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Post-prenylation-processing enzymes as new targets in oncogenesis

Abstract

RAS and many other oncogenic proteins undergo a complex series of post-translational modifications that are initiated by the addition of an isoprenoid lipid through a process known as prenylation. Following prenylation, these proteins usually undergo endoproteolytic processing by the RCE1 protease and then carboxyl methylation by a unique methyltransferase known as isoprenylcysteine carboxyl methyltransferase (ICMT). Although inhibitors that have been designed to target the prenylation step are now in advanced-stage clinical trials, their utility and efficacy seem to be limited. Recent findings, however, indicate that the inhibition of these post-prenylation-processing steps — particularly that of ICMT-catalysed methylation — might provide a better approach to the control of cancer-cell proliferation.

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Figure 1: An overview of CAAX-protein processing.
Figure 2: Roles for CAAX proteins in oncogenesis.

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References

  1. Glomset, J. A. & Farnsworth, C. C. Role of protein modification reactions in programming interactions between ras-related GTPases and cell membranes. Annu. Rev. Cell Biol. 10, 181–205 (1994).

    CAS  PubMed  Google Scholar 

  2. Zhang, F. L. & Casey, P. J. Protein prenylation: molecular mechanisms and functional consequences. Annu. Rev. Biochem. 65, 241–269 (1996).

    CAS  PubMed  Google Scholar 

  3. Casey, P. J. & Seabra, M. C. Protein prenyltransferases. J. Biol. Chem. 271, 5289–5292 (1996).

    CAS  PubMed  Google Scholar 

  4. Ashby, M. N. CaaX converting enzymes. Curr. Opin. Lipidol. 9, 99–102 (1998).

    CAS  PubMed  Google Scholar 

  5. Young, S. G., Ambroziack, P., Kim, E. & Clarke, S. in The Enzymes 3rd edn Vol. 21 (eds Tamanoi, F. and Sigman, D. G.) 156–213 (Academic, San Diego, 2001).

    Google Scholar 

  6. Bos, J. L. ras oncogenes in human cancer: a review. Cancer Res. 49, 4682–4689 (1989).

    CAS  PubMed  Google Scholar 

  7. Malumbres, M. & Barbacid, M. RAS oncogenes: the first 30 years. Nature Rev. Cancer 3, 459–465 (2003).

    CAS  Google Scholar 

  8. Hahn, W. C. et al. Creation of human tumour cells with defined genetic elements. Nature 400, 464–468 (1999).

    CAS  PubMed  Google Scholar 

  9. Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 103, 211–225 (2000).

    CAS  PubMed  Google Scholar 

  10. Gschwind, A., Fischer, O. M. & Ullrich, A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nature Rev. Cancer 4, 361–370 (2004).

    CAS  Google Scholar 

  11. Jaffe, A. B. & Hall, A. Rho GTPases in transformation and metastasis. Adv. Cancer Res. 84, 57–80 (2002).

    CAS  PubMed  Google Scholar 

  12. Sahai, E. & Marshall, C. J. RHO-GTPases and cancer. Nature Rev. Cancer 2, 133–142 (2002).

    Google Scholar 

  13. Ishida, D. et al. Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice. Cancer Cell 4, 55–65 (2003).

    CAS  PubMed  Google Scholar 

  14. Daaka, Y. G proteins in cancer: the prostate cancer paradigm. Sci. STKE 216, re2 (2004).

    Google Scholar 

  15. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Schwindinger, W. F. & Robishaw, J. D. Heterotrimeric G-protein βγ-dimers in growth and differentiation. Oncogene 20, 1653–1660 (2001).

    CAS  PubMed  Google Scholar 

  17. Heasley, L. E. Autocrine and paracrine signaling through neuropeptide receptors in human cancer. Oncogene 20, 1563–1569 (2001).

    CAS  PubMed  Google Scholar 

  18. Fromm, C., Coso, O. A., Montaner, S., Xu, N. & Gutkind, J. S. The small GTP-binding protein Rho links G protein-coupled receptors and Gα12 to the serum response element and to cellular transformation. Proc. Natl Acad. Sci. USA 94, 10098–10103 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Cates, C. A. et al. Prenylation of oncogenic human PTP(CAAX) protein tyrosine phosphatases. Cancer Lett. 110, 49–55 (1996).

