Encyclopedia of Signaling Molecules

2012 Edition
| Editors: Sangdun Choi

Protein Farnesyltransferase

  • Lai N. Chan
  • Fuyuhiko Tamanoi
Reference work entry
DOI: https://doi.org/10.1007/978-1-4419-0461-4_361

Synonyms

Historical Background

Protein prenylation is a posttranslational modification of proteins involving the addition of isoprenyl lipids (Tamanoi and Sigman 2001). It is a post-translational modification that occurs in the cytosol and is essential for the proper localization and functions of many proteins. There are three kinds of prenyltransferases: protein farnesyltransferase (FTase), protein geranylgeranyltransferase-I (GGTase-I), and Rab geranylgeranyltransferase (RabGGTase). No additional prenyltransferases have been described to date. Farnesyltransferase (FTase) catalyzes the addition of a 15-carbon farnesyl group to proteins such as Ras proteins, Rheb proteins, nuclear lamins, and Hdj2 that end with the Cys-A1-A2-X (CA1A2X)motif, where A is an aliphatic amino acid and X is usually serine, methionine, glutamine or alanine. The lipid is covalently attached to the Cys via a thioether linkage between C1 of the farnesyl...

This is a preview of subscription content, log in to check access

References

  1. Bowers KE, Fierke CA. Positively charged side chains in protein farnesyltransferase enhance catalysis by stabilizing the formation of the diphosphate leaving group. Biochemistry. 2004;43:5256–65.PubMedGoogle Scholar
  2. Chintala L, Kurzrock R, Fu S, Naing A, Wheler JJ, Moulder SL, Newman R, Gagel R, Sebti S, Wright JJ, Hong DS. Phase I study of tipifarnib and sorafenib in patients with biopsiable advanced cancer. J Clin Oncol. 2008;26:3595 (NCI protocol 7156).Google Scholar
  3. Cui G, Wang B, Merz KM. Computational studies of the farnesyltransferase ternary complex part I: substrate binding. Biochemistry. 2005;44:16513–23.PubMedGoogle Scholar
  4. Fong LG, Frost D, Meta M, Qiao X, Yang SH, Coffinier C, Young SG. A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science. 2006;311:1621–3.PubMedGoogle Scholar
  5. Gau CL, Kato-Stankiewicz J, Jiang C, Miyamoto S, Guo L, Tamanoi F. Farnesyltransferase inhibitors reverse altered growth and distribution of actin filaments in Tsc-deficient cells via inhibition of both rapamycin-sensitive and -insensitive pathways. Mol Cancer Ther. 2005;4:918–26.PubMedGoogle Scholar
  6. Goalstone M, Kamath V, Kowluru A. Glucose activates prenyltransferases in pancreatic islet beta-cells. Biochem Biophys Res Commun. 2010;391:895–8.PubMedGoogle Scholar
  7. Hougland JL, Hicks KA, Hartman HL, Kelly RA, Watt TJ, Fierke CA. Identification of novel peptide substrates for protein farnesyltransferase reveals two substrate classes with distinct sequence selectivities. J Mol Biol. 2009;395:176–90.PubMedGoogle Scholar
  8. Kim KW, Chung HH, Chung CW, Kim IK, Miura M, Wang S, Zhu H, Moon KD, Rha GB, Park JH, Jo DG, Woo HN, Song YH, Kim BJ, Yuan J, Jung YK. Inactivation of farnesyltransferase and geranylgeranyltransferase I by caspase-3: cleavage of the common alpha subunit during apoptosis. Oncogene. 2001;20:358–66.PubMedGoogle Scholar
  9. Kim CK, Choi YK, Lee H, Ha K-S, Won M-H, Kwon Y-G, Kim Y-M. The farnesyltransferase inhibitor LB42708 suppresses vascular endothelial growth factor-induced angiogenesis by inhibiting ras-dependent mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signal pathways. Mol Pharmacol. 2010;78:142–50.PubMedGoogle Scholar
  10. Kohl NE, Omer CA, Conner MW, Anthony NJ, Davide JP, deSolms SJ, Giuliani EA, Gomez RP, Graham SL, Hamilton K, et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med. 1995;1:792–7.PubMedGoogle Scholar
  11. Kumar A, Mehta KD. p21ras farnesyltransferase alpha- and beta-subunits are phosphorylated in PC-12 cells: TGF-beta signaling pathway independent phosphorylation. Neurosci Lett. 1997;231:143–6.PubMedGoogle Scholar
