The product of ras is a GTPase and the T24 oncogenic mutant is deficient in this activity

Sweet, Raymond W.; Yokoyama, Shiro; Kamata, Tohru; Feramisco, James R.; Rosenberg, Martin; Gross, Mitchell

doi:10.1038/311273a0

Cited by 520 publications

(249 citation statements)

References 29 publications

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“…The greater biologic activity of mutant p21 is believed to result from the mutant proteins being placed more or less constitutively in the active, GTP-bound form in vivo. In accord with this hypothesis, the intrinsic GTPase activity of jmost highly transforming p21 proteins, including p2lv-ras , is significantly lower than that of normal p21 proteins (6,12,20). Highly transforming forms of p21 are resistant to a widely expressed intracellular protein (GTPase-activating protein) that can markedly accelerate the intrinsic GTPase activity of normal p21 (23).…”

mentioning

confidence: 51%

p21-ras effector domain mutants constructed by "cassette" mutagenesis.

Stone¹,

Vass²,

Willumsen³

et al. 1988

Mol. Cell. Biol.

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mentioning

confidence: 51%

p21-ras effector domain mutants constructed by "cassette" mutagenesis.

Stone¹,

Vass²,

Willumsen³

et al. 1988

Mol. Cell. Biol.

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“…The amino acid substitutions predicted by the missense changes found in codon 12 and 13 in CS are well-known activating alterations in HRAS, which affect guanine nucleotide binding and cause reduction of GTP hydrolysis, resulting in a gain of function [Gibbs et al, 1984;McGrath et al, 1984;Sweet et al, 1984]. Substitution of any amino acid other than proline may cause activation, albeit with varying transformation efficiencies [Fasano et al, 1984;Seeburg et al, 1984].…”

Section: Discussionmentioning

confidence: 99%

HRAS mutations in Costello syndrome: Detection of constitutional activating mutations in codon 12 and 13 and loss of wild‐type allele in malignancy

Estep

Tidyman

Teitell

et al. 2005

American J of Med Genetics Pt A

172

157

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Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies, and a predisposition to develop neoplasia. Based on similarities with other cancer syndromes, we previously hypothesized that CS is likely due to activation of signal transduction through the Ras/MAPK pathway [Tartaglia et al., 2003]. In this study, the HRAS coding region was sequenced for mutations in a large, well‐characterized cohort of 36 CS patients. Heterogeneous missense point mutations predicting an amino acid substitution were identified in 33/36 (92%) patients. The majority (91%) had a 34G → A transition in codon 12. Less frequent mutations included 35G → C (codon 12) and 37G → T (codon 13). Parental samples did not have an HRAS mutation supporting the hypothesis of de novo heterogeneous mutations. There is phenotypic variability among patients with a 34G → A transition. The most consistent features included characteristic facies and skin, failure to thrive, developmental delay, musculoskeletal abnormalities, visual impairment, cardiac abnormalities, and generalized hyperpigmentation. The two patients with 35G → C had cardiac arrhythmias whereas one patient with a 37G → T transversion had an enlarged aortic root. Of the patients with a clinical diagnosis of CS, neoplasia was the most consistent phenotypic feature for predicating an HRAS mutation. To gain an understanding of the relationship between constitutional HRAS mutations and malignancy, HRAS was sequenced in an advanced biphasic rhabdomyosarcoma/fibrosarcoma from an individual with a 34G → A mutation. Loss of the wild‐type HRAS allele was observed, suggesting tumorigenesis in CS patients is accompanied by additional somatic changes affecting HRAS. Finally, due to phenotypic overlap between CS and cardio‐facio‐cutaneuos (CFC) syndromes, the HRAS coding region was sequenced in a well‐characterized CFC cohort. No mutations were found which support a distinct genetic etiology between CS and CFC syndromes. © 2005 Wiley‐Liss, Inc.