    CAS  PubMed  Google Scholar 

  20. Collins, S. P., Reoma, J. L., Gamm, D. M. & Uhler, M. D. LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo. Biochem. J. 345, 673–680 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hutchison, C. J. Lamins: building blocks or regulators of gene expression? Nature Rev. Mol. Cell Biol. 3, 848–858 (2002).

    CAS  Google Scholar 

  22. Ashar, H. R. et al. Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules. J. Biol. Chem. 275, 30451–30457 (2000).

    CAS  PubMed  Google Scholar 

  23. Kloog, Y. & Cox, A. D. Prenyl-binding domains: potential targets for Ras inhibitors and anti-cancer drugs. Semin. Cancer Biol. 14, 253–261 (2004).

    CAS  PubMed  Google Scholar 

  24. Kato, K. et al. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc. Natl Acad. Sci. USA 89, 6403–6407 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hori, Y. et al. Post-translational modifications of the C-terminal region of the rho protein are important for its interaction with membranes and the stimulatory and inhibitory GDP/GTP exchange proteins. Oncogene 6, 515–522 (1991).

    CAS  PubMed  Google Scholar 

  26. Allal, C. et al. RhoA prenylation is required for promotion of cell growth and transformation and cytoskeleton organization but not for induction of serum response element transcription. J. Biol. Chem. 275, 31001–31008 (2000).

    CAS  PubMed  Google Scholar 

  27. Fukada, Y. et al. Farnesylated γ-subunit of photoreceptor G protein indispensable for GTP-binding. Nature 346, 658–660 (1990).

    CAS  PubMed  Google Scholar 

  28. Gibbs, J. B., Oliff, A. & Kohl, N. E. Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell 77, 175–178 (1994).

    CAS  PubMed  Google Scholar 

  29. Mazieres, J., Pradines, A. & Favre, G. Perspectives on farnesyl transferase inhibitors in cancer therapy. Cancer Lett. 206, 159–167 (2004).

    CAS  PubMed  Google Scholar 

  30. Kohl, N. E. et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nature Med. 1, 792–797 (1995).

    CAS  PubMed  Google Scholar 

  31. Doll, R. J., Kirschmeier, P. & Bishop, W. R. Farnesyltransferase inhibitors as anticancer agents: critical crossroads. Curr. Opin. Drug Discov. Devel. 7, 478–486 (2004).

    CAS  PubMed  Google Scholar 

  32. Gotlib, J. Farnesyltransferase inhibitor therapy in acute myelogenous leukemia. Curr. Hematol. Rep. 4, 77–84 (2005).

    CAS  PubMed  Google Scholar 

  33. Cox, A. D. & Der, C. J. Farnesyltransferase inhibitors: promises and realities. Curr. Opin. Pharmacol. 2, 388–393 (2002).

    CAS  PubMed  Google Scholar 

  34. James, G. L., Goldstein, J. L. & Brown, M. S. Polylysine and CVIM sequences of K-RasB dictate specificity of prenylation and confer resistance to benzodiazepine peptidomimetic in vitro. J. Biol. Chem. 270, 6221–6226 (1995).

    CAS  PubMed  Google Scholar 

  35. Whyte, D. B. et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J. Biol. Chem. 272, 14459–14464 (1997).

    CAS  PubMed  Google Scholar 

  36. Sebti, S. M. & Der, C. J. Searching for the elusive targets of farnesyltransferase inhibitors. Nature Rev. Cancer 3, 945–951 (2003).

    CAS  Google Scholar 

  37. Kim, E. et al. Disruption of the mouse Rce1 gene results in defective Ras processing and mislocalization of Ras within cells. J. Biol. Chem. 274, 8383–8390 (1999).

    CAS  PubMed  Google Scholar 

  38. Bergo, M. O. et al. Targeted inactivation of the isoprenylcysteine carboxyl methyltransferase gene causes mislocalization of K-Ras in mammalian cells. J. Biol. Chem. 275, 17605–17610 (2000).

    CAS  PubMed  Google Scholar 

  39. Clarke, S. & Tamanoi, F. Fighting cancer by disrupting C-terminal methylation of signaling proteins. J. Clin. Invest. 113, 513–515 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Boyartchuk, V. L., Ashby, M. N. & Rine, J. Modulation of Ras and a-factor function by carboxyl-terminal proteolysis. Science 275, 1796–1800 (1997).

    CAS  PubMed  Google Scholar 

  41. Otto, J. C., Kim, E., Young, S. G. & Casey, P. J. Cloning and characterization of a mammalian prenyl protein-specific protease. J. Biol. Chem. 274, 8379–8382 (1999).