  12. Lebowitz PF, Casey PJ, Prendergast GC, Thissen JA. Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB. J Biol Chem. 1997;272:15591–4.PubMedGoogle Scholar
  13. Lin AE, Gripp KG, Kerr BK. Management of genetic syndromes. 2nd ed. Hoboken: Wiley; 2005.Google Scholar
  14. Liu M, Sjogren AK, Karlsson C, Ibrahim MX, Andersson KM, Olofsson FJ, Wahlstrom AM, Dalin M, Yu H, Chen Z, Yang SH, Young SG, Bergo MO. Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer. Proc Natl Acad Sci USA. 2010;107:6471–6.PubMedGoogle Scholar
  15. Mijimolle N, Velasco J, Dubus P, Guerra C, Weinbaum CA, Casey PJ, Campuzano V, Barbacid M. Protein farnesyltransferase in embryogenesis, adult homeostasis, and tumor development. Cancer Cell. 2005;7:313–24.PubMedGoogle Scholar
  16. Mouri W, Tachibana K, Tomiyama A, Sunayama J, Sato A, Sakurada K, Kayama T, Kitanaka C. Downregulation of Ras C-terminal processing by JNK inhibition. Biochem Biophys Res Commun. 2008;371:273–7.PubMedGoogle Scholar
  17. Park H-W, Boduluri SR, Moomaw JF, Casey PJ, Beese LS. Crystal structure of protein farnesyltransferase at 2.25 angstrom resolution. Science. 1997;275:1800–4.PubMedGoogle Scholar
  18. Pickett JS, Bowers KE, Fierke CA. Mutagenesis studies of protein farnesyltransferase implicate aspartate beta 352 as a magnesium ligand. J Biol Chem. 2003;278:51243–50.PubMedGoogle Scholar
  19. Reid TS, Beese LS. Crystal structures of the anticancer clinical candidates R115777 (Tipifarnib) and BMS-214662 complexed with protein farnesyltransferase suggest a mechanism of FTI selectivity. Biochemistry. 2004;43:6877–84.PubMedGoogle Scholar
  20. Reid TS, Terry KL, Casey PJ, Beese LS. Crystallographic analysis of CaaX prenyltransferases complexed with substrates defines rules of protein substrate selectivity. J Mol Biol. 2004;343:417–33.PubMedGoogle Scholar
  21. Sjogren AK, Andersson KM, Liu M, Cutts BA, Karlsson C, Wahlstrom AM, Dalin M, Weinbaum C, Casey PJ, Tarkowski A, Swolin B, Young SG, Bergo MO. GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS-induced lung cancer. J Clin Invest. 2007;117:1294–304.PubMedGoogle Scholar
  22. Solomon CS, Goalstone ML. Dominant negative farnesyltransferase alpha-subunit inhibits insulin mitogenic effects. Biochem Biophys Res Commun. 2001;285:161–6.PubMedGoogle Scholar
  23. Tamanoi F, Sigman DS, editors. The enzymes, vol. 21. San Diego: Academic Press; 2001.Google Scholar
  24. Taylor JS, Reid TS, Terry KL, Casey PJ, Beese LS. Structure of mammalian protein geranylgeranyltransferase type-I. EMBO J. 2003;22:5963–74.PubMedGoogle Scholar
  25. Whyte DB, Kirschmeier P, Hockenberry TN, Nunez-Oliva I, James L, Catino JJ, Bishop WR, Pai JK. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem. 1997;272:14459–64.PubMedGoogle Scholar
  26. Yang SH, Bergo MO, Farber E, Qiao X, Fong LG, Young SG. Caution! Analyze transcripts from conditional knockout alleles. Transgenic Res. 2009;18:483–9.PubMedGoogle Scholar
  27. Yang Y, Chakravorty DK, Merz KM. Finding a needle in the haystack: computational modeling of Mg2+ binding in the active site of protein farnesyltransferase. Biochemistry. 2010;49:9658–66.PubMedGoogle Scholar
  28. Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem. 1996;65:241–70.PubMedGoogle Scholar
  29. Zheng H, Liu A, Liu B, Li M, Yu H, Luo X. Ras homologue enriched in brain is a critical target of farnesyltransferase inhibitors in non-small cell lung cancer cells. Cancer Lett. 2010;297:117–25.PubMedGoogle Scholar
  30. Zhou J, Vos CC, Gjyrezi A, Yoshida M, Khuri FR, Tamanoi F, Giannakakou P. The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner. J Biol Chem. 2009;284:9648–55.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Lai N. Chan
    • 1
    • 2
  • Fuyuhiko Tamanoi
    • 1
    • 2
  1. 1.Molecular Biology InstituteLos AngelesUSA
  2. 2.Department of Microbiology, Immunology & Molecular GeneticsUniversity of CaliforniaLos AngelesUSA