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First published online April 28, 2005
doi: 10.1242/10.1242/jcs.02321

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14-3-3 and calmodulin control subcellular distribution of Kir/Gem and its regulation of cell shape and calcium channel activity

Pascal Béguin^1,*,, Ramasubbu N. Mahalakshmi^1,*, Kazuaki Nagashima², Damian H. K. Cher¹, Akira Takahashi², Yuichiro Yamada², Yutaka Seino² and Walter Hunziker^1,

¹ Epithelial Cell Biology Laboratory, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Republic of Singapore
² Department of Diabetes and Clinical Nutrition, Graduate School of Medicine Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan

Authors for correspondence (e-mail: hunziker{at}imcb.a-star.edu.sg; beguinp{at}imcb.a-star.edu.sg)

Accepted 11 February 2005

Individual members of the RGK family of Ras-related GTPases, which comprise Rad, Gem/Kir, Rem and Rem2, have been implicated in important functions such as the regulation of voltage-gated calcium channel activity and remodeling of cell shape. The GTPase Kir/Gem inhibits the activity of calcium channels by interacting with the ß-subunit and also regulates cytoskeleton dynamics by inhibiting the Rho-Rho kinase pathway. In addition, Kir/Gem interacts with 14-3-3 and calmodulin, but the significance of this interaction on Kir/Gem function is poorly understood. Here, we present a comprehensive analysis of the binding of 14-3-3 and calmodulin to Kir/Gem. We show that 14-3-3, in conjunction with calmodulin, regulates the subcellular distribution of Kir/Gem between the cytoplasm and the nucleus. In addition, 14-3-3 and calmodulin binding modulate Kir/Gem-mediated cell shape remodeling and downregulation of calcium channel activity. Competition experiments show that binding of 14-3-3, calmodulin and calcium channel ß-subunits to Kir/Gem is mutually exclusive, providing a rationale for the observed regulatory effects of 14-3-3 and calmodulin on Kir/Gem localization and function.

Key words: 14-3-3, Calcium channel, Calmodulin, Cytoskeleton, GTPase, Small G protein

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