    CAS  PubMed  Google Scholar 

  42. Schmidt, W. K., Tam, A., Fujimura-Kamada, K. & Michaelis, S. Endoplasmic reticulum membrane localization of Rce1p and Ste24p, yeast proteases involved in carboxyl-terminal CAAX protein processing and amino-terminal a-factor cleavage. Proc. Natl Acad. Sci. USA 95, 11175–11180 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Jang, G. F. & Gelb, M. H. Substrate specificity of mammalian prenyl protein-specific endoprotease activity. Biochemistry 37, 4473–4481 (1998).

    CAS  PubMed  Google Scholar 

  44. Chen, Y., Ma, Y. T. & Rando, R. R. Solubilization, partial purification, and affinity labeling of the membrane-bound isoprenylated protein endoprotease. Biochemistry 35, 3227–3237 (1996).

    CAS  PubMed  Google Scholar 

  45. Pei, J. & Grishin, N. V. Type II CAAX prenyl endopeptidases belong to a novel superfamily of putative membrane-bound metalloproteases. Trends Biochem. Sci. 26, 275–277 (2001).

    CAS  PubMed  Google Scholar 

  46. Trueblood, C. E. et al. The CaaX proteases, Afc1p and Rce1p, have overlapping but distinct substrate specificities. Mol. Cell. Biol. 20, 4381–4392 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Bergo, M. O. et al. On the physiological importance of endoproteolysis of CAAX proteins: heart-specific RCE1 knockout mice develop a lethal cardiomyopathy. J. Biol. Chem. 279, 4729–4736 (2004).

    CAS  PubMed  Google Scholar 

  48. Dai, Q. et al. Mammalian prenylcysteine carboxyl methyltransferase is in the endoplasmic reticulum. J. Biol. Chem. 273, 15030–15034 (1998).

    CAS  PubMed  Google Scholar 

  49. Romano, J. D., Schmidt, W. K. & Michaelis, S. The Saccharomyces cerevisiae prenylcysteine carboxyl methyltransferase Ste14p is in the endoplasmic reticulum membrane. Mol. Biol. Cell 9, 2231–2247 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Marr, R. S., Blair, L. C. & Thorner, J. Saccharomyces cerevisiae STE14 gene is required for COOH-terminal methylation of a-factor mating pheromone. J. Biol. Chem. 265, 20057–20060 (1990).

    CAS  PubMed  Google Scholar 

  51. Hrycyna, C. A., Sapperstein, S. K., Clarke, S. & Michaelis, S. The Saccharomyces cerevisiae STE14 gene encodes a methyltransferase that mediates C-terminal methylation of a-factor and RAS proteins. EMBO J. 10, 1699–1709 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Kagan, R. M. & Clarke, S. Widespread occurrence of three sequence motifs in diverse S-adenosylmethionine-dependent methyltransferases suggests a common structure for these enzymes. Arch. Biochem. Biophys. 310, 417–427 (1994).

    CAS  PubMed  Google Scholar 

  53. Tan, E. W., Perez-Sala, D., Canada, F. J. & Rando, R. R. Identifying the recognition unit for G protein methylation. J. Biol. Chem. 266, 10719–10722 (1991).

    CAS  PubMed  Google Scholar 

  54. Lin, X. et al. Prenylcysteine carboxylmethyltransferase is essential for the earliest stages of liver development in mice. Gastroenterology 123, 345–351 (2002).

    CAS  PubMed  Google Scholar 

  55. Bergo, M. O. et al. Isoprenylcysteine carboxyl methyltransferase deficiency in mice. J. Biol. Chem. 276, 5841–5845 (2001).

    CAS  PubMed  Google Scholar 

  56. Smeland, T. E., Seabra, M. C., Goldstein, J. L. & Brown, M. S. Geranylgeranylated Rab proteins terminating in Cys-Ala-Cys, but not Cys-Cys, are carboxyl-methylated by bovine brain membranes in vitro. Proc. Natl Acad. Sci. USA 91, 10712–10716 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Takai, Y., Sasaki, T. & Matozaki, T. Small GTP-binding proteins. Physiol. Rev. 81, 153–208 (2001).

    CAS  PubMed  Google Scholar 

  58. Silvius, J. R. & l'Heureux, F. Fluorimetric evaluation of the affinities of isoprenylated peptides for lipid bilayers. Biochemistry 33, 3014–3022 (1994).

