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Characterization of Ha-Ras, N-Ras, Ki-Ras4A, and Ki-Ras4B as in Vitro Substrates for Farnesyl Protein Transferase and Geranylgeranyl Protein Transferase Type I
Open accessAbstract
Ras proteins are small GTP-binding proteins which are critical for cell signaling and proliferation. Four Ras isoforms exist: Ha-Ras, N-Ras, Ki-Ras4A, and Ki-Ras4B. The carboxyl termini of all four isoforms are post-translationally modified by farnesyl protein transferase (FPT). Prenylation is required for oncogenic Ras to transform cells. Recently, it was reported that Ki-Ras4B is also an in vitro substrate for the related enzyme geranylgeranyl protein transferase-1 (GGPT-1) (James, G. L., Goldstein, J. L., and Brown, M. S. (1995) J. Biol. Chem. 270, 6221-6226). In the current studies, we compared the four isoforms of Ras as substrates for FPT and GGPT-1. The affinity of FPT for Ki-Ras4B (Km = 30 nM) is 10-20-fold higher than that for the other Ras isoforms. Consistent with this, when the different Ras isoforms are tested at equimolar concentrations, it requires 10-20-fold higher levels of CAAX-competitive compounds to inhibit Ki-Ras4B farnesylation. Additionally, we found that, as reported for Ki-Ras4B, N-Ras and Ki-Ras4A are also in vitro substrates for GGPT-1. Of the Ras isoforms, N-Ras is the highest affinity substrate for GGPT-1 and is similar in affinity to a standard GGPT-1 substrate terminating in leucine. However, the catalytic efficiencies of these geranylgeranylation reactions are between 15- and 140-fold lower than the corresponding farnesylation reactions, largely reflecting differences in affinity. Carboxyl-terminal peptides account for many of the properties of the Ras proteins. One interesting exception is that, unlike the full-length N-Ras protein, a carboxyl-terminal N-Ras peptide is not a GGPT-1 substrate, raising the possibility that upstream sequences in this protein may play a role in its recognition by GGPT-1. Studies with various carboxyl-terminal peptides from Ki-Ras4B suggest that both the carboxyl-terminal methionine and the upstream polylysine region are important determinants for geranylgeranylation. Furthermore, it was found that full-length Ki-Ras4B, but not other Ras isoforms, can be geranylgeranylated in vitro by FPT. These findings suggest that the different distribution of Ras isoforms and the ability of cells to alternatively process these proteins may explain in part the resistance of some cell lines to FPT inhibitors.
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“However, preclinical excitement did not transcribe to clinical utility with multiple negative phase II and phase III studies, likely due to presence of bypass prenylation pathway by geranylgeranylation [79].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [79]
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Metadata
- Authors
- Zhang, F. L., Kirschmeier, P., Carr, D., James, L., Bond, R. W., Wang, L., Patton, R., Windsor, W. T., Syto, R., Zhang, R., & Bishop, W. R.
- Corresponding author
- Bishop, W. Robert
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1997-04
- Volume
- 272
- Issue
- 15
- Pages
- 10232-10239
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2156654096
- Cited by
- 197
- References
- 41
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 6 · 2022: 2 · 2021: 6 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 4 · 2014: 2 · 2013: 4 · 2012: 7
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- 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 › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
- Keywords
- Ras isoforms, Ha-ras, NRAS, farnesyltransferase, protein prenylation, geranylgeranylation, CAAX motif, substrate affinity, carboxyl-terminal peptide, polylysine, oncogenic Ras, cell transformation
- MeSH terms
- Benzazepines, Binding Sites, Enzyme Inhibitors, Humans, Kinetics, Methionine, Piperidines, Polylysine, Transferases, Protein Prenylation, ras Proteins, Alkyl and Aryl Transferases
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