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Review
. 2007 May;117(5):1223-5.
doi: 10.1172/JCI32108.

Geranylgeranyltransferase I as a target for anti-cancer drugs

Mark R Philips  1 , Adrienne D Cox
Affiliations
Review

Geranylgeranyltransferase I as a target for anti-cancer drugs

Mark R Philips et al. J Clin Invest. 2007 May.

Abstract

Posttranslational modification is critical for the function of the gene products of ras oncogenes, which are frequently mutated in cancer. Ras proteins are modified by farnesyltransferase (FTase), but many related small GTPases that also end in a CAAX motif (where C is cysteine, A is often an aliphatic amino acid, and X is any amino acid) are modified by a closely related enzyme known as geranylgeranyltransferase type I (GGTase-I). Accordingly, inhibitors for both of these enzymes have been developed, and those active against FTase are in clinical trials. In this issue of the JCI, Sjogren et al. report the development of a mouse strain homozygous for a conditional allele of the gene that encodes GGTase-I (see the related article beginning on page 1294). They found that ablation of the GGTase-I-encoding gene in cells destined to produce lung tumors driven by oncogenic K-Ras resulted in delayed onset and decreased severity of disease, validating in a genetic model the theory that GGTase-I is a good target for anti-cancer drug development.

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Figures

Figure 1
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.
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References

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