    CAS  PubMed  Google Scholar 

  59. Chen, Z., Otto, J. C., Bergo, M. O., Young, S. G. & Casey, P. J. The C-terminal polylysine region and methylation of K-Ras are critical for the interaction between K-Ras and microtubules. J. Biol. Chem. 275, 41251–41257 (2000).

    CAS  PubMed  Google Scholar 

  60. Michaelson, D., Ahearn, I., Bergo, M., Young, S. & Philips, M. Membrane trafficking of heterotrimeric G proteins via the endoplasmic reticulum and Golgi. Mol. Biol. Cell 13, 3294–3302 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Michaelson, D. et al. Postprenylation CAAX processing is required for proper localization of Ras but not Rho GTPases. Mol. Biol. Cell (in the press).

  62. Hrycyna, C. A. & Clarke, S. Farnesyl cysteine C-terminal methyltransferase activity is dependent upon the STE14 gene product in Saccharomyces cerevisiae. Mol. Cell. Biol. 10, 5071–5076 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Sapperstein, S., Berkower, C. & Michaelis, S. Nucleotide sequence of the yeast STE14 gene, which encodes farnesylcysteine carboxyl methyltransferase, and demonstration of its essential role in a-factor export. Mol. Cell. Biol. 14, 1438–1449 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Parish, C. A., Smrcka, A. V. & Rando, R. R. Functional significance of βγ subunit carboxymethylation for the activation of phospholipase C and phosphoinositide 3-kinase. Biochemistry 34, 7722–7727 (1995).

    CAS  PubMed  Google Scholar 

  65. Fukada, Y. et al. Effects of carboxyl methylation of photoreceptor G protein γ subunit in visual transduction. J. Biol. Chem. 269, 5163–5170 (1994).

    CAS  PubMed  Google Scholar 

  66. Maske, C. P. et al. A carboxyl-terminal interaction of lamin B1 is dependent on the CAAX endoprotease Rce1 and carboxymethylation. J. Cell Biol. 162, 1223–1232 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Backlund, P. S. Jr. Post-translational processing of RhoA. Carboxyl methylation of the carboxyl-terminal prenylcysteine increases the half-life of RhoA. J. Biol Chem. 272, 33175–33180 (1997).

    CAS  PubMed  Google Scholar 

  68. Bergo, M. O. et al. Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J. Clin. Invest. 113, 539–550 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Philips, M. R. et al. Carboxyl methylation of Ras-related proteins during signal transduction in neutrophils. Science 259, 977–980 (1993).

    CAS  PubMed  Google Scholar 

  70. Perez, E., West, A. H., Stock, A. M. & Djordjevic, S. Discrimination between different methylation states of chemotaxis receptor Tar by receptor methyltransferase CheR. Biochemistry 43, 953–961 (2004).

    CAS  PubMed  Google Scholar 

  71. Kort, E. N., Goy, M. F., Larsen, S. H. & Adler, J. Methylation of a membrane protein involved in bacterial chemotaxis. Proc. Natl Acad. Sci. USA 72, 3939–3943 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Choi, Y. J. et al. Assays of human postprenylation processing enzymes. Methods Enzymol. 332, 103–114 (2001).

    CAS  PubMed  Google Scholar 

  73. Tan, E. W. & Rando, R. R. Identification of an isoprenylated cysteine methyl ester hydrolase activity in bovine rod outer segment membranes. Biochemistry 31, 5572–5578 (1992).

    CAS  PubMed  Google Scholar 

  74. Dunten, R. L., Wait, S. J. & Backlund, P. S. Jr. Fractionation and characterization of protein C-terminal prenyl-cysteine methylesterase activities from rabbit brain. Biochem. Biophys. Res. Commun. 208, 174–182 (1995).

    CAS  PubMed  Google Scholar 

  75. Bergo, M. O. et al. Absence of the CAAX endoprotease Rce1: effects on cell growth and transformation. Mol. Cell. Biol. 22, 171–181 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Aiyagari, A. L., Taylor, B. R., Aurora, V., Young, S. G. & Shannon, K. M. Hematologic effects of inactivating the Ras processing enzyme Rce1. Blood 101, 2250–2252 (2003).

    CAS  PubMed  Google Scholar 

  77. Schlitzer, M., Winter-Vann, A. & Casey, P. J. Non-peptidic, non-prenylic inhibitors of the prenyl protein-specific protease Rce1. Bioorg. Med. Chem. Lett. 11, 425–427 (2001).

