Reactome | ICMT methylates S-Farn RAS proteins

ICMT methylates S-Farn RAS proteins

Stable Identifier

R-HSA-9647977

Type

Reaction [transition]

Species

Homo sapiens

Compartment

endoplasmic reticulum membrane

ReviewStatus

5/5

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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
26706195	Inhibition of isoprenylcysteine carboxylmethyltransferase augments BCR-ABL1 tyrosine kinase inhibition-induced apoptosis in chronic myeloid leukemia Chuah, C, Bunte, RM, Asari, K, Casey, PJ, Sun, WT, Xiang, W, Wang, M, Ng, BL	Exp. Hematol.	2016
12750467	Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate Kamen, BA, Casey, PJ, Bergo, MO, Melnyk, S, Young, SG, Winter-Vann, AM, James, SJ	Proc. Natl. Acad. Sci. U.S.A.	2003
15659645	Postprenylation CAAX processing is required for proper localization of Ras but not Rho GTPases Ali, W, Philips, M, Silletti, J, Chiu, VK, Michaelson, D, Bergo, M, Young, SG, Wright, L	Mol. Biol. Cell	2005
22195972	Mechanism of isoprenylcysteine carboxyl methylation from the crystal structure of the integral membrane methyltransferase ICMT Zhang, Z, Yang, J, Kulkarni, K, Mas-Droux, C, Manolaridis, I, Barford, D, Dodd, RB	Mol. Cell	2011
27791178	Structural basis of recognition of farnesylated and methylated KRAS4b by PDEδ Dharmaiah, S, Bindu, L, Ghirlando, R, Frank, PH, McCormick, F, Gillette, WK, Tran, TH, Stephen, AG, Nissley, DV, Esposito, D, Simanshu, DK	Proc. Natl. Acad. Sci. U.S.A.	2016
18502828	Inactivating Icmt ameliorates K-RAS-induced myeloproliferative disease Liu, M, Sjogren, AK, Andersson, KM, Wahlstrom, AM, Cutts, BA, Karlsson, C, Lindskog, A, Bergo, MO, Young, SG	Blood	2008
20622895	Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth Casey, PJ, Wang, M, Liu, S, Coolman, B, Zhou, J, Hossain, MS, Tan, W	Oncogene	2010
21779505	Therapeutic strategies for targeting ras proteins McCormick, F, Salt, M, Young, A, Gysin, S	Genes Cancer	2011
29311131	Posttranslational Modifications of RAS Proteins Philips, MR, Zhou, M, Ahearn, I	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 Casey, PJ, Zhu, WL, Wang, M, Manu, KA, Chai, TF, Teh, JT	Mol. Cancer Ther.	2017
14966563	Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf Gavino, BJ, Casey, PJ, Bergo, MO, Beigneux, AP, McMahon, M, Young, SG, Hong, C	J. Clin. Invest.	2004
14660603	Carboxyl methylation of Ras regulates membrane targeting and effector engagement Loukeris, K, Pillinger, MH, Silletti, J, Ou, G, Chiu, VK, Philips, MR, Wiener, H, Dinsell, V	J. Biol. Chem.	2004