Nuclear Sequestration of β-Subunits by Rad and Rem is Controlled by 14-3-3 and Calmodulin and Reveals a Novel Mechanism for Ca2+ Channel Regulation

Béguin, Pascal; Mahalakshmi, Ramasubbu N.; Nagashima, Kazuaki; Cher, Damian Hwee Kiat; Ikeda, Hiroki; Yamada, Yoshio; Seino, Yutaka; Hunziker, Walter

doi:10.1016/j.jmb.2005.10.013

Cited by 95 publications

(164 citation statements)

References 36 publications

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“…Rad is an in vitro substrate for several kinases, including PKA, PKC, CaMKII, and casein kinase II [12], which phosphorylate several distinct serine residues within the protein. 14-3-3 proteins interact specifically with RGK proteins phosphorylated on N-and C-terminal serines [41][42][43][44][45] and 14-3-3 binding appears to modulate the subcellular localization of Rad, Rem, Rem2, and Gem/Kir proteins [41,43,44,46,47]. Phosphorylation of Rad by PKC or casein kinase II, on the other hand, reduces binding to CaM [12].…”

Section: Post-translational Modificationmentioning

confidence: 99%

“…RGK proteins do not contain canonical lipid modification motifs [48], though there is enrichment of these proteins at the plasma membrane, and individual proteins have been shown to be localized to the cytosol, nucleus, and with both the actin and microtubule networks [4,5,18,41,43,44,[46][47][48][49][50][51][52][53][54]. The carboxyl terminus is well conserved (Fig.…”

Section: Subcellular Localizationmentioning

confidence: 99%

“…The carboxyl terminus is well conserved (Fig. 1) and has been shown to play a critical role in the function of all RGK GTPases [49,55], regulating subcellular distribution [4,5,53], and directing protein-protein interactions [45,53,55], to control both Ca 2+ channel activity [49,53,55] and cytoskeletal reorganization [41][42][43][44]46,47,52]. This region contains a cysteine residue within a highly conserved domain termed the C-7 motif (Fig.…”

Section: Subcellular Localizationmentioning

confidence: 99%

“…In addition to plasma membrane targeting through the C-terminus, three specific nuclear localization signals are well conserved in all RGK proteins [46,47]. Recent studies suggest that nuclear sequestration may play a role in regulating RGK GTPase function, and appears to be controlled in part through interactions with both calmodulin and 14-3-3 proteins (see sections 5 and 6) [41][42][43][44]46,47].…”

Section: Subcellular Localizationmentioning

confidence: 99%

“…RGK proteins have been found to promote cell shape remodeling through the regulation of the actin [21,26,[41][42][43][44][58][59][60][61], and perhaps microtubule, cytoskeletons [29,51]. The identification of the microtubule-associated protein, kinesin-like protein (KIF9), as a Gem-binding partner suggests that microtubule localization may facilitate Gem-dependent activation of downstream effector proteins [51].…”

Section: Rgk Regulation Of Cytoskeletal Dynamics: Modulation Of Rho-dmentioning

confidence: 99%

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The RGK family of GTP-binding proteins: Regulators of voltage-dependent calcium channels and cytoskeleton remodeling

Correll¹,

Pang²,

Niedowicz³

et al. 2008

Cellular Signalling

100

136

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RGK proteins constitute a novel subfamily of small Ras-related proteins that function as potent inhibitors of voltage-dependent (VDCC) Ca 2+ channels and regulators of actin cytoskeletal dynamics. Within the larger Ras superfamily, RGK proteins have distinct regulatory and structural characteristics, including nonconservative amino acid substitutions within regions known to participate in nucleotide binding and hydrolysis and a C-terminal extension that contains conserved regulatory sites which control both subcellular localization and function. RGK GTPases interact with the VDCC β-subunit (Ca V β) and inhibit Rho/Rho kinase signaling to regulate VDCC activity and the cytoskeleton respectively. Binding of both calmodulin and 14-3-3 to RGK proteins, and regulation by phosphorylation controls cellular trafficking and the downstream signaling of RGK proteins, suggesting that a complex interplay between interacting protein factors and trafficking contribute to their regulation.

