ICMT methylates S-Farn RAS proteins

Stable Identifier
R-HSA-9647977
Type
Reaction [transition]
Species
Homo sapiens
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RAS proteins undergo C-terminal carboxymethylation by isoprenylcysteine methyltransferase (ICMT) (Yang et al, 2011; Dharmaiah et al, 2016; reviewed in Gysin et al, 2011; Ahearn et al, 2018). LIke prenylation, methylation is required for plasma membrane localization and function of RAS proteins, and disruption of ICMT or interference with the methylation reaction inhibits cell growth and KRAS-dependent transformation (Chiu et al, 2004; Michaelson et al, 2005; Bergo et al, 2004; Wahlstrom et al, 2008; Winter-Vann et al, 2003). Consistent with this, a number of small molecule inhibitors of ICMT have been shown to decrease tumor proliferation (Wang et al, 2009; Manu et al, 2017; Sun et al, 2016).

Literature References
PubMed ID Title Journal Year
12750467 Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate

Winter-Vann, AM, Kamen, BA, Bergo, MO, Young, SG, Melnyk, S, James, SJ, Casey, PJ

Proc. Natl. Acad. Sci. U.S.A. 2003
26706195 Inhibition of isoprenylcysteine carboxylmethyltransferase augments BCR-ABL1 tyrosine kinase inhibition-induced apoptosis in chronic myeloid leukemia

Sun, WT, Xiang, W, Ng, BL, Asari, K, Bunte, RM, Casey, PJ, Wang, M, Chuah, C

Exp. Hematol. 2016
15659645 Postprenylation CAAX processing is required for proper localization of Ras but not Rho GTPases

Michaelson, D, Ali, W, Chiu, VK, Bergo, M, Silletti, J, Wright, L, Young, SG, Philips, M

Mol. Biol. Cell 2005
22195972 Mechanism of isoprenylcysteine carboxyl methylation from the crystal structure of the integral membrane methyltransferase ICMT

Yang, J, Kulkarni, K, Manolaridis, I, Zhang, Z, Dodd, RB, Mas-Droux, C, Barford, D

Mol. Cell 2011
27791178 Structural basis of recognition of farnesylated and methylated KRAS4b by PDE╬┤

Dharmaiah, S, Bindu, L, Tran, TH, Gillette, WK, Frank, PH, Ghirlando, R, Nissley, DV, Esposito, D, McCormick, F, Stephen, AG, Simanshu, DK

Proc. Natl. Acad. Sci. U.S.A. 2016
18502828 Inactivating Icmt ameliorates K-RAS-induced myeloproliferative disease

Wahlstrom, AM, Cutts, BA, Liu, M, Lindskog, A, Karlsson, C, Sjogren, AK, Andersson, KM, Young, SG, Bergo, MO

Blood 2008
20622895 Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth

Wang, M, Hossain, MS, Tan, W, Coolman, B, Zhou, J, Liu, S, Casey, PJ

Oncogene 2010
21779505 Therapeutic strategies for targeting ras proteins

Gysin, S, Salt, M, Young, A, McCormick, F

Genes Cancer 2011
29311131 Posttranslational Modifications of RAS Proteins

Ahearn, I, Zhou, M, Philips, MR

Cold Spring Harb Perspect Med 2018
28167504 Inhibition of Isoprenylcysteine Carboxylmethyltransferase Induces Cell-Cycle Arrest and Apoptosis through p21 and p21-Regulated BNIP3 Induction in Pancreatic Cancer

Manu, KA, Chai, TF, Teh, JT, Zhu, WL, Casey, PJ, Wang, M

Mol. Cancer Ther. 2017
14966563 Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf

Bergo, MO, Gavino, BJ, Hong, C, Beigneux, AP, McMahon, M, Casey, PJ, Young, SG

J. Clin. Invest. 2004
14660603 Carboxyl methylation of Ras regulates membrane targeting and effector engagement

Chiu, VK, Silletti, J, Dinsell, V, Wiener, H, Loukeris, K, Ou, G, Philips, MR, Pillinger, MH

J. Biol. Chem. 2004
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Title
protein C-terminal S-isoprenylcysteine carboxyl O-methyltransferase activity of ICMT:Zn2+ [endoplasmic reticulum membrane]
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