Roles of 14-3-3 and calmodulin binding in subcellular localization and function of the small G-protein Rem2

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Abstract
Kir/Gem, Rad, Rem and Rem2 comprise the RGK (Rad/Gem/kir) family of Ras-related small G-proteins. Two important functions of RGK proteins are the regulation of the VDCC (voltage-dependent Ca2+ channel) activity and cell-shape remodelling. RGK proteins interact with 14-3-3 and CaM (calmodulin), but their role on RGK protein function is poorly understood. In contrast with the other RGK family members, Rem2 has been reported to bind neither 14-3-3 nor induce membrane extensions. Furthermore, although Rem2 inhibits VDCC activity, it does not prevent cell-surface transport of Ca2+ channels as has been shown for kir/Gem. In the present study, we re-examined the functions of Rem2 and its interaction with 14-3-3 and CaM. We show that Rem2 in fact does interact with 14-3-3 and CaM and induces dendrite-like extensions in COS cells. 14-3-3, together with CaM, regulates the subcellular distribution of Rem2 between the cytoplasm and the nucleus. Rem2 also interacts with the β-subunits of VDCCs in a GTP-dependent fashion and inhibits Ca2+ channel activity by blocking the α-subunit expression at the cell surface. Thus Rem2 shares many previously unrecognized features with the other RGK family members.