Author:
Kuga Takahisa,Kume Hideaki,Kawasaki Naoko,Sato Misako,Adachi Jun,Shiromizu Takashi,Hoshino Isamu,Nishimori Takanori,Matsubara Hisahiro,Tomonaga Takeshi
Abstract
Keratin filaments form cytoskeletal networks in epithelial cells. Dynamic rearrangement of keratin filament networks is required for epithelial cells to perform cellular processes such as cell migration and polarization; however, the mechanism governing keratin filament rearrangement remains unclear. Here, we found a novel mechanism of keratin cytoskeleton organization mediated by casein kinase Iα (CK-1α) and a newly identified keratin-associated protein, FAM83H. FAM83H knockdown induces keratin filament bundling, whereas FAM83H overexpression disassembles keratin filaments, suggesting that FAM83H regulates the filamentous state of keratins. Intriguingly, keratin filament bundling is concomitant with the dissociation of CK-1α from keratin filaments, while aberrant speckle-like localization of CK-1α is observed concomitantly with keratin filament disassembly. Furthermore, CK-1α inhibition, like FAM83H knockdown, causes keratin filament bundling and reverses keratin filament disassembly induced by FAM83H overexpression, suggesting that CK-1α mediates FAM83H-dependent reorganization of keratin filaments. Since the N-terminal region of FAM83H interacts with CK-1α, whereas the C-terminal region interacts with keratins, FAM83H might tether CK-1α to keratins. Colorectal cancer tissue also shows keratin filament disassembly accompanied with FAM83H overexpression and aberrant CK-1α localization, and FAM83H-overexpressing cancer cells exhibit loss or alteration of epithelial cell polarity. Importantly, FAM83H knockdown inhibits cell migration accompanied by keratin cytoskeleton rearrangement in colorectal cancer cells. These results suggest that keratin cytoskeleton organization is regulated by FAM83H-mediated recruitment of CK-1α to keratins, and that keratin filament disassembly caused by FAM83H overexpression and aberrant localization of CK-1α may contribute to the progression of colorectal cancer.
Publisher
The Company of Biologists
Cited by
57 articles.
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