Genetic Analyses of the CAAX Protein Prenyltransferases in Mice

The RAS and RHO family proteins, the nuclear lamins, and other so-called CAAX proteins undergo three sequential posttranslational processing steps: prenylation, endoproteolysis, and carboxyl methylation. These steps are mediated by four different enzymes: farnesyltransferase (FTase) or geranylgeranyltransferase type I (GGTase-I), RAS converting enzyme 1 (RCE1), and isoprenylcysteine carboxyl methyltransferase (ICMT). Over the past 20 years, there has been an intense interest in understanding the biological significance of CAAX protein processing and its impact on CAAX protein stability, membrane targeting, protein-protein interactions, signaling, and function. Perhaps, the greatest interest has stemmed from the efforts of targeting the CAAX protein prenyltransferases FTase and GGTase-I as a strategy to interfere with the activity of disease-causing mutants of CAAX proteins such as RAS and prelamin A in the treatment of cancer and progeroid disorders. Mice with targeted conditional knockout alleles for FTase and GGTase-I have been used to shed light on those topics. Here, we review the genetic studies that have provided new information on the biochemical and medical importance of CAAX protein prenylation.