The GTPase superfamily: a conserved switch for diverse cell functions

Bourne, Henry R.; Sanders, D.A.R.; McCormick, Frank

doi:10.1038/348125a0

Cited by 2,274 publications

(1,307 citation statements)

References 123 publications

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“…The members of each family can be further subdivided into evolutionarily conserved subfamilies reflecting additional levels of structural, biochemical, and functional conservation [1]. Despite these family differences, all Ras-related GTPases contain five highly conserved domains (G1-G5) and function as guanine nucleotide-dependent molecular switches, alternating between an active GTP-bound and an inactive GDP-bound conformational state [2]. Guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) [2] influence the relative proportions of molecules in the active and inactive conformation.…”

Section: Introductionmentioning

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

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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.

show abstract

Section: Introductionmentioning

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

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“…Guanine nucleotide exchange factors activate RhoA by catalysing the release of GDP in exchange for GTP. GTPase-activating proteins (GAPs) inhibit RhoA by catalysing the hydrolysis of GTP to GDP (Bourne et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Neuropeptide-stimulated cell migration in prostate cancer cells is mediated by RhoA kinase signaling and inhibited by neutral endopeptidase

et al. 2006

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“…Lovastatin prevents the conversion of HMG CoA to mevalonate, and thereby inhibits the synthesis of the other products of the mevalonate pathway. This includes geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP) (Grunler et al, 1994), which modify and target small GTPases, including Ras and Rho, to their site of action (Sinensky and Lutz, 1992;Bourne et al, 1990). The small GTPases act as molecular switches, tra cking from a membrane-bound (active) GTP-bound state, to a cytosolic (inactive) GDP-bound state (Bourne et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line

et al. 1999

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Prostate cancer cells derived from transgenic mice with adenocarcinoma of the prostate (TRAMP cells) were treated with the HMG-CoA reductase inhibitor, lovastatin. This caused inactivation of the small GTPase RhoA, actin stress ®ber disassembly, cell rounding, growth arrest in the G1 phase of the cell cycle, cell detachment and apoptosis. Addition of geranylgeraniol (GGOL) in the presence of lovastatin, to stimulate protein geranylgeranylation, prevented lovastatin's e ects. That is, RhoA was activated, actin stress ®bers were assembled, the cells assumed a¯at morphology and cell growth resumed. The following observations support an essential role for RhoA in TRAMP cell growth: (1) TRAMP cells expressing dominant-negative RhoA (T19N) mutant protein displayed few actin stress ®bers and grew at a slower rate than controls (35 h doubling time for cells expressing RhoA (T19N) vs 20 h for untransfected cells); (2) TRAMP cells expressing constitutively active RhoA (Q63L) mutant protein displayed a contractile phenotype and grew faster than controls (13 h doubling time). Interestingly, addition of farnesol (FOL) with lovastatin, to stimulate protein farnesylation, prevented lovastatin-induced cell rounding, cell detachment and apoptosis, and stimulated cell spreading to a spindle shaped morphology. However, RhoA remained inactive and growth arrest persisted. The morphological e ects of FOL addition were prevented in TRAMP cells expressing dominant-negative H-Ras (T17N) mutant protein. Thus, it appears that H-Ras is capable of inducing cell spreading, but incapable of supporting cell proliferation, in the absence of geranylgeranylated proteins like RhoA.

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The GTPase superfamily: a conserved switch for diverse cell functions

Cited by 2,274 publications

References 123 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

Neuropeptide-stimulated cell migration in prostate cancer cells is mediated by RhoA kinase signaling and inhibited by neutral endopeptidase

Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line

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