CoChat
Sign Up
Cited by 198Protein Kinase Regulation and GTPase SignalingSphingolipid Metabolism and SignalingPlant biochemistry and biosynthesis

Characterization of Ha-Ras, N-Ras, Ki-Ras4A, and Ki-Ras4B as in Vitro Substrates for Farnesyl Protein Transferase and Geranylgeranyl Protein Transferase Type I

Open access
Zhang, Fang L., Kirschmeier, Paul, Carr, Donna, James, Linda, Bond, Richard W., Wang, Lynn, Patton, Robert, Windsor, William T. +3 more·1997·Journal of Biological Chemistry
DOI 10.1074/jbc.272.15.10232
Open this paper in CoChat — free account

Abstract

Ras proteins are small GTP-binding proteins which are critical for cell signaling and proliferation. Four Ras isoforms exist: Ha-Ras, N-Ras, Ki-Ras4A, and Ki-Ras4B. The carboxyl termini of all four isoforms are post-translationally modified by farnesyl protein transferase (FPT). Prenylation is required for oncogenic Ras to transform cells. Recently, it was reported that Ki-Ras4B is also an in vitro substrate for the related enzyme geranylgeranyl protein transferase-1 (GGPT-1) (James, G. L., Goldstein, J. L., and Brown, M. S. (1995) J. Biol. Chem. 270, 6221-6226). In the current studies, we compared the four isoforms of Ras as substrates for FPT and GGPT-1. The affinity of FPT for Ki-Ras4B (Km = 30 nM) is 10-20-fold higher than that for the other Ras isoforms. Consistent with this, when the different Ras isoforms are tested at equimolar concentrations, it requires 10-20-fold higher levels of CAAX-competitive compounds to inhibit Ki-Ras4B farnesylation. Additionally, we found that, as reported for Ki-Ras4B, N-Ras and Ki-Ras4A are also in vitro substrates for GGPT-1. Of the Ras isoforms, N-Ras is the highest affinity substrate for GGPT-1 