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“…They bind GTP and GDP (30) and have an intrinsic GTPase activity (14,21,35). Moreover, some oncogenic forms of Ras protein are deficient in GTPase activity (14,21,35). Based on these properties, and reasoning by analogy to other known guanine nucleotide-binding proteins, the G proteins (reviewed in reference 15), most investigators think that Ras proteins act as transducers to convey extracellular signals to an intracellular effector pathway.…”

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confidence: 99%

“…In mammals, Ras proteins are 21,000-dalton molecules that are localized to the cytoplasmic side of the cell membrane (44). They bind GTP and GDP (30) and have an intrinsic GTPase activity (14,21,35). Moreover, some oncogenic forms of Ras protein are deficient in GTPase activity (14,21,35).…”

mentioning

confidence: 99%

Guanine nucleotide activation of, and competition between, RAS proteins from Saccharomyces cerevisiae.

Field¹,

Broek²,

Kataoka³

et al. 1987

Mol. Cell. Biol.

111

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In the yeast Saccharomyces cerevisiae, yeast RAS proteins are potent activators of adenylate cyclase. In the present work we measured the activity of adenylate cyclase in membranes from Saccharomyces cerevisiae which overexpress this enzyme. The response of the enzyme to added RAS2 proteins bound with various guanine nucleotides and their analogs suggests that RAS2 proteins are active in their GTP-bound form and are virtually inactive in their GDP-bound form. Also, active RAS2 protein is not inhibited by inactive RAS2, suggesting that the inactive form does not compete with the active form in binding to its effector.ras genes are ubiquitous in eucaryotes (9,24,27,32). In mammals, they comprise a family of at least three members (H-, K-, and N-ras) which share structural and functional properties. They were first identified, in their mutant forms, as potent oncogenes (4,5,7,12,22,26,29,33,36,38,39). Although the normal ras genes are not oncogenic, they too can cause the malignant transformation of cells when expressed at abnormally high levels (7). In mammals, Ras proteins are 21,000-dalton molecules that are localized to the cytoplasmic side of the cell membrane (44). They bind GTP and GDP (30) and have an intrinsic GTPase activity (14,21,35). Moreover, some oncogenic forms of Ras protein are deficient in GTPase activity (14,21,35). Based on these properties, and reasoning by analogy to other known guanine nucleotide-binding proteins, the G proteins (reviewed in reference 15), most investigators think that Ras proteins act as transducers to convey extracellular signals to an intracellular effector pathway. According to this model, Ras protein bound to GTP activates its effector, and then shuts itself off through its intrinsic GTPase activity. Mutant Ras proteins which are defective in GTPase would thus cause abnormally prolonged stimulation of the effector system, explaining their oncogenicity.The RAS1 and RAS2 proteins of the yeast Saccharomyces cerevisiae provide an ideal system for testing aspects of this model. They are structurally, biochemically, and functionally similar to the mammalian Ras proteins, and at least one of their effector systems is known (3,9,10,18,24,37,41,42). The yeast RAS genes were originally isolated by using mammalian ras genes as probes to screen libraries of S. cerevisiae genomic DNA. They encode proteins which are highly homologous to the mammalian Ras proteins, particularly at their amino termini (9, 24). They undergo processing events very similar to those of their mammalian counterparts and localize to membrane fractions (8,13,25,31,44). Like the mammalian proteins, they bind guanine nucleotides; they have an intrinsic GTPase activity, and this activity is reduced in the mutant (17), and that has enabled us to create yeast strains which greatly overexpress that enzyme. As a result, we have been able to develop a more sensitive biochemical assay for Ras proteins. Using this system we have reexamined the guanine nucleotide dependence of RAS2 protein and conclude that RAS2 may b...

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The product of ras is a GTPase and the T24 oncogenic mutant is deficient in this activity

Cited by 520 publications

References 29 publications

p21-ras effector domain mutants constructed by "cassette" mutagenesis.

p21-ras effector domain mutants constructed by "cassette" mutagenesis.

HRAS mutations in Costello syndrome: Detection of constitutional activating mutations in codon 12 and 13 and loss of wild‐type allele in malignancy

Guanine nucleotide activation of, and competition between, RAS proteins from Saccharomyces cerevisiae.

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