Isoprenylcysteine carboxyl methyltransferase (ICMT)

Isoprenylcysteine carboxyl methyltransferase (ICMT) is an integral membrane enzyme in the endoplasmic reticulum that catalyzes the post-translational methylation of the C-terminal isoprenylated cysteine residue of proteins containing CAAX or CXC motifs, such as RAS, Rho, and certain RAB GTPases. This modification is the final step in the prenylation pathway and is essential for proper membrane localization, activation, and biological function of substrates involved in key cellular processes including signal transduction, cell proliferation, migration, and polarity. ICMT is considered a promising anticancer drug target due to its critical role in the activation and function of oncogenic RAS proteins and regulators of cancer metastasis; inhibition of ICMT induces mislocalization and loss of function of these substrates, impairing tumor growth and dissemination. ICMT is unique among protein methyltransferases in its structure, substrate specificity, and mechanistic features, and its only known physiological role is methylation of isoprenylated protein substrates.

Other names

Protein-S-isoprenylcysteine O-methyltransferasePrenylcysteine carboxyl methyltransferasePrenylated protein carboxyl methyltransferasePCCMTPPMTpcCMTHSTE14MST098MSTP098PCMTSte14 (yeast ortholog)

Inhibition of post-translational methylation of C-terminal isoprenylcysteine residues on CAAX/CXC motif proteins, leading to mislocalization and functional disruption of CAAX/CXC GTPases, notably RAS and RAB GTPases, thereby impairing cell signaling relevant to proliferation and migration.