A Cytoplasmic Protein Stimulates Normal N- ras p21 GTPase, But Does Not Affect Oncogenic Mutants

Trahey, Meg; McCormick, Frank

doi:10.1126/science.2821624

Cited by 1,211Protein Kinase Regulation and GTPase SignalingProtein Tyrosine PhosphatasesCellular transport and secretion

A Cytoplasmic Protein Stimulates Normal N- ras p21 GTPase, But Does Not Affect Oncogenic Mutants

Trahey, Meg, McCormick, Frank·1987·Science

DOI 10.1126/science.2821624

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Abstract

The role of guanine nucleotides in ras p21 function was determined by using the ability of p21 protein to induce maturation of Xenopus oocytes as a quantitative assay for biological activity. Two oncogenic mutant human N- ras p21 proteins, Asp12 and Val12, actively induced maturation, whereas normal Gly12 p21 was relatively inactive in this assay. Both mutant proteins were found to be associated with guanosine triphosphate (GTP) in vivo. In contrast, Gly12 p21 was predominantly guanosine diphosphate (GDP)-bound because of a dramatic stimulation of Gly12 p21-associated guanosine triphosphatase (GTPase) activity. A cytoplasmic protein was shown to be responsible for this increase in activity. This protein stimulated GTP hydrolysis by purified Gly12 p21 more than 200-fold in vitro, but had no effect on Asp12 or Val12 mutants. A similar factor could be detected in extracts from mammalian cells. It thus appears that, in Xenopus oocytes, this protein maintains normal p21 in a biologically inactive, GDP-bound state through its effect on GTPase activity. Furthermore, it appears that the major effect of position 12 mutations is to prevent this protein from stimulating p21 GTPase activity, thereby allowing these mutants to remain in the active GTP-bound state.

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From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [34]
The oncogenic properties associated with KRAS G12X mutation are characterized by deficiency of intrinsic GTPase activity and insensitivity for GTPase-activating proteins (GAPs).
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From Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling (2018) · cites this paper as [4]
Every missense mutation at KRAS G12 (G12X) is oncogenic.
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Authors: Trahey, M., & McCormick, F.
Affiliations: Department of Molecular Biology, Cetus Corporation, Emeryville, CA 94608.
ORCID: McCormick, Frank
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 1987-10-23
Volume: 238
Issue: 4826
Pages: 542-545
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.2821624
OpenAlex: W2058511768
Cited by: 1,211
References: 23
Citations by year: 2026: 12 · 2025: 19 · 2024: 19 · 2023: 12 · 2022: 12 · 2021: 19 · 2020: 14 · 2019: 9 · 2018: 17 · 2017: 18 · 2016: 20 · 2015: 17 · 2014: 10 · 2013: 9 · 2012: 18
FWCI: 32.07
Type: journal article
Language: en
Open access: closed
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords: GTPase activity, GDP-bound state, GTP hydrolysis, cytosolic proteins, guanine nucleotides
MeSH terms: Animals, Biological Assay, Cytoplasm, Female, Guanine Nucleotides, Guanosine Diphosphate, Guanosine Triphosphate, Guanylyl Imidodiphosphate, Hydrolysis, Immunosorbent Techniques, Mutation, Oocytes, Phosphoric Monoester Hydrolases, Proteins, Proto-Oncogene Proteins, Structure-Activity Relationship, Xenopus laevis, Proto-Oncogene Proteins p21(ras), GTP Phosphohydrolases

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A Cytoplasmic Protein Stimulates Normal N- ras p21 GTPase, But Does Not Affect Oncogenic Mutants

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