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Fighting Cancer by Disrupting C-Terminal Methylation of Signaling Proteins

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Fighting Cancer by Disrupting C-Terminal Methylation of Signaling Proteins Fighting cancer by disrupting C-terminal methylation of signaling proteins Steven Clarke, Fuyuhiko Tamanoi J Clin Invest. 2004;113(4):513-515. https://doi.org/10.1172/JCI21059. Commentary Protein methylation at the C-terminus of mammalian isoprenylated proteins has been implicated in membrane attachment, protein-protein interactions, and protein stability. A new paper describes surprising results: in the absence of methylation some target proteins have increased stability, whereas others have decreased stability. The decreased stability of the RhoA protein is correlated with an increased resistance to Ras-dependent transformation and suggests the basis for the development of a new approach to antitumor therapy . Find the latest version: https://jci.me/21059/pdf 18. Kimura, T., et al. 2003. High-density lipoprotein 23. Mineo, C., Yuhanna, I.S., Quon, M.J., and Shaul, 28. Kuvin, J.T., et al. 2002. 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Fighting cancer by disrupting C-terminal are modified in this way, including methylation of signaling proteins some nuclear lamins, a cGMP phos- phodiesterase, and several small G- Steven Clarke1,2 and Fuyuhiko Tamanoi2,3 proteins involved in cell signaling, such as the Ras and Rho proteins. The 1Department of Chemistry and Biochemistry, importance of Ras, especially the acti- 2Molecular Biology Institute, and vated oncogenic forms, has led to a 3Department of Microbiology, Immunology, and Molecular Genetics, Jonsson large interest in this pathway in terms Comprehensive Cancer Center, University of California, Los Angeles, California, USA of the possibility of controlling human cancers. Protein methylation at the C-terminus of mammalian isoprenylated pro- These reactions can provide the teins has been implicated in membrane attachment, protein-protein inter- modified protein increased membrane actions, and protein stability. A new paper describes surprising results: in attachment with the newly formed the absence of methylation some target proteins have increased stability, hydrophobic C-terminus (4), directed whereas others have decreased stability. The decreased stability of the RhoA binding to signaling partners via the protein is correlated with an increased resistance to Ras-dependent trans- isoprenyl and methyl groups (5, 6), formation and suggests the basis for the development of a new approach and protection against proteolytic to antitumor therapy (see the related article beginning on page 539). degradation (7, 8). In this issue of the JCI, Bergo et al. provide new insight J. Clin. Invest. 113:513–515 (2004). doi:10.1172/JCI200421059. into these functions and have identi- fied new targets for the development Covalent modification of proteins number of reactions that modify intra- of anticancer drugs (9). In this study, facilitates a tremendous expansion of cellular eucaryotic proteins are three they developed transgenic mice (and their functional potential. Some mod- sequential enzymatic steps that recog- fibroblast cell lines derived from these ifications serve to enlarge the chemical nize proteins synthesized with a C-ter- mice) where the expression of the Icmt diversity of proteins beyond that pro- minal CAAX tetrapeptide motif, where gene encoding isoprenylcysteine car- vided by the 20 standard amino acids C is a cysteine residue, A is generally an boxyl methyltransferase (Icmt) can be utilized in protein synthesis, providing aliphatic residue, and X can be a vari- controlled by the Cre-loxP system. the new shapes and reactive groups ety of residues (1–3). Such proteins are There are two striking results from that allow new types of binding and initially lipidated in a reaction that this study. First, the authors show that catalytic interactions. Other modifica- adds either a 15-carbon farnesyl or a loss of the methyltransferase can have tions, often reversible, serve to modu- 20-carbon geranylgeranyl group to the different effects in different methyl- late protein function. Among the large sulfur atom of the cysteine residue. accepting proteins. For example, they This step is followed by the removal of show that Ras proteins are stabilized Address correspondence to: Steven Clarke, the three AAX amino acids generating but the RhoA protein is destabilized. 640 Boyer Hall, University of California, Los Angeles, California 90095-1569, USA. a C-terminal isoprenylcysteine residue. Second, they show that the decreased Phone: (310) 825-8754; Fax: (310) 825-1968; The third step is a potentially re- levels of RhoA in the absence of methy- E-mail: [email protected]. versible methyl esterification reaction lation results in increased levels of Conflict of interest: The authors have of the newly exposed C-terminal cys- p21Cip1 and the inhibition of the cell declared that no conflict of interest exists. teinyl carboxyl group by a membrane- cycle. The authors thus present a case Nonstandard abbreviations used: isoprenylcysteine carboxyl methyltransferase bound enzyme of the endoplasmic for anticancer therapeutic approaches (Icmt); S-adenosylhomocysteine (AdoHcy). reticulum (Figure 1). Many proteins based on inhibiting Icmt. The Journal of Clinical Investigation | February 2004 | Volume 113 | Number 4 513 Figure 1 Modification pathway of proteins for iso- prenylation/methylation and effects of inhibitors of each enzymatic step. Proteins ending with the CAAX motif undergo farne- sylation in the cytosol. Subsequent removal of three C-terminal amino acids and C-ter- minal methylation are catalyzed by the endo- plasmic reticulum–bound enzymes Rce1 and Icmt, respectively. Inhibition of Icmt leads to rapid turnover of RhoA, increase of p21Cip1, and cell cycle block. R115777, SCH66336, and BMS214662 are farnesyltransferase (Ftase) inhibitors, while farnesylcysteine and AdoHcy inhibit Icmt. Stabilization of isoprenylated played just the opposite behavior! Signaling from the endoplasmic proteins by methyl ester formation They measured an increase in the half- reticulum Unmethylated isoprenylated cysteine life of K-Ras from 13.9 hours to 32.5 The finding by Bergo et al. (9) that K-Ras groups at the C-terminus of a protein hours (9). Clearly, there is now no can signal activation of downstream can be particularly susceptible to pro- direct relationship between proteolyt- events — even though they show that teolytic attack. For example, in yeast ic stability and the presence of the car- K-Ras is not associated with the plasma strains lacking the STE14 gene encod- boxyl terminal methyl ester. membrane — is quite intriguing. What ing the ortholog of the mammalian could account for this observation? It is Icmt gene, a soluble form of the Ras Loss of methyl esterification possible that a small amount of K-Ras is protein accumulates and has the gel by the Icmt enzyme is associated associated with the plasma membrane mobility of the non-isoprenylated pre- with cell growth inhibition
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