Roles of Rho-associated Kinase in Cytokinesis; Mutations in Rho-associated Kinase Phosphorylation Sites Impair Cytokinetic Segregation of Glial Filaments

doi:10.1083/jcb.143.5.1249

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© The Rockefeller University Press, 0021-9525/1998//1249 $5.00
The Journal of Cell Biology, Volume 143, Number 5, , 1998 1249-1258

Article

Roles of Rho-associated Kinase in Cytokinesis; Mutations in Rho-associated Kinase Phosphorylation Sites Impair Cytokinetic Segregation of Glial Filaments

Yoshihiro Yasui^*, Mutsuki Amano, Koh-ichi Nagata^*, Naoyuki Inagaki^*, Hideo Nakamura, Hideyuki Saya, Kozo Kaibuchi, and Masaki Inagaki^*

^* Laboratory of Biochemistry, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya 464-0021, Japan; Division of Signal Transduction, Nara Institute of Science and Technology, Ikoma 630-0101, Japan; Department of Tumor Genetics and Biology, Kumamoto University School of Medicine, 2-2-1, Honjo, Kumamoto 860-0811, Japan

Rho-associated kinase (Rho-kinase), which is activated by thesmall GTPase Rho, regulates formation of stress fibers and focaladhesions, myosin fiber organization, and neurite retractionthrough the phosphorylation of cytoskeletal proteins, includingmyosin light chain, the ERM family proteins (ezrin, radixin, and moesin) and adducin. Rho-kinase was found to phosphorylatea type III intermediate filament (IF) protein, glial fibrillaryacidic protein (GFAP), exclusively at the cleavage furrow duringcytokinesis. In the present study, we examined the roles ofRho-kinase in cytokinesis, in particular organization of glialfilaments during cytokinesis. Expression of the dominant-negativeform of Rho-kinase inhibited the cytokinesis of Xenopus embryoand mammalian cells, the result being production of multinuclei.We then constructed a series of mutant GFAPs, where Rho-kinasephosphorylation sites were variously mutated, and expressedthem in type III IF-negative cells. The mutations induced impairedsegregation of glial filament (GFAP filament) into postmitoticdaughter cells. As a result, an unusually long bridge-like cytoplasmicstructure formed between the unseparated daughter cells. Alterationof other sites, including the cdc2 kinase phosphorylation site, led to no remarkable defect in glial filament separation.These results suggest that Rho-kinase is essential not onlyfor actomyosin regulation but also for segregation of glialfilaments into daughter cells which in turn ensures correctcytokinetic processes.

Key Words: intermediate filament • glial fibrillary acidic protein (GFAP) • Rho • Rho-associated kinase • cytokinesis

Abbreviations used in this paper: aa, amino acid(s); CF, cleavage furrow; EL cells, L cells that express E-cadherin; ERM, ezrin, radixin, and moesin; IF, intermediate filament; GFAP, glial fibrillary acidic protein; MBS, myosin-binding subunit of myosin phosphatase; MLC, myosin light chain; PH, pleckstrin homology; PI, propidium iodide; PKN, protein kinase N.

This research was supported in part by Grants-in-Aid for ScientificResearch and Cancer Research from the Ministry of Education,Science, Sports, and Culture of Japan, Japan Society of thePromotion of Science Research for the Future, special coordinationfunds from the Science and Technology Agency of the Governmentof Japan, and a grant from Bristol-Myers-Squibb.

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