title: FAM83H and casein kinase I regulate the organization of the keratin cytoskeleton and formation of desmosomes.
abstract: FAM83H is essential for the formation of dental enamel because a mutation in the FAM83H gene causes amelogenesis imperfecta (AI). We previously reported that the overexpression of FAM83H often occurs and disorganizes the keratin cytoskeleton in colorectal cancer cells. We herein show that FAM83H regulates the organization of the keratin cytoskeleton and maintains the formation of desmosomes in ameloblastoma cells. FAM83H is expressed and localized on keratin filaments in human ameloblastoma cell lines and in mouse ameloblasts and epidermal germinative cells in vivo. FAM83H shows preferential localization to keratin filaments around the nucleus that often extend to cell-cell junctions. Alterations in the function of FAM83H by its overexpression, knockdown, or an AI-causing truncated mutant prevent the proper organization of the keratin cytoskeleton in ameloblastoma cells. Furthermore, the AI-causing mutant prevents desmosomal proteins from being localized to cell-cell junctions. The effects of the AI-causing mutant depend on its binding to and possible inhibition of casein kinase I (CK-1). The suppression of CK-1 by its inhibitor, D4476, disorganizes the keratin cytoskeleton. Our results suggest that AI caused by the FAM83H mutation is mediated by the disorganization of the keratin cytoskeleton and subsequent disruption of desmosomes in ameloblasts.
authors.affiliation: Department of Biochemistry &Molecular Biology, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kuga
authors.affiliation: Laboratory of Animal Models for Human Diseases, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Mitsuho
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Division of Anatomical and Cellular Pathology, Department of Pathology, Iwate Medical University, Shiwa-gun, Iwate 028-3694, Japan.
authors.forename: Toshinari
authors.initials: T
authors.lastname: Mikami
authors.affiliation: Department of Histology and Developmental Biology, Tokyo Dental College, Chiyoda-ku, Tokyo 101-0061, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miake
authors.affiliation: Laboratory of Proteome Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Adachi
authors.affiliation: Laboratory of Proteome Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Department of Biochemistry &Molecular Biology, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Youhei
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Laboratory of Animal Models for Human Diseases, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Koura
authors.affiliation: Division of Anatomical and Cellular Pathology, Department of Pathology, Iwate Medical University, Shiwa-gun, Iwate 028-3694, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: Laboratory of Animal Models for Human Diseases, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Matsuda
authors.affiliation: Laboratory of Proteome Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tomonaga
authors.affiliation: Department of Biochemistry &Molecular Biology, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakayama
mesh_terms: D000565:Ameloblasts / Q000378:metabolism* / Q000473:pathology; D000567:Amelogenesis Imperfecta / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D003896:Desmosomes / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007633:Keratins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C527308:FAM83H protein, human; D011506:Proteins; D007633:Keratins; D047389:Casein Kinase I