Post-prenylation-processing enzymes as new targets in oncogenesis
Abstract
RAS and many other oncogenic proteins undergo a complex series of post-translational modifications that are initiated by the addition of an isoprenoid lipid through a process known as prenylation. Following prenylation, these proteins usually undergo endoproteolytic processing by the RCE1 protease and then carboxyl methylation by a unique methyltransferase known as isoprenylcysteine carboxyl methyltransferase (ICMT). Although inhibitors that have been designed to target the prenylation step are now in advanced-stage clinical trials, their utility and efficacy seem to be limited. Recent findings, however, indicate that the inhibition of these post-prenylation-processing steps--particularly that of ICMT-catalysed methylation--might provide a better approach to the control of cancer-cell proliferation.
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Membrane association requires C-terminal prenylation, which for RhoA involves the addition of a geranylgeranyl moiety to the cysteine residue Cys190 in the CAAX motif.
“Membrane association requires C-terminal prenylation, which is an irreversible PTM; for RhoA, this involves the addition of a geranylgeranyl (20-carbon chain) moiety to the cysteine residue (Cys190) in the CAAX motif.”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [48]
After prenylation, RhoA undergoes proteolytic removal of the last three C-terminal residues by RCE1 and methylation of Cys190 by ICMT at the endoplasmic reticulum.
“The prenylation step takes place in the cytosol and is followed by proteolytic removal of the last three C-terminal (AAX) residues by the protease RAS-converting enzyme 1 (RCE1) and methylation of the prenylated Cys190 by isoprenylcysteine carboxyl methyltransferase (ICMT) at the cytoplasmic surface of the endoplasmic reticulum (ER) [47,48].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [48]
Prenylation of RhoA is catalyzed by GGTase-I, which transfers the geranylgeranyl moiety from geranylgeranyl pyrophosphate produced by the mevalonate pathway.
“This step is catalyzed by the geranylgeranyltransferase enzyme I (GGTase-I), which transfers the geranylgeranyl moiety from geranylgeranyl pyrophosphate, produced as a product of the mevalonate pathway involved in cholesterol synthesis, to RhoA.”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [48]
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- Authors
- Winter-Vann, A. M., & Casey, P. J.
- Affiliations
- Duke Medical Center (US)
- Duke University (US)
- Corresponding author
- Casey, Patrick J.
- ORCID
- Casey, Patrick J.
- Venue
- Nature Reviews Cancer
- Published
- 2005-05
- Volume
- 5
- Issue
- 5
- Pages
- 405-412
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- OpenAlex
- W1487258982
- Cited by
- 357
- References
- 4
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 13 · 2023: 12 · 2022: 14 · 2021: 9 · 2020: 19 · 2019: 16 · 2018: 14 · 2017: 14 · 2016: 11 · 2015: 14 · 2014: 19 · 2013: 17 · 2012: 21
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Institut National de la Santé et de la Recherche Médicale
- National Institutes of Health
- National Health and Medical Research Council
- National Medical Research Council
- 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 › Cancer-related gene regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- Ras, isoprenylcysteine carboxyl methyltransferase, IcmT, carboxyl methylation, endoproteolytic processing, prenylation inhibitors, tumor cell proliferation, carcinogenesis, therapeutic target
- MeSH terms
- Animals, Humans, Neoplasms, Endopeptidases, Protein Methyltransferases, Protein Processing, Post-Translational, Protein Prenylation, ras Proteins, Alkyl and Aryl Transferases, Cell Proliferation
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