Isoprenylcysteine carboxyl methyltransferase deficiency in mice

undergo endoproteolytic processing by Reel and methylation of the isoprenyl cysteine by Icmt (isoprenylcysteine carboxyl methyltransferase). We reporte d previously that Rce1-deficient mice died during late gestation or soon af ter birth. We hypothesized that Icmt deficiency might cause a milder phenot ype, in part because of reports suggesting the existence of more than one a ctivity for methylating isoprenylated proteins. To address this hypothesis and also to address the issue of other methyltransferase activities, we gen erated Icmt-deficient mice. Contrary to our expectation, Icmt deficiency ca used a more severe phenotype than Reel deficiency, with virtually all of th e knockout embryos (Icmt-/-) dying by mid-gestation. An analysis of chimeri c mice produced from Icmt-/- embryonic stem cells showed that the Icmt-/- c ells retained the capacity to contribute to some tissues (e.g. skeletal mus cle) but not to others (e.g. brain). Lysates from Icmt-/- embryos lacked th e ability to methylate either recombinant K-Ras or small molecule substrate s (e.g, N-acetyl-S-geranylgeranyl-L-cysteine). In addition, Icmt -/- cells lacked the ability to methylate Rab proteins. Thus, Icmt appears to be the only enzyme participating in the carboxyl methylation of isoprenylated prot eins.