Control of RhoA Methylation by Carboxylesterase I

Cushman, Ian; Cushman, Stephanie M.; Potter, Philip M.; Casey, Patrick J.

doi:10.1074/jbc.m113.467407

Cited by 13 publications

(13 citation statements)

References 33 publications

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“…PMPMEase, which plays a vital role in regulating the function of polyisoprenylated proteins such as K-Ras, may serve as a viable alternative drug target for inhibiting or reversing PC tumor growth. It has recently been shown that siRNA targeting hCE1/PMPMEase disrupt F-actin organization by inhibiting the demethylation of RhoA leading to altered cell morphology [23]. This is consistent with our own studies showing the effects of PMPMEase inhibition-induced changes on cell morphology [9, 10].…”

Section: Resultssupporting

confidence: 92%

Polyisoprenylated methylated protein methyl esterase: A putative biomarker and therapeutic target for pancreatic cancer

Aguilar¹,

Nkembo²,

Duverna³

et al. 2014

European Journal of Medicinal Chemistry

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Pancreatic cancer is the most deadly neoplasm with a 5-year survival rate of less than 6%. Over 90% of cases harbor K-Ras mutations, which are the most challenging to treat due to lack of effective therapies. Here, we reveal that polyisoprenylated methylated protein methyl esterase (PMPMEase) is overexpressed in 93% of pancreatic ductal adenocarcinoma. We further present polyisoprenylated cysteinyl amide inhibitors (PCAIs) as novel compounds designed with structural elements for optimal in vivo activities and selective disruption of polyisoprenylation-mediated protein functions. The PCAIs inhibited PMPMEase with Ki values ranging from 3.7 to 20 µM. The 48 h EC50 values for pancreatic cancer Mia PaCa-2 and BxPC-3 cell lines were as low as 1.9 µM while salirasib and farnesylthiosalicylamide were ineffective at 20 µM. The PCAIs thus have the potential to serve as effective therapies for pancreatic and other cancers with hyperactive growth signaling pathways mediated by Ras and related G-proteins.

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Section: Resultssupporting

confidence: 92%

Polyisoprenylated methylated protein methyl esterase: A putative biomarker and therapeutic target for pancreatic cancer

Aguilar¹,

Nkembo²,

Duverna³

et al. 2014

European Journal of Medicinal Chemistry

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“…Indeed, CES1 silencing or ICMT overexpression increased RhoA activity and prompted strong changes in cytoskeletal organization in breast cancer cells 15 . In this study we found that not only Rho1 (RhoA ortholog) and Cdc42, but also Rho2 and Ras1 are present in fission yeast as pools of methylated and unmethylated isoforms at a ~1:1 ratio.…”

Section: Discussionmentioning

confidence: 99%

Distinct functional relevance of dynamic GTPase cysteine methylation in fission yeast

Franco

Soto

Martín‐García

et al. 2017

Sci Rep

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The final step in post-translational processing of Ras and Rho GTPases involves methylation of the prenylated cysteine residue by an isoprenylcysteine-O-carboxyl methyltransferase (ICMT). ICMT activity is essential for cell growth and development in higher eukaryotes, and inhibition of GTPase methylation has become an attractive target in cancer therapy to inactivate prenylated oncoproteins. However, the specificity and dynamics of the GTPase methylation process remain to be fully clarified. Notably, cells lacking Mam4, the ICMT ortholog in the fission yeast Schizosaccharomyces pombe, are viable. We have exploited this feature to analyze the role of methylation on GTPase localization and function. We show that methylation differentially affects GTPase membrane localization, being particularly relevant for plasma membrane tethering and downstream signaling of palmitoylated and farnesylated GTPases Ras1 and Rho2 lacking C-terminal polybasic motifs. Indeed, Ras1 and Rho2 cysteine methylation is required for proper regulation of differentiation elicited by MAPK Spk1 and for stress-dependent activation of the cell integrity pathway (CIP) and its main effector MAPK Pmk1. Further, Mam4 negatively regulates TORC2 signaling by a cross-inhibitory mechanism relying on Rho GTPase methylation. These results highlight the requirement for a tight control of GTPase methylation in vivo to allow adequate GTPase function.

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“…Dynamic regulation of protein carboxymethylation may have relevant consequences as suggested by the identification of carboxylesterase 1 (CES1), a carboxylesterase affecting the methylation status of RHOA. Interestingly, RHOA activity and cytoskeleton organization in breast cancer cells were similarly affected by CES1 silencing and ICMT overexpression ( 82 ).…”

Section: Icmt Targets In Oncogenesismentioning

confidence: 99%

Beyond the Mevalonate Pathway: Control of Post-Prenylation Processing by Mutant p53

et al. 2020

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Missense mutations in the TP53 gene are among the most frequent alterations in human cancer. Consequently, many tumors show high expression of p53 point mutants, which may acquire novel activities that contribute to develop aggressive tumors. An unexpected aspect of mutant p53 function was uncovered by showing that some mutants can increase the malignant phenotype of tumor cells through alteration of the mevalonate pathway. Among metabolites generated through this pathway, isoprenoids are of particular interest, since they participate in a complex process of posttranslational modification known as prenylation. Recent evidence proposes that mutant p53 also enhances this process through transcriptional activation of ICMT, the gene encoding the methyl transferase responsible for the last step of protein prenylation. In this way, mutant p53 may act at different levels to promote prenylation of key proteins in tumorigenesis, including several members of the RAS and RHO families. Instead, wild type p53 acts in the opposite way, downregulating mevalonate pathway genes and ICMT. This oncogenic circuit also allows to establish potential connections with other metabolic pathways. The demand of acetyl-CoA for the mevalonate pathway may pose limitations in cell metabolism. Likewise, the dependence on S-adenosyl methionine for carboxymethylation, may expose cells to methionine stress. The involvement of protein prenylation in tumor progression offers a novel perspective to understand the antitumoral effects of mevalonate pathway inhibitors, such as statins, and to explore novel therapeutic strategies.

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Control of RhoA Methylation by Carboxylesterase I

Cited by 13 publications

References 33 publications

Polyisoprenylated methylated protein methyl esterase: A putative biomarker and therapeutic target for pancreatic cancer

Polyisoprenylated methylated protein methyl esterase: A putative biomarker and therapeutic target for pancreatic cancer

Distinct functional relevance of dynamic GTPase cysteine methylation in fission yeast

Beyond the Mevalonate Pathway: Control of Post-Prenylation Processing by Mutant p53

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