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Section: Post-translational Modificationmentioning

confidence: 99%

Section: Subcellular Localizationmentioning

confidence: 99%

Section: Subcellular Localizationmentioning

confidence: 99%

Section: Subcellular Localizationmentioning

confidence: 99%

Section: Rgk Regulation Of Cytoskeletal Dynamics: Modulation Of Rho-dmentioning

confidence: 99%

See 3 more Smart Citations

The RGK family of GTP-binding proteins: Regulators of voltage-dependent calcium channels and cytoskeleton remodeling

Correll¹,

Pang²,

Niedowicz³

et al. 2008

Cellular Signalling

100

136

View full text Add to dashboard Cite

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The GTPase Rem2 regulates synapse development and dendritic morphology

Ghiretti

Paradis

2011

Developmental Neurobiology

108

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Rem2 is a member of the Rad/Rem/Rem2/Gem/Kir (RGK) subfamily of small Ras-like GTPases that was identified as an important mediator of synapse development. We performed a comprehensive, loss-of-function analysis of Rem2 function in cultured hippocampal neurons using RNAi to substantially decrease Rem2 protein levels. We found that knockdown of Rem2 decreases the density and maturity of dendritic spines, the primary site of excitatory synapses onto pyramidal neurons in the hippocampus. Knockdown of Rem2 also alters the gross morphology of dendritic arborizations, increasing the number of dendritic branches without altering total neurite length. Thus, Rem2 functions to inhibit dendritic branching and promote the development of dendritic spines and excitatory synapses. Interestingly, binding to the calcium binding protein calmodulin (CaM) is required for Rem2 regulation of dendritic branching. However, this interaction is completely dispensable for synapse development. Overall, our results suggest that Rem2 regulates dendritic branching and synapse development via distinct and overlapping signal transduction pathways.

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Regulation of high‐voltage‐activated Ca²⁺ channel function, trafficking, and membrane stability by auxiliary subunits

Felix

Calderón-Rivera

Andrade

2013

WIREs Membr Transp Signal

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Voltage-gated Ca2+ (CaV) channels mediate Ca2+ ions influx into cells in response to depolarization of the plasma membrane. They are responsible for initiation of excitation-contraction and excitation-secretion coupling, and the Ca2+ that enters cells through this pathway is also important in the regulation of protein phosphorylation, gene transcription, and many other intracellular events. Initial electrophysiological studies divided CaV channels into low-voltage-activated (LVA) and high-voltage-activated (HVA) channels. The HVA CaV channels were further subdivided into L, N, P/Q, and R-types which are oligomeric protein complexes composed of an ion-conducting CaVα1 subunit and auxiliary CaVα2δ, CaVβ, and CaVγ subunits. The functional consequences of the auxiliary subunits include altered functional and pharmacological properties of the channels as well as increased current densities. The latter observation suggests an important role of the auxiliary subunits in membrane trafficking of the CaVα1 subunit. This includes the mechanisms by which CaV channels are targeted to the plasma membrane and to appropriate regions within a given cell. Likewise, the auxiliary subunits seem to participate in the mechanisms that remove CaV channels from the plasma membrane for recycling and/or degradation. Diverse studies have provided important clues to the molecular mechanisms involved in the regulation of CaV channels by the auxiliary subunits, and the roles that these proteins could possibly play in channel targeting and membrane Stabilization.

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Nuclear Sequestration of β-Subunits by Rad and Rem is Controlled by 14-3-3 and Calmodulin and Reveals a Novel Mechanism for Ca2+ Channel Regulation

Cited by 95 publications

References 36 publications

The RGK family of GTP-binding proteins: Regulators of voltage-dependent calcium channels and cytoskeleton remodeling

The RGK family of GTP-binding proteins: Regulators of voltage-dependent calcium channels and cytoskeleton remodeling

The GTPase Rem2 regulates synapse development and dendritic morphology

Regulation of high‐voltage‐activated Ca²⁺ channel function, trafficking, and membrane stability by auxiliary subunits

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Nuclear Sequestration of β-Subunits by Rad and Rem is Controlled by 14-3-3 and Calmodulin and Reveals a Novel Mechanism for Ca2+ Channel Regulation

Cited by 95 publications

References 36 publications

The RGK family of GTP-binding proteins: Regulators of voltage-dependent calcium channels and cytoskeleton remodeling

The RGK family of GTP-binding proteins: Regulators of voltage-dependent calcium channels and cytoskeleton remodeling

The GTPase Rem2 regulates synapse development and dendritic morphology

Regulation of high‐voltage‐activated Ca2+ channel function, trafficking, and membrane stability by auxiliary subunits

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Product

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Regulation of high‐voltage‐activated Ca²⁺ channel function, trafficking, and membrane stability by auxiliary subunits