Ges, a Human Gtpase of the Rad/Gem/Kir Family, Promotes Endothelial Cell Sprouting and Cytoskeleton Reorganization

Pan, Julie Y.; Fieles, William; White, Anne M.; Egerton, M.; Silberstein, David S.

doi:10.1083/jcb.149.5.1107

Cited by 37 publications

(37 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This would be similar to the ability of the Rnd3/RhoE GTPase to both inhibit ROK [67] and act to recruit and activate p190Rho-GAP [68]. Finally, it is important to note that both Rem and Rem2 have been reported to induce cytoskeletal reorganization [41,43,47,58]. However, it remains unclear whether Rem or Rem2 can activate Gmip and neither protein associates with ROK [50], suggesting that an additional regulatory mechanism may remain to be defined.…”

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

confidence: 74%

“…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%

See 1 more Smart Citation

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

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.

show abstract

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

confidence: 74%

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

confidence: 99%

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

show abstract

“…Recent studies suggest that RGK proteins regulate cytoskeleton dynamics (24)(25)(26). Because reorganization of the cytoskeleton might interfere with Ca 2ϩ channel function, it is important to distinguish between selective Rem-dependent effects on Ca 2ϩ channels and a general blockade of protein sorting.…”

Section: Discussionmentioning

confidence: 99%

Regulation of voltage-gated calcium channel activity by the Rem and Rad GTPases

Finlin

Crump²,

Satin³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

200

233

View full text Add to dashboard Cite

Rem, Rem2, Rad, and Gem͞Kir (RGK) represent a distinct GTPase family with largely unknown physiological functions. We report here that both Rem and Rad bind directly to Ca 2؉ channel ␤-subunits ( R em, Rem2, Rad, and Gem͞Kir (RGK) are members of a Ras-related GTPase subfamily (RGK family), with many unique characteristics that distinguish them from other members of the Ras superfamily (1-5). The common structure for all RGK proteins consists of a conserved Ras-related core domain, a series of nonconservative amino acid substitutions within regions known to be involved in guanine nucleotide binding and hydrolysis, a non-CAAX-containing C-terminal extension, and large N-terminal extensions relative to other Ras family proteins. The conservation of structural features within the RGK proteins suggests shared mechanisms of regulation and the control of common cellular signal transduction networks. However, RGK subfamily members differ from each other and from other Ras-related proteins in their putative effector (G2) domains, suggesting that they interact with distinct regulatory and effector proteins, and each exhibits distinct tissue-specific expression patterns (1-5). Thus, despite their conserved structural and biochemical properties, functional evidence to suggest a unified mechanism of action has been limited.In this study, we investigated the ability of Rem and Rad to regulate Ca 2ϩ channel activity. Our results demonstrate that, although both proteins have distinct effector interaction domains, they each bind directly to Ca V ␤ subunits and inhibit detectable ionic current expression from the native cardiac L type, but not from T type, Ca 2ϩ channels when coexpressed in human embryonic kidney (HEK)293 cells. The Rem protein is expressed in striated muscle cells, and we demonstrate that Rem inhibits L type Ca 2ϩ channel activity in differentiated C2C12 myotubes. Deletion analysis demonstrates that the C terminus of Rem plays an important role in Ca V ␤ subunit association and is necessary for regulation of channel activity. Taken together, these studies indicate that Rem functions as a potent regulator of L type Ca 2ϩ channel function in muscle and suggest that a conserved physiological role for the RGK GTPase gene family is the control of Ca 2ϩ channel activity via modulation of Ca V ␤ subunit function. Experimental ProceduresRNase Protection Assays and Cell Culture. C2C12DS and C2C12(E) mouse muscle myoblast cell lines were from Robert Krauss (Mount Sinai School of Medicine, New York) and were cultured and induced to differentiate as described (6). Primary mouse muscle cultures and MM14 cells were provided by

show abstract

“…Trafficking-Previous studies have shown that Rem has a complex subcellular distribution, since it is found in both the cytosol and in association with the plasma membrane when expressed in a variety of cells (5,18,22,23). Since Rem has been shown to directly interact with Ca V ␤ subunits, and this association appears to be required for Rem-mediated blockade of surfacelocalized Ca 2ϩ channels, we used confocal microscopy to examine whether Ca V ␤2a subunit expression modulates Rem trafficking to the plasma membrane.…”

