14-3-3 and calmodulin control subcellular distribution of Kir/Gem and its regulation of cell shape and calcium channel activity
Author:
Béguin Pascal1, Mahalakshmi Ramasubbu N.1, Nagashima Kazuaki2, Cher Damian H. K.1, Takahashi Akira2, Yamada Yuichiro2, Seino Yutaka2, Hunziker Walter1
Affiliation:
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
Abstract
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 β-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 β-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.
Publisher
The Company of Biologists
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