    CAS  PubMed  Google Scholar 

  78. Ma, Y. T., Gilbert, B. A. & Rando, R. R. Inhibitors of the isoprenylated protein endoprotease. Biochemistry 32, 2386–2393 (1993).

    CAS  PubMed  Google Scholar 

  79. Chen, Y. Selective inhibition of Ras-transformed cell growth by a novel fatty acid-based chloromethyl ketone designed to target Ras endoprotease. Ann. NY Acad. Sci. 886, 103–108 (1999).

    CAS  PubMed  Google Scholar 

  80. Shi, Y. Q. & Rando, R. R. Kinetic mechanism of isoprenylated protein methyltransferase. J. Biol. Chem. 267, 9547–9551 (1992).

    CAS  PubMed  Google Scholar 

  81. Winter-Vann, A. M. et al. Targeting Ras signaling through inhibition of carboxyl methylation: An unexpected property of methotrexate. Proc. Natl Acad. Sci. USA 100, 6529–6534 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang, H. et al. Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine. J. Biol. Chem. 272, 25380–25385 (1997).

    CAS  PubMed  Google Scholar 

  83. Kramer, K. et al. Isoprenylcysteine carboxyl methyltransferase activity modulates endothelial cell apoptosis. Mol. Biol. Cell 14, 848–857 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Lu, Q. et al. Isoprenylcysteine carboxyl methyltransferase modulates endothelial monolayer permeability. Involvement of RhoA carboxyl methylation. Circ. Res. 94, 306–315 (2004).

    CAS  PubMed  Google Scholar 

  85. Hoffman, D. R., Cornatzer, W. E. & Duerre, J. A. Relationship between tissue levels of S-adenosylmethionine, S-adenylhomocysteine, and transmethylation reactions. Can. J. Biochem. 57, 56–65 (1979).

    CAS  PubMed  Google Scholar 

  86. Chiang, P. K. et al. S-adenosylmethionine and methylation. FASEB J. 10, 471–480 (1996).

    CAS  PubMed  Google Scholar 

  87. Perez-Sala, D., Gilbert, B. A., Tan, E. W. & Rando, R. R. Prenylated protein methyltransferases do not distinguish between farnesylated and geranylgeranylated substrates. Biochem. J. 284, 835–840 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Kowluru, A. et al. Glucose- and GTP-dependent stimulation of the carboxyl methylation of CDC42 in rodent and human pancreatic islets and pure β cells. Evidence for an essential role of GTP-binding proteins in nutrient-induced insulin secretion. J. Clin. Invest. 98, 540–555 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Chiu, V. K. et al. Carboxyl methylation of ras regulates membrane targeting and effector engagment. J. Biol. Chem. 279, 7346–7352 (2003).

    PubMed  Google Scholar 

  90. Roullet, J. B. et al. Farnesyl analogues inhibit vasoconstriction in animal and human arteries. J. Clin. Invest. 97, 2384–2390 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Scheer, A. & Gierschik, P. Farnesylcysteine analogues inhibit chemotactic peptide receptor-mediated G-protein activation in human HL-60 granulocyte membranes. FEBS Lett. 319, 110–114 (1993).

    CAS  PubMed  Google Scholar 

  92. Ma, Y. T. et al. Mechanistic studies on human platelet isoprenylated protein methyltransferase: farnesylcysteine analogs block platelet aggregation without inhibiting the methyltransferase. Biochemistry 33, 5414–5420 (1994).

    CAS  PubMed  Google Scholar 

  93. Ding, J. et al. Farnesyl-l-cysteine analogs can inhibit or initiate superoxide release by human neutrophils. J. Biol. Chem. 269, 16837–16844 (1994).

    CAS  PubMed  Google Scholar 

  94. Philips, M. R. Methotrexate and Ras methylation: a new trick for an old drug? Sci. STKE 225, pe13 (2004).

    Google Scholar 

  95. Chen, Y. Inhibition of K-ras-transformed rodent and human cancer cell growth via induction of apoptosis by irreversible inhibitors of Ras endoprotease. Cancer Lett. 131, 191–200 (1998).

    CAS  PubMed  Google Scholar 

  96. Backlund, P. S. Post-translational processing of RhoA. Carboxyl methylation of the carboxyl-terminal prenylcysteine increases the half-life of Rhoa. J. Biol. Chem. 272, 33175–33180 (1997).