Section: The Rem C Terminus Is Required For Plasma Membranementioning

confidence: 99%

Plasma Membrane Targeting Is Essential for Rem-mediated Ca2+ Channel Inhibition

Correll¹,

Pang²,

Finlin³

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The small GTPase Rem is a potent negative regulator of high voltage-activated Ca 2؉ channels and a known interacting partner for Ca 2؉ channel accessory ␤ subunits. The mechanism for Rem-mediated channel inhibition remains controversial, although it has been proposed that Ca V ␤ association is required. Previous work has shown that a C-terminal truncation of Rem (Rem-(1-265)) displays reduced in vivo binding to membranelocalized ␤2a and lacks channel regulatory function. In this paper, we describe a role for the Rem C terminus in plasma membrane localization through association with phosphatidylinositol lipids. Moreover, Rem-(1-265) can associate with ␤2a in vitro and ␤1b in vivo, suggesting that the C terminus does not directly participate in Ca V ␤ association. Despite demonstrated ␤1b binding, Rem-(1-265) was not capable of regulating a Ca V 1.2-␤1b channel complex, indicating that ␤ subunit binding is not sufficient for channel regulation. However, fusion of the CAAX domain from K-Ras4B or H-Ras to the Rem-(1-265) C terminus restored membrane localization and Ca 2؉ channel regulation, suggesting that ␤ binding and membrane localization are independent events required for channel inhibition.High voltage-activated Ca 2ϩ channels (Ca V 1 and Ca V 2 families) transduce electrical activity into increased intracellular calcium that mediates a diverse array of essential cellular processes, including hormone secretion, neurotransmitter release, and excitation-contraction coupling in muscle systems (1). The cardiac L-type Ca 2ϩ channel is a multiprotein complex consisting of the pore-forming Ca V 1.2 ␣ subunit and auxiliary subunits, including Ca V ␤ and ␣ 2 -␦ subunits (1). The Ca V ␣ subunit determines the ion selectivity and single channel conductance of the mature channel, whereas co-expression of Ca V ␤ or ␣ 2 ␦ facilitates cell surface trafficking of the ␣ 1 subunit, increases Ca 2ϩ current amplitude, and alters channel gating properties (1, 2). Ca V ␤ subunits are encoded by four genes (␤1-␤4), each subject to complex splicing (3). Ca V ␤2a, a ␤ isoform found in the heart, is subject to post-translational palmitoylation, which directs plasma membrane localization, whereas other ␤ isoforms are predominantly localized to the cytosol when not bound to Ca V ␣ 1 (3).Recently, members of the RGK 3 family of Ras-related GTPases, including Rem (4), Rem2 (5), Rad (6), and Gem/Kir (7), have been identified as potent regulators of HVA Ca 2ϩ channel function (8 -10). Although all RGK GTPases associate with Ca V ␤ subunits and prevent de novo expression of L-type I Ca (8 -10), the mechanism of RGK protein-mediated Ca 2ϩ channel inhibition remains controversial. It was originally hypothesized that RGK protein binding blocked Ca V ␣1/␤ association, leading to a reduction of functional channels at the cell surface (8,(11)(12)(13)(14). However, a series of recent studies suggests instead that the majority of RGK proteins inhibit the activity of the preassembled channel complex at the plasma membrane (10, 15, 16), although Ca V...

show abstract

Ges, a Human Gtpase of the Rad/Gem/Kir Family, Promotes Endothelial Cell Sprouting and Cytoskeleton Reorganization

Cited by 37 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

Regulation of voltage-gated calcium channel activity by the Rem and Rad GTPases

Plasma Membrane Targeting Is Essential for Rem-mediated Ca2+ Channel Inhibition

Contact Info

Product

Resources

About