Cited by 178Protein Kinase Regulation and GTPase SignalingCellular transport and secretionPI3K/AKT/mTOR signaling in cancer

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The Ras-related Protein Rheb Is Farnesylated and Antagonizes Ras Signaling and Transformation

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Clark, Geoffrey J., Kinch, Michael S., Rogers-Graham, Kelley, Sebti, Said M., Hamilton, Andrew D., Der, Channing J.·1997·Journal of Biological Chemistry

DOI 10.1074/jbc.272.16.10608

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Abstract

Presently, nothing is known about the function of the Ras-related protein Rheb. Since Rheb shares significant sequence identity with the core effector domains of Ras and KRev-1/Rap1A, it may share functional similarities with these two structurally related, yet functionally distinct, small GTPases. Furthermore, since like Ras, Rheb terminates with a COOH terminus that is likely to signal for farnesylation, it may be a target for the farnesyltransferase inhibitors that block Ras processing and function. To compare Rheb function with those of Ras and KRev-1, we introduced mutations into Rheb that generate constitutively active or dominant negative forms of Ras and Ras-related proteins and were designated Rheb(64L) and Rheb(20N), respectively. Expression of wild type or mutant Rheb did not alter the morphology or growth properties of NIH 3T3 cells. Thus, aberrant Rheb function is distinct from that of Ras and fails to cause cellular transformation. Instead, similar to KRev-1, co-expression of Rheb antagonized oncogenic Ras transformation and signaling. In vitro and in vivo analyses showed that like Ras, Rheb proteins are farnesylated and are sensitive to farnesyltransferase inhibition. Thus, it is possible that Rheb function may be inhibited by farnesyltransferase inhibitors treatment and, consequently, may contribute to the ability of these inhibitors to impair Ras transformation.

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Authors: Clark, G. J., Kinch, M. S., Rogers-Graham, K., Sebti, S. M., Hamilton, A. D., & Der, C. J.
Affiliations: University of North Carolina at Chapel Hill (US)
Purdue University West Lafayette (US)
University of Pittsburgh (US)
Corresponding author: Clark, Geoffrey J.
ORCID: Kinch, Michael S.
Hamilton, Andrew D.
Der, Channing J.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1997-04
Volume: 272
Issue: 16
Pages: 10608-10615
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.272.16.10608
OpenAlex: W2071673579
Cited by: 177
References: 67
Citations by year: 2026: 2 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 6 · 2021: 6 · 2020: 5 · 2019: 5 · 2018: 5 · 2017: 6 · 2016: 4 · 2015: 6 · 2014: 6 · 2013: 5 · 2012: 2
FWCI: 2.84
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 8592 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institutes of Health (7r01ca055008-03, 5r01ca042978-30, CA42978)
National Cancer Institute (CA42978, R01CA063071, CA 55008, CA63071)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords: Rheb, farnesyltransferase, farnesylation, Ras signaling, farnesyltransferase inhibitors
MeSH terms: Ras Homolog Enriched in Brain Protein, Amino Acid Sequence, Animals, Cell Division, Cell Transformation, Neoplastic, Fetus, Growth Substances, Kinetics, Liver, Molecular Sequence Data, Neuropeptides, Oocytes, Genes, ras, Recombinant Fusion Proteins, Transfection, Xenopus laevis, Signal Transduction, Transcriptional Activation, Gene Library, 3T3 Cells, Protein Prenylation, Sequence Homology, Amino Acid, DNA, Complementary, ras Proteins, GTP-Binding Proteins, Monomeric GTP-Binding Proteins, Mice, Rats

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The Ras-related Protein Rheb Is Farnesylated and Antagonizes Ras Signaling and Transformation

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