    CAS  PubMed  Google Scholar 

  97. Garnett, M. J. & Marais, R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6, 313–319 (2004).

    CAS  PubMed  Google Scholar 

  98. Rowinsky, E. K. Signal events: cell signal transduction and its inhibition in cancer. Oncologist 8 (Suppl. 3), 5–17 (2003).

    CAS  PubMed  Google Scholar 

  99. Reid, T. S., Terry, K. L., Casey, P. J. & Beese, L. S. Crystallographic analysis of CaaX prenyltransferases complexed with substrates defines rules of protein substrate selectivity. J. Mol. Biol. 343, 417–433 (2004).

    CAS  PubMed  Google Scholar 

  100. McFarlane, S. I., Muniyappa, R., Francisco, R. & Sowers, J. R. Clinical review 145: pleiotropic effects of statins: lipid reduction and beyond. J. Clin. Endocrinol. Metab. 87, 1451–1458 (2002).

    CAS  PubMed  Google Scholar 

  101. Auer, J., Berent, R., Weber, T. & Eber, B. Clinical significance of pleiotropic effects of statins: lipid reduction and beyond. Curr. Med. Chem. 9, 1831–1850 (2002).

    CAS  PubMed  Google Scholar 

  102. Chan, K. K., Oza, A. M. & Siu, L. L. The statins as anticancer agents. Clin. Cancer Res. 9, 10–19 (2003).

    CAS  PubMed  Google Scholar 

  103. Soltis, D. A. et al. Expression, purification, and characterization of the human squalene synthase: use of yeast and baculoviral systems. Arch. Biochem. Biophys. 316, 713–723 (1995).

    CAS  PubMed  Google Scholar 

  104. Sagami, H., Morita, Y. & Ogura, K. Purification and properties of geranylgeranyl-diphosphate synthase from bovine brain. J. Biol. Chem. 269, 20561–20566 (1994).

    CAS  PubMed  Google Scholar 

  105. Furfine, E. S., Leban, J. J., Landavazo, A., Moomaw, J. F. & Casey, P. J. Protein farnesyltransferase: kinetics of farnesyl pyrophosphate binding and product release. Biochemistry 34, 6857–6862 (1995).

    CAS  PubMed  Google Scholar 

  106. Kusama, T. et al. Inhibition of epidermal growth factor-induced RhoA translocation and invasion of human pancreatic cancer cells by 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors. Cancer Res. 61, 4885–4891 (2001).

    CAS  PubMed  Google Scholar 

  107. Thorpe, J. L., Doitsidou, M., Ho, S. Y., Raz, E. & Farber, S. A. Germ cell migration in zebrafish is dependent on HMGCoA reductase activity and prenylation. Dev. Cell 6, 295–302 (2004).

    CAS  PubMed  Google Scholar 

  108. Ye, J. et al. Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation. Proc. Natl Acad. Sci. USA 100, 15865–15870 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Chiu, V. K. et al. Ras signalling on the endoplasmic reticulum and the Golgi. Nature Cell Biol. 4, 343–350 (2002).

    CAS  PubMed  Google Scholar 

  110. Michaelson, D. et al. Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. J. Cell Biol. 152, 111–126 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Adamson, P., Paterson, H. F. & Hall, A. Intracellular localization of the P21rho proteins. J. Cell Biol. 119, 617–627 (1992).

    CAS  PubMed  Google Scholar 

  112. Kwiatkowski, D. J. Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis. Cancer Biol. Ther. 2, 471–476 (2003).

    CAS  PubMed  Google Scholar 

  113. Bardelli, A. et al. PRL-3 expression in metastatic cancers. Clin. Cancer Res. 9, 5607–5615 (2003).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Funding for work on protein prenylation in the authors' laboratory is supported by the National Institutes of Health. A.M.W. was also supported by a Howard Hughes Medical Institute Predoctoral Fellowship.

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Correspondence to Patrick J. Casey.

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DATABASES

Entrez Gene

ICMT

RCE1

KRAS

BRAF

Cancer.gov

pancreatic cancer

melanoma

FURTHER INFORMATION

Compilation of Known and Hypothetical Prenylated CaaX Proteins in the Human Genome

The Casey laboratory

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Winter-Vann, A., Casey, P. Post-prenylation-processing enzymes as new targets in oncogenesis. Nat Rev Cancer 5, 405–412 (2005). https://doi.org/10.1038/nrc1612

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