Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 21 March 1997:
Vol. 275. no. 5307, pp. 1796 - 1800
DOI: 10.1126/science.275.5307.1796
Prev | Table of Contents | Next

Reports

Modulation of Ras and a-Factor Function by Carboxyl-Terminal Proteolysis

Victor L. Boyartchuk, Matthew N. Ashby, Jasper Rine *

Prenylated proteins contain a covalently linked cholesterol intermediate near their carboxyl-termini. Maturation of most prenylated proteins involves proteolytic removal of the last three amino acids. Two genes in Saccharomyces cerevisiae, RCE1 and AFC1, were identified that appear to be responsible for this processing. The Afc1 protein is a zinc protease that participates in the processing of yeast a-factor mating pheromone. The Rce1 protein contributes to the processing of both Ras protein and a-factor. Deletion of both AFC1 and RCE1 resulted in the loss of proteolytic processing of prenylated proteins. Disruption of RCE1 led to defects in Ras localization and signaling and suppressed the activated phenotype associated with the allele RAS2val19.

V. L. Boyartchuk and J. Rine, 401 Barker Hall, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
M. N. Ashby, Acacia Biosciences Incorporated, 4136 Lakeside Drive, Richmond, CA 94806, USA.
*   To whom correspondence should be addressed.

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
USP17 Regulates Ras Activation and Cell Proliferation by Blocking RCE1 Activity.
J. F. Burrows, A. A. Kelvin, C. McFarlane, R. E. Burden, M. J. McGrattan, M. De la Vega, U. Govender, D. J. Quinn, K. Dib, M. Gadina, et al. (2009)
J. Biol. Chem. 284, 9587-9595
   Abstract »    Full Text »    PDF »
An ABC Transporter Controls Export of a Drosophila Germ Cell Attractant.
S. Ricardo and R. Lehmann (2009)
Science 323, 943-946
   Abstract »    Full Text »    PDF »
Significant conservation of synthetic lethal genetic interaction networks between distantly related eukaryotes.
S. J. Dixon, Y. Fedyshyn, J. L. Y. Koh, T. S. K. Prasad, C. Chahwan, G. Chua, K. Toufighi, A. Baryshnikova, J. Hayles, K.-L. Hoe, et al. (2008)
PNAS 105, 16653-16658
   Abstract »    Full Text »    PDF »
Metadegradomics: Toward in Vivo Quantitative Degradomics of Proteolytic Post-translational Modifications of the Cancer Proteome.
A. Doucet, G. S. Butler, D. Rodriguez, A. Prudova, and C. M. Overall (2008)
Mol. Cell. Proteomics 7, 1925-1951
   Abstract »    Full Text »    PDF »
Isoprenylcysteine Methylation and Demethylation Regulate Abscisic Acid Signaling in Arabidopsis.
D. H. Huizinga, O. Omosegbon, B. Omery, and D. N. Crowell (2008)
PLANT CELL 20, 2714-2728
   Abstract »    Full Text »    PDF »
Functional Analysis of Arabidopsis Postprenylation CaaX Processing Enzymes and Their Function in Subcellular Protein Targeting.
K. Bracha-Drori, K. Shichrur, T. C. Lubetzky, and S. Yalovsky (2008)
Plant Physiology 148, 119-131
   Abstract »    Full Text »    PDF »
Small-Molecule Inhibitors of the Rce1p CaaX Protease.
S. P. Manandhar, E. R. Hildebrandt, and W. K. Schmidt (2007)
J Biomol Screen 12, 983-993
   Abstract »    PDF »
Isoprenylcysteine Carboxy Methylation Is Essential for Development in Dictyostelium discoideum.
Y. Chen, K. J. McQuade, X.-J. Guan, P. A. Thomason, M. S. Wert, J. B. Stock, and E. C. Cox (2007)
Mol. Biol. Cell 18, 4106-4118
   Abstract »    Full Text »    PDF »
From the Cover: HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells.
C. Coffinier, S. E. Hudon, E. A. Farber, S. Y. Chang, C. A. Hrycyna, S. G. Young, and L. G. Fong (2007)
PNAS 104, 13432-13437
   Abstract »    Full Text »    PDF »
Sequence Dependence and Differential Expression of G{gamma}5 Subunit Isoforms of the Heterotrimeric G Proteins Variably Processed after Prenylation in Mammalian Cells.
