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Gene Review

Icmt  -  isoprenylcysteine carboxyl methyltransferase

Mus musculus

Synonyms: 1700008E11Rik, C80758, Gm13095, HSTE14, Isoprenylcysteine carboxylmethyltransferase, ...
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Disease relevance of Icmt

  • In a human colon cancer cell line, cysmethynil treatment blocks anchorage-independent growth, and this effect is reversed by overexpression of Icmt [1].

High impact information on Icmt

  • Cysmethynil treatment results in inhibition of cell growth in an Icmt-dependent fashion, demonstrating mechanism-based activity of the compound [1].
  • Prelamin A processing was defective both in fibroblasts lacking Zmpste24 and in fibroblasts lacking the CAAX carboxyl methyltransferase Icmt but was normal in fibroblasts lacking the CAAX endoprotease Rce1 [2].
  • After isoprenylation, the Ras proteins and other CAAX proteins undergo two additional enzymatic modifications-endoproteolytic release of the last three amino acids of the protein by the protease Rce1 and methylation of the carboxyl-terminal isoprenylcysteine by the methyltransferase Icmt [3].
  • To address this issue, we performed a series of experiments with mouse embryonic fibroblasts (MEFs) lacking Rce1 (responsible for removal of the -AAX sequence) or Icmt (responsible for carboxyl methylation of the isoprenylcysteine) [4].
  • Swapping geranylgeranylation for farnesylation on Ras proteins or vice versa on Rho proteins reversed the differential sensitivities to Rce1 and Icmt deficiency [4].

Biological context of Icmt

  • Thus, Icmt appears to be the only enzyme participating in the carboxyl methylation of isoprenylated proteins [5].
  • We hypothesized that Icmt deficiency might cause a milder phenotype, in part because of reports suggesting the existence of more than one activity for methylating isoprenylated proteins [5].

Anatomical context of Icmt

  • An analysis of chimeric mice produced from Icmt-/- embryonic stem cells showed that the Icmt-/- cells retained the capacity to contribute to some tissues (e.g. skeletal muscle) but not to others (e.g. brain) [5].
  • Genetic experiments showed that Icmt-deficient embryos die at mid-gestation, whereas conditional inactivation of Icmt in the liver, spleen, and bone marrow is not associated with obvious pathology [6].

Associations of Icmt with chemical compounds

  • After isoprenylation, the Ras proteins and other proteins terminating with a so-called CAAX motif undergo two additional modifications: (1) endoproteolytic cleavage of the -AAX by Ras converting enzyme 1 (Rce1) and (2) carboxyl methylation of the isoprenylated cysteine residue by isoprenylcysteine carboxyl methyltransferase (Icmt) [6].

Other interactions of Icmt


  1. A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells. Winter-Vann, A.M., Baron, R.A., Wong, W., dela Cruz, J., York, J.D., Gooden, D.M., Bergo, M.O., Young, S.G., Toone, E.J., Casey, P.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect. Bergo, M.O., Gavino, B., Ross, J., Schmidt, W.K., Hong, C., Kendall, L.V., Mohr, A., Meta, M., Genant, H., Jiang, Y., Wisner, E.R., Van Bruggen, N., Carano, R.A., Michaelis, S., Griffey, S.M., Young, S.G. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  3. Absence of the CAAX endoprotease Rce1: effects on cell growth and transformation. Bergo, M.O., Ambroziak, P., Gregory, C., George, A., Otto, J.C., Kim, E., Nagase, H., Casey, P.J., Balmain, A., Young, S.G. Mol. Cell. Biol. (2002) [Pubmed]
  4. Postprenylation CAAX processing is required for proper localization of Ras but not Rho GTPases. Michaelson, D., Ali, W., Chiu, V.K., Bergo, M., Silletti, J., Wright, L., Young, S.G., Philips, M. Mol. Biol. Cell (2005) [Pubmed]
  5. Isoprenylcysteine carboxyl methyltransferase deficiency in mice. Bergo, M.O., Leung, G.K., Ambroziak, P., Otto, J.C., Casey, P.J., Gomes, A.Q., Seabra, M.C., Young, S.G. J. Biol. Chem. (2001) [Pubmed]
  6. Genetic and pharmacologic analyses of the role of icmt in ras membrane association and function. Svensson, A.W., Casey, P.J., Young, S.G., Bergo, M.O. Meth. Enzymol. (2005) [Pubmed]
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