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Gene Review

ICMT  -  isoprenylcysteine carboxyl methyltransferase

Homo sapiens

Synonyms: HSTE14, Isoprenylcysteine carboxylmethyltransferase, MST098, MSTP098, PCCMT, ...
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Disease relevance of ICMT


High impact information on ICMT

  • Fibroblasts harboring a floxed Icmt allele and expressing activated K-Ras (K-Ras-Icmt(flx/flx)) were treated with Cre-adenovirus, producing K-Ras-Icmt(Delta/Delta) fibroblasts [2].
  • Inactivation of Icmt inhibited cell growth and K-Ras-induced oncogenic transformation, both in soft agar assays and in a nude mice model [2].
  • Whereas cells expressing wild-type levels of Icmt are inhibited by methotrexate, stable expression of myristoylated H-Ras, which does not require carboxyl methylation for membrane attachment (7), confers resistance to methotrexate [3].
  • Additionally, cells lacking Icmt are highly resistant to methotrexate [3].
  • Because carboxyl methylation of Ras is important for proper plasma membrane localization and function (6), we investigated the role of Icmt in the antiproliferative effect of methotrexate [3].

Biological context of ICMT

  • To determine the consequences of ICMT inhibition, we investigated the effect of AFC on p38 mitogen-activated protein (MAP) kinase phosphorylation, which is downstream of Rac1 [4].
  • We found that N-acetyl-S-geranylgeranyl-L-cysteine (AGGC) and N-acetyl-S-farnesyl-L-cysteine (AFC), which inhibit ICMT by competing with endogenous substrates for methylation, caused apoptosis [5].
  • Transient overexpression of ICMT inhibited apoptosis caused by Ado/HC, UV light exposure, or tumor necrosis factor-alpha [5].
  • Notably, four of the five loss-of-function mutations arising from random mutagenesis alter residues that are highly conserved among the ICMT family [6].
  • This region is similar among all ICMT family members, two phospholipid methyltransferases, several ergosterol biosynthetic enzymes, and a group of bacterial open reading frames of unknown function [6].

Anatomical context of ICMT

  • These findings suggest that inhibition of ICMT causes endothelial cell apoptosis by attenuation of Ras GTPase methylation and activation and its downstream antiapoptotic signaling pathway [5].
  • Mammalian pcCMT was not expressed at the plasma membrane but rather restricted to the endoplasmic reticulum [7].
  • Mammalian prenylcysteine carboxyl methyltransferase is in the endoplasmic reticulum [7].
  • An anti-pcCMT antiserum detected a 33-kDa protein in myeloid cell membranes [7].
  • However, endogenous geranylgeranylated non-methylated Rab-CAAX and Rab-CXC proteins were significantly redistributed to the cytosol at steady-state levels and redistribution correlates with higher affinity of RabGDI for non-methylated Rabs in Icmt-deficient cells [8].

Associations of ICMT with chemical compounds

  • Ras and Rho proteins possess a C-terminal CAAX motif (C is cysteine, A is usually an aliphatic residue, and X is any amino acid), in which the cysteine is prenylated, followed by proteolytic cleavage of the AAX peptide and carboxyl methylation by the Rce1 CAAX protease and Icmt methyltransferase, respectively [8].
  • A potential mechanism for the detrimental effects of homocysteine is cellular hypomethylation from an increase in S-adenosylhomocysteine (5), an inhibitor of methyltransferases including isoprenylcysteine carboxyl methyltransferase (Icmt) [3].

Other interactions of ICMT


Analytical, diagnostic and therapeutic context of ICMT

  • The ICMT (International Center for Medical Technologies) Museum for Artificial Organs (Museum) was completed after phase I, II, and III expansions of the exhibit booths, which were made over the last two years [11].


  1. Prenylcysteine carboxymethyltransferase type III activity is decreased in retinoic acid-treated SH-SY5Y neuroblastoma cells. Van Dessel, G.A., De Busser, H.M., Lagrou, A.R. Int. J. Biochem. Cell Biol. (2002) [Pubmed]
  2. Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. Bergo, M.O., Gavino, B.J., Hong, C., Beigneux, A.P., McMahon, M., Casey, P.J., Young, S.G. J. Clin. Invest. (2004) [Pubmed]
  3. Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate. Winter-Vann, A.M., Kamen, B.A., Bergo, M.O., Young, S.G., Melnyk, S., James, S.J., Casey, P.J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. Tumor necrosis factor alpha stimulation of Rac1 activity. Role of isoprenylcysteine carboxylmethyltransferase. Papaharalambus, C., Sajjad, W., Syed, A., Zhang, C., Bergo, M.O., Alexander, R.W., Ahmad, M. J. Biol. Chem. (2005) [Pubmed]
  5. Isoprenylcysteine carboxyl methyltransferase activity modulates endothelial cell apoptosis. Kramer, K., Harrington, E.O., Lu, Q., Bellas, R., Newton, J., Sheahan, K.L., Rounds, S. Mol. Biol. Cell (2003) [Pubmed]
  6. Topological and mutational analysis of Saccharomyces cerevisiae Ste14p, founding member of the isoprenylcysteine carboxyl methyltransferase family. Romano, J.D., Michaelis, S. Mol. Biol. Cell (2001) [Pubmed]
  7. Mammalian prenylcysteine carboxyl methyltransferase is in the endoplasmic reticulum. Dai, Q., Choy, E., Chiu, V., Romano, J., Slivka, S.R., Steitz, S.A., Michaelis, S., Philips, M.R. J. Biol. Chem. (1998) [Pubmed]
  8. Rab GTPases Containing a CAAX Motif Are Processed Post-geranylgeranylation by Proteolysis and Methylation. Leung, K.F., Baron, R., Ali, B.R., Magee, A.I., Seabra, M.C. J. Biol. Chem. (2007) [Pubmed]
  9. Role of isoprenylcysteine carboxyl methyltransferase in tumor necrosis factor-alpha stimulation of expression of vascular cell adhesion molecule-1 in endothelial cells. Ahmad, M., Zhang, Y., Zhang, Y., Papharalambus, C., Alexander, R.W. Arterioscler. Thromb. Vasc. Biol. (2002) [Pubmed]
  10. Identification of novel oligodendroglioma-associated candidate tumor suppressor genes in 1p36 and 19q13 using microarray-based expression profiling. Tews, B., Felsberg, J., Hartmann, C., Kunitz, A., Hahn, M., Toedt, G., Neben, K., Hummerich, L., von Deimling, A., Reifenberger, G., Lichter, P. Int. J. Cancer (2006) [Pubmed]
  11. The artificial organ museum in Cleveland (1979-1999) moved to Houston, Texas, and named in 2002 as the ICMT Museum for Artificial Organs. Nosé, Y. Artificial organs. (2003) [Pubmed]
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