E. L. Kilpatrick and J. D. Hildebrandt (2007)
J. Biol. Chem. 282, 14038-14047
   Abstract »    Full Text »    PDF »
Activation Status-Coupled Transient S Acylation Determines Membrane Partitioning of a Plant Rho-Related GTPase.
N. Sorek, L. Poraty, H. Sternberg, E. Bar, E. Lewinsohn, and S. Yalovsky (2007)
Mol. Cell. Biol. 27, 2144-2154
   Abstract »    Full Text »    PDF »
Prelamin A Farnesylation and Progeroid Syndromes.
S. G. Young, M. Meta, S. H. Yang, and L. G. Fong (2006)
J. Biol. Chem. 281, 39741-39745
   Abstract »    Full Text »    PDF »
Saccharomyces cerevisiae a-Factor Mutants Reveal Residues Critical for Processing, Activity, and Export..
G. Huyer, A. Kistler, F. J. Nouvet, C. M. George, M. L. Boyle, and S. Michaelis (2006)
Eukaryot. Cell 5, 1560-1570
   Abstract »    Full Text »    PDF »
Farnesylated lamins, progeroid syndromes and farnesyl transferase inhibitors..
A. E. Rusinol and M. S. Sinensky (2006)
J. Cell Sci. 119, 3265-3272
   Abstract »    Full Text »    PDF »
Evidence for a novel protease governing regulated intramembrane proteolysis and resistance to antimicrobial peptides in Bacillus subtilis.
C. D. Ellermeier and R. Losick (2006)
Genes & Dev. 20, 1911-1922
   Abstract »    Full Text »    PDF »
Thematic review series: Lipid Posttranslational Modifications. Protein palmitoylation by a family of DHHC protein S-acyltransferases.
D. A. Mitchell, A. Vasudevan, M. E. Linder, and R. J. Deschenes (2006)
J. Lipid Res. 47, 1118-1127
   Abstract »    Full Text »    PDF »
Thematic review series: Lipid Posttranslational Modifications CAAX modification and membrane targeting of Ras.
L. P. Wright and M. R. Philips (2006)
J. Lipid Res. 47, 883-891
   Abstract »    Full Text »    PDF »
G{gamma}13 Interacts with PDZ Domain-containing Proteins.
Z. Li, O. Benard, and R. F. Margolskee (2006)
J. Biol. Chem. 281, 11066-11073
   Abstract »    Full Text »    PDF »
Plasma Membrane Localization of Ras Requires Class C Vps Proteins and Functional Mitochondria in Saccharomyces cerevisiae.
G. Wang and R. J. Deschenes (2006)
Mol. Cell. Biol. 26, 3243-3255
   Abstract »    Full Text »    PDF »
Mutational Analysis of the Ras Converting Enzyme Reveals a Requirement for Glutamate and Histidine Residues.
L. J. Plummer, E. R. Hildebrandt, S. B. Porter, V. A. Rogers, J. McCracken, and W. K. Schmidt (2006)
J. Biol. Chem. 281, 4596-4605
   Abstract »    Full Text »    PDF »
Thematic Review Series: Lipid Posttranslational Modifications. Prelamin A, Zmpste24, misshapen cell nuclei, and progeria--new evidence suggesting that protein farnesylation could be important for disease pathogenesis.
S. G. Young, L. G. Fong, and S. Michaelis (2005)
J. Lipid Res. 46, 2531-2558
   Abstract »    Full Text »    PDF »
Protein Geranylgeranyltransferase I Is Involved in Specific Aspects of Abscisic Acid and Auxin Signaling in Arabidopsis.
C. D. Johnson, S. N. Chary, E. A. Chernoff, Q. Zeng, M. P. Running, and D. N. Crowell (2005)
Plant Physiology 139, 722-733
   Abstract »    Full Text »    PDF »
The Isoprenoid Substrate Specificity of Isoprenylcysteine Carboxylmethyltransferase: DEVELOPMENT OF NOVEL INHIBITORS.
J. L. Anderson, B. S. Henriksen, R. A. Gibbs, and C. A. Hrycyna (2005)
J. Biol. Chem. 280, 29454-29461
   Abstract »    Full Text »    PDF »
Unique Aspects of Gene Expression during Candida albicans Mating and Possible G1 Dependency.
