A novel mechanism of keratin cytoskeleton organization through casein kinase Ialpha and FAM83H in colorectal cancer.
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Kuga T, Kume H, Kawasaki N, Sato M, Adachi J, Shiromizu T, Hoshino I, Nishimori T, Matsubara H, Tomonaga T
A novel mechanism of keratin cytoskeleton organization through casein kinase Ialpha and FAM83H in colorectal cancer.
J Cell Sci. 2013 Oct 15;126(Pt 20):4721-31. doi: 10.1242/jcs.129684. Epub 2013 Jul 31.
- PubMed ID
- 23902688 [ View in PubMed]
- 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 describe a novel mechanism of keratin cytoskeleton organization mediated by casein kinase Ialpha (CK-1alpha) 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-1alpha from keratin filaments, whereas aberrant speckle-like localization of CK-1alpha is observed concomitantly with keratin filament disassembly. Furthermore, CK-1alpha inhibition, similar to FAM83H knockdown, causes keratin filament bundling and reverses keratin filament disassembly induced by FAM83H overexpression, suggesting that CK-1alpha mediates FAM83H-dependent reorganization of keratin filaments. Because the N-terminal region of FAM83H interacts with CK-1alpha and the C-terminal region interacts with keratins, FAM83H might tether CK-1alpha to keratins. Colorectal cancer tissue also shows keratin filament disassembly accompanied with FAM83H overexpression and aberrant CK-1alpha 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-1alpha to keratins, and that keratin filament disassembly caused by overexpression of FAM83H and aberrant localization of CK-1alpha could contribute to the progression of colorectal cancer.