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

• After isoprenylation, Ras and other CAAX proteins undergo endoproteolytic processing by Rce1 and methylation of the isoprenylcysteine by Icmt (isoprenylcysteine carboxyl methyltransferase) [5].
• Consistent with the latter finding, RhoGDI binding and actin remodeling were normal in Rce1- and Icmt-deficient cells [4].

References