R. Zhao, K. J. Daniels, S. R. Lockhart, K. M. Yeater, L. L. Hoyer, and D. R. Soll (2005)
Eukaryot. Cell 4, 1175-1190
   Abstract »    Full Text »    PDF »
Tumor Necrosis Factor {alpha} Stimulation of Rac1 Activity: ROLE OF ISOPRENYLCYSTEINE CARBOXYLMETHYLTRANSFERASE.
C. Papaharalambus, W. Sajjad, A. Syed, C. Zhang, M. O. Bergo, R. W. Alexander, and M. Ahmad (2005)
J. Biol. Chem. 280, 18790-18796
   Abstract »    Full Text »    PDF »
Roles of C-Terminal Processing, and Involvement in Transacylation Reaction of Human Group IVC Phospholipase A2 (cPLA2{gamma}).
A. Yamashita, R. Kamata, N. Kawagishi, H. Nakanishi, H. Suzuki, T. Sugiura, and K. Waku (2005)
J. Biochem. 137, 557-567
   Abstract »    Full Text »    PDF »
Postprenylation CAAX Processing Is Required for Proper Localization of Ras but Not Rho GTPases.
D. Michaelson, W. Ali, V. K. Chiu, M. Bergo, J. Silletti, L. Wright, S. G. Young, and M. Philips (2005)
Mol. Biol. Cell 16, 1606-1616
   Abstract »    Full Text »    PDF »
A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells.
A. M. Winter-Vann, R. A. Baron, W. Wong, J. dela Cruz, J. D. York, D. M. Gooden, M. O. Bergo, S. G. Young, E. J. Toone, and P. J. Casey (2005)
PNAS 102, 4336-4341
   Abstract »    Full Text »    PDF »
Methotrexate and Ras Methylation: A New Trick for an Old Drug?.
M. R. Philips (2004)
Sci. STKE 2004, pe13
   Abstract »    Full Text »    PDF »
On the Physiological Importance of Endoproteolysis of CAAX Proteins: HEART-SPECIFIC RCE1 KNOCKOUT MICE DEVELOP A LETHAL CARDIOMYOPATHY.
M. O. Bergo, H. D. Lieu, B. J. Gavino, P. Ambroziak, J. C. Otto, P. J. Casey, Q. M. Walker, and S. G. Young (2004)
J. Biol. Chem. 279, 4729-4736
   Abstract »    Full Text »    PDF »
AtFACE-2, a functional Prenylated Protein Protease from Arabidopsis thaliana Related to Mammalian Ras-converting Enzymes.
J. Cadinanos, I. Varela, D. A. Mandel, W. K. Schmidt, A. Diaz-Perales, C. Lopez-Otin, and J. M. P. Freije (2003)
J. Biol. Chem. 278, 42091-42097
   Abstract »    Full Text »    PDF »
Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia.
A. K. Agarwal, J.-P. Fryns, R. J. Auchus, and A. Garg (2003)
Hum. Mol. Genet. 12, 1995-2001
   Abstract »    Full Text »    PDF »
A Novel Ras Inhibitor, Eri1, Engages Yeast Ras at the Endoplasmic Reticulum.
A. K. Sobering, M. J. Romeo, H. A. Vay, and D. E. Levin (2003)
Mol. Cell. Biol. 23, 4983-4990
   Abstract »    Full Text »    PDF »
Erf4p and Erf2p Form an Endoplasmic Reticulum-associated Complex Involved in the Plasma Membrane Localization of Yeast Ras Proteins.
L. Zhao, S. Lobo, X. Dong, A. D. Ault, and R. J. Deschenes (2002)
J. Biol. Chem. 277, 49352-49359
   Abstract »    Full Text »    PDF »
Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect.
M. O. Bergo, B. Gavino, J. Ross, W. K. Schmidt, C. Hong, L. V. Kendall, A. Mohr, M. Meta, H. Genant, Y. Jiang, et al. (2002)
PNAS 99, 13049-13054
   Abstract »    Full Text »    PDF »
A Cell-Specific, Prenylation-Independent Mechanism Regulates Targeting of Type II RACs.
M. Lavy, K. Bracha-Drori, H. Sternberg, and S. Yalovsky (2002)
PLANT CELL 14, 2431-2450
   Abstract »    Full Text »    PDF »
The Arabidopsis AtSTE24 Is a CAAX Protease with Broad Substrate Specificity.
K. Bracha, M. Lavy, and S. Yalovsky (2002)
J. Biol. Chem. 277, 29856-29864
   Abstract »    Full Text »    PDF »
Role of Isoprenylcysteine Carboxyl Methyltransferase in Tumor Necrosis Factor-{alpha} Stimulation of Expression of Vascular Cell Adhesion Molecule-1 in Endothelial Cells.
M. Ahmad, Y. Zhang, Y. Zhang, C. Papharalambus, and R. W. Alexander (2002)
Arterioscler. Thromb. Vasc. Biol. 22, 759-764
   Abstract »    Full Text »    PDF »
Absence of the CAAX Endoprotease Rce1: Effects on Cell Growth and Transformation.
M. O. Bergo, P. Ambroziak, C. Gregory, A. George, J. C. Otto, E. Kim, H. Nagase, P. J. Casey, A. Balmain, and S. G. Young (2002)
Mol. Cell. Biol. 22, 171-181
   Abstract »    Full Text »    PDF »
The Multispanning Membrane Protein Ste24p Catalyzes CAAX Proteolysis and NH2-terminal Processing of the Yeast a-Factor Precursor.
A. Tam, W. K. Schmidt, and S. Michaelis (2001)
J. Biol. Chem. 276, 46798-46806
   Abstract »    Full Text »    PDF »
A Portrait of Alzheimer Secretases--New Features and Familiar Faces.
W. P. Esler and M. S. Wolfe (2001)
Science 293, 1449-1454
   Abstract »    Full Text »    PDF »
CAC3 (MSI1) Suppression of RAS2G19V Is Independent of Chromatin Assembly Factor I and Mediated by NPR1.
S. D. Johnston, S. Enomoto, L. Schneper, M. C. McClellan, F. Twu, N. D. Montgomery, S. A. Haney, J. R. Broach, and J. Berman (2001)
Mol. Cell. Biol. 21, 1784-1794
   Abstract »    Full Text »
Compartmentalization of Ras proteins.
I. Prior and J. Hancock (2001)
J. Cell Sci. 114, 1603-1608
   Abstract »    PDF »
Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?.
C. W. M. Reuter, M. A. Morgan, and L. Bergmann (2000)
Blood 96, 1655-1669
   Abstract »    Full Text »    PDF »
The CaaX Proteases, Afc1p and Rce1p, Have Overlapping but Distinct Substrate Specificities.
C. E. Trueblood, V. L. Boyartchuk, E. A. Picologlou, D. Rozema, C. D. Poulter, and J. Rine (2000)
Mol. Cell. Biol. 20, 4381-4392
   Abstract »    Full Text »
H-ras but Not K-ras Traffics to the Plasma Membrane through the Exocytic Pathway.
A. Apolloni, I. A. Prior, M. Lindsay, R. G. Parton, and J. F. Hancock (2000)
Mol. Cell. Biol. 20, 2475-2487
   Abstract »    Full Text »
Reconstitution of the Ste24p-dependent N-terminal Proteolytic Step in Yeast a-Factor Biogenesis.
W. K. Schmidt, A. Tam, and S. Michaelis (2000)
J. Biol. Chem. 275, 6227-6233
   Abstract »    Full Text »    PDF »
Mutations in the Yeast Hsp40 Chaperone Protein Ydj1 Cause Defects in Axl1 Biogenesis and Pro-a-factor Processing.
G. C. Meacham, B. L. Browne, W. Zhang, R. Kellermayer, D. M. Bedwell, and D. M. Cyr (1999)
J. Biol. Chem. 274, 34396-34402
   Abstract »    Full Text »    PDF »
Erf2, a Novel Gene Product That Affects the Localization and Palmitoylation of Ras2 in Saccharomyces cerevisiae.
D. J. Bartels, D. A. Mitchell, X. Dong, and R. J. Deschenes (1999)
Mol. Cell. Biol. 19, 6775-6787
   Abstract »    Full Text »    PDF »
Multiple Sex Pheromones and Receptors of a Mushroom-producing Fungus Elicit Mating in Yeast.
T. J. Fowler, S. M. DeSimone, M. F. Mitton, J. Kurjan, and C. A. Raper (1999)
Mol. Biol. Cell 10, 2559-2572
   Abstract »    Full Text »
The Yck2 Yeast Casein Kinase 1 Isoform Shows Cell Cycle-specific Localization to Sites of Polarized Growth and Is Required for Proper Septin Organization.
L. C. Robinson, C. Bradley, J. D. Bryan, A. Jerome, Y. Kweon, and H. R. Panek (1999)
Mol. Biol. Cell 10, 1077-1092
   Abstract »    Full Text »
Cloning and Characterization of a Mammalian Prenyl Protein-specific Protease.
J. C. Otto, E. Kim, S. G. Young, and P. J. Casey (1999)
J. Biol. Chem. 274, 8379-8382
   Abstract »    Full Text »    PDF »
Disruption of the Mouse Rce1 Gene Results in Defective Ras Processing and Mislocalization of Ras within Cells.
E. Kim, P. Ambroziak, J. C. Otto, B. Taylor, M. Ashby, K. Shannon, P. J. Casey, and S. G. Young (1999)
J. Biol. Chem. 274, 8383-8390
   Abstract »    Full Text »    PDF »
Endoplasmic reticulum membrane localization of Rce1p and Ste24p, yeast proteases involved in carboxyl-terminal CAAX protein processing and amino-terminal a-factor cleavage.
W. K. Schmidt, A. Tam, K. Fujimura-Kamada, and S. Michaelis (1998)
PNAS 95, 11175-11180
   Abstract »    Full Text »    PDF »
Roles of Prenyl Protein Proteases in Maturation of Saccharomyces cerevisiae a-Factor.
V. L. Boyartchuk and J. Rine (1998)
Genetics 150, 95-101
   Abstract »    Full Text »
Prenylcysteine alpha -Carboxyl Methyltransferase in Suspension-Cultured Tobacco Cells.
D. N. Crowell, S. E. Sen, and S. K. Randall (1998)
Plant Physiology 118, 115-123
   Abstract »    Full Text »
Dual Roles for Ste24p in Yeast a-Factor Maturation: NH2-terminal Proteolysis and COOH-terminal CAAX Processing.
A. Tam, F. J. Nouvet, K. Fujimura-Kamada, H. Slunt, S. S. Sisodia, and S. Michaelis (1998)
J. Cell Biol. 142, 635-649
   Abstract »    Full Text »    PDF »
The Saccharomyces cerevisiae Prenylcysteine Carboxyl Methyltransferase Ste14p Is in the Endoplasmic Reticulum Membrane.
J. D. Romano, W. K. Schmidt, and S. Michaelis (1998)
Mol. Biol. Cell 9, 2231-2247
   Abstract »    Full Text »
Transdominant genetic analysis of a growth control pathway.
G. Caponigro, M. R. Abedi, A. P. Hurlburt, A. Maxfield, W. Judd, and A. Kamb (1998)
PNAS 95, 7508-7513
   Abstract »    Full Text »    PDF »
Mammalian Prenylcysteine Carboxyl Methyltransferase Is in the Endoplasmic Reticulum.
Q. Dai, E. Choy, V. Chiu, J. Romano, S. R. Slivka, S. A. Steitz, S. Michaelis, and M. R. Philips (1998)
J. Biol. Chem. 273, 15030-15034
   Abstract »    Full Text »    PDF »
Substrate specificity determinants in the farnesyltransferase beta -subunit.
C. E. Trueblood, V. L. Boyartchuk, and J. Rine (1997)
PNAS 94, 10774-10779
   Abstract »    Full Text »    PDF »
Isoprenylcysteine Carboxyl Methyltransferase Deficiency in Mice.
M. O. Bergo, G. K. Leung, P. Ambroziak, J. C. Otto, P. J. Casey, A. Q. Gomes, M. C. Seabra, and S. G. Young (2001)
J. Biol. Chem. 276, 5841-5845
   Abstract »    Full Text »    PDF »
The C-terminal Polylysine Region and Methylation of K-Ras Are Critical for the Interaction between K-Ras and Microtubules.
Z. Chen, J. C. Otto, M. O. Bergo, S. G. Young, and P. J. Casey (2000)
J. Biol. Chem. 275, 41251-41257
   Abstract »    Full Text »    PDF »
Biochemical Studies of Zmpste24-deficient Mice.
G. K. Leung, W. K. Schmidt, M. O. Bergo, B. Gavino, D. H. Wong, A. Tam, M. N. Ashby, S. Michaelis, and S. G. Young (2001)
J. Biol. Chem. 276, 29051-29058
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)