ArticleHepatology (Baltimore, Md.)2015
PKC412 normalizes mutation-related keratin filament disruption and hepatic injury in mice by promoting keratin-myosin binding.
Article in Hepatology (Baltimore, Md.), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 32 citations in OpenAlex.
- Keratin filaments and soluble vimentin interact with isoform specificity to organize cell signaling.Genes & development · 2026Article
- Regulation of Keratin Chemical Modifications: Potential Molecular Mechanisms in Proliferative Diseases.International journal of molecular sciences · 2026Review
- Pathological Mechanisms Involved in Epidermolysis Bullosa Simplex: Current Knowledge and Therapeutic Perspectives.International journal of molecular sciences · 2024Review
- Deacetylation via SIRT2 prevents keratin-mutation-associated injury and keratin aggregation.JCI insight · 2023Article
- A cell-based drug discovery assay identifies inhibition of cell stress responses as a new approach to treatment of epidermolysis bullosa simplex.Journal of cell science · 2021Article
- Cytoskeletal control of early mammalian development.Nature reviews. Molecular cell biology · 2021Review
- Article
- Growth, lifetime, directional movement and myosin-dependent motility of mutant keratin granules in cultured cells.Scientific reports · 2021Article
- Targeting and extending the eukaryotic druggable genome with natural products: cytoskeletal targets of natural products.Natural product reports · 2020Review
- Intermediate filaments and IF-associated proteins: from cell architecture to cell proliferation.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2019Review
- Keratin 6 regulates collective keratinocyte migration by altering cell-cell and cell-matrix adhesion.The Journal of cell biology · 2018Article
- The role of keratins in the digestive system: lessons from transgenic mouse models.Histochemistry and cell biology · 2018Review
- Types I and II Keratin Intermediate Filaments.Cold Spring Harbor perspectives in biology · 2018Review
- Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics.Cold Spring Harbor perspectives in biology · 2017Review
- Intracellular Motility of Intermediate Filaments.Cold Spring Harbor perspectives in biology · 2017Review
- Intermediate filament proteins of digestive organs: physiology and pathophysiology.American journal of physiology. Gastrointestinal and liver physiology · 2017Review
- High-Throughput Screening for Drugs that Modulate Intermediate Filament Proteins.Methods in enzymology · 2016Article
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10 authors at 5 institutions in 2 countries.
Funding
Abstract
unlabelledKeratins, among other cytoskeletal intermediate filament proteins, are mutated at a highly conserved arginine with consequent severe disease phenotypes due to disruption of keratin filament organization. We screened a kinase inhibitor library, using A549 cells that are transduced with a lentivirus keratin 18 (K18) construct, to identify compounds that normalize filament disruption due to K18 Arg90Cys mutation at the conserved arginine. High-throughput screening showed that PKC412, a multikinase inhibitor, ameliorated K18 Arg90Cys-mediated keratin filament disruption in cells and in the livers of previously described transgenic mice that overexpress K18 Arg90Cys. Furthermore, PKC412 protected cultured A549 cells that express mutant or wild-type K18 and mouse livers of the K18 Arg90Cys-overexpressing transgenic mice from Fas-induced apoptosis. Proteomic analysis of proteins that associated with keratins after exposure of K18-expressing A549 cells to PKC412 showed that nonmuscle myosin heavy chain-IIA (NMHC-IIA) partitions with the keratin fraction. The nonmuscle myosin-IIA (NM-IIA) association with keratins was confirmed by immune staining and by coimmunoprecipitation. The keratin-myosin association is myosin dephosphorylation-dependent; occurs with K8, the obligate K18 partner; is enhanced by PKC412 in cells and mouse liver; and is blocked by hyperphosphorylation conditions in cultured cells and mouse liver. Furthermore, NMHC-IIA knockdown inhibits PKC412-mediated normalization of K18 R90C filaments.
conclusionThe inhibitor PKC412 normalizes K18 Arg90Cys mutation-induced filament disruption and disorganization by enhancing keratin association with NM-IIA in a myosin dephosphorylation-regulated manner. Targeting of intermediate filament disorganization by compounds that alter keratin interaction with their associated proteins offers a potential novel therapeutic approach for keratin and possibly other intermediate filament protein-associated diseases.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.