsmith Robert,
Nagy Laura E.,
Hinds Terry D.
Publication year - 2022
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.32467
Subject(s) - kinome , biology , kinase , receptor tyrosine kinase , fibrosis , signal transduction , cancer research , tyrosine kinase , ask1 , microbiology and biotechnology , protein kinase a , mitogen activated protein kinase kinase , medicine , pathology
Abstract Background and Aims Resolution of pathways that converge to induce deleterious effects in hepatic diseases, such as in the later stages, have potential antifibrotic effects that may improve outcomes. We aimed to explore whether humans and rodents display similar fibrotic signaling networks. Approach and Results We assiduously mapped kinase pathways using 340 substrate targets, upstream bioinformatic analysis of kinase pathways, and over 2000 random sampling iterations using the PamGene PamStation kinome microarray chip technology. Using this technology, we characterized a large number of kinases with altered activity in liver fibrosis of both species. Gene expression and immunostaining analyses validated many of these kinases as bona fide signaling events. Surprisingly, the insulin receptor emerged as a considerable protein tyrosine kinase that is hyperactive in fibrotic liver disease in humans and rodents. Discoidin domain receptor tyrosine kinase, activated by collagen that increases during fibrosis, was another hyperactive protein tyrosine kinase in humans and rodents with fibrosis. The serine/threonine kinases found to be the most active in fibrosis were dystrophy type 1 protein kinase and members of the protein kinase family of kinases. We compared the fibrotic events over four models: humans with cirrhosis and three murine models with differing levels of fibrosis, including two models of fatty liver disease with emerging fibrosis. The data demonstrate a high concordance between human and rodent hepatic kinome signaling that focalizes, as shown by our network analysis of detrimental pathways. Conclusions Our findings establish a comprehensive kinase atlas for liver fibrosis, which identifies analogous signaling events conserved among humans and rodents.