A novel mechanism of keratin cytoskeleton organization through casein kinase Iα and FAM83H in colorectal cancer

Abstract

SummaryKeratin 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 describe a novel mechanism of keratin cytoskeleton organization mediated by casein kinase Ia (CK-1a) and a newly identified keratin-associated protein, FAM83H. Knockdown of FAM83H induces keratin filament bundling, whereas overexpression of FAM83H disassembles keratin filaments, suggesting that FAM83H regulates the filamentous state of keratins. Intriguingly, keratin filament bundling is concomitant with the dissociation of CK-1a from keratin filaments, whereas aberrant speckle-like localization of CK-1a is observed concomitantly with keratin filament disassembly. Furthermore, CK-1a inhibition, similar to FAM83H knockdown, causes keratin filament bundling and reverses keratin filament disassembly induced by FAM83H overexpression, suggesting that CK-1a mediates FAM83H-dependent reorganization of keratin filaments. Because the N-terminal region of FAM83H interacts with CK-1a and the C-terminal region interacts with keratins, FAM83H might tether CK-1a to keratins. Colorectal cancer tissue also shows keratin filament disassembly accompanied with FAM83H overexpression and aberrant CK-1a localization, and FAM83H-overexpressing cancer cells exhibit loss or alteration of epithelial cell polarity. Importantly, knockdown of FAM83H 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-1a to keratins, and that keratin filament disassembly caused by overexpression of FAM83H and aberrant localization of CK-1a could contribute to the progression of colorectal cancer.

Lamin B2 prevents chromosome instability by ensuring proper mitotic chromosome segregation

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Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…The casein kinase I (CK-1a) scaffold protein FAM83H regulates keratin networks by recruiting CK-1a directly to keratins (Kuga et al 2013). It may be additionally involved in membrane localization of desmosomal proteins and in regulating desmosome -keratin interactions (Kuga et al 2016).…”