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Background
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Isoprenylcysteine Carboxyl Methyl Transferase (ICMT) is a 284 amino acid multi-pass membrane protein that localizes to the endoplasmic reticulum and belongs to the Isoprenylcysteine O-methyltransferase family. ICMT functions as the third of three enzymes that post translationally modify isoprenylated C-terminal cysteine residues in certain proteins (CAAX proteins, e.g., Ras and Rho proteins) and target those proteins to the cell membrane. ICMT uses divalent cations (such as zinc) to catalyze the post-translational methylation of isoprenylated C-terminal cysteine residues. This protein modification pathway plays a significant role in cancer biology as many oncogenic proteins undergo prenylation. Methylation of the C terminus by ICMT is the final step in the prenylation pathway. Inhibition of ICMT affects Ras function and causes endothelial apoptosis, an event that leads to a decrease in oncogenic transformation. Multiple isoforms of ICMT exist due to alternative splicing and is ubiquitously expressed in brain tissue. Inhibition of ICMT is of significance as a potential target for the development of cancer chemotherapeutic agents. Inhibition of methylation reduces migration of the highly metastatic MDA-MB-231 breast cancer cell line. Inhibition of ICMT impairs cell adhesion and cell spreading and also significantly decreases the activation of both prenylated proteins, RhoA and Rac1. Inhibition of ICMT causes endothelial cell apoptosis, an effect correlated with decreased Ras and RhoA carboxyl methylation and GTPase activities. The human ICMT gene maps to chromosome 1p36.31 and encodes a 284 amino acid protein.
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