Geranylgeranyltransferase I as a target for anti-cancer drugs
J. Clin. Invest. Mark R. Philips, et al. 117:1223 doi:10.1172/JCI32108 [Go to this article.]

Figure 1
Prenylation of CAAX proteins. The CAAX sequence of Ras proteins ends in methionine (M) or serine (S) and is therefore recognized preferentially by FTase, which lipidates the protein with a 15-carbon farnesyl isoprenoid at the CAAX cysteine. Farnesylated Ras is then further processed on the surface of the ER by a protease (Rce1) and isoprenylcysteine carboxyl methyltransferase (Icmt) and then transported to the plasma membrane. The product of this three-step processing is a C-terminal cysteine that is both farnesylated and methyl esterified (-OMe) such that it is hydrophobic and associates with the phospholipid bilayer. This entire processing sequence can be blocked by farnesyl transferase inhibitors (FTIs). Ras-related GTPases that end with a CAAX sequence in which X is a leucine (L) are lipidated instead with a 20-carbon geranylgeranyl isoprenoid by GGTase-I. Several of these proteins, e.g., RhoA, RhoC, Rac1, Cdc42, RalA, and RalB, are required for Ras-mediated cellular transformation, making GGTase-I a target for drug discovery. When FTase is inhibited by FTI, N-Ras and K-Ras are processed instead by GGTase-I, but H-Ras cannot be alternatively prenylated. Alternative prenylation of Ras has heightened interest in the development of GGTIs. In this issue of the JCI, Sjogren et al. (9) have conditionally deleted GGTase-I and shown that K-Ras–driven tumors are inhibited, presumably because one or more of the substrates for this enzyme are required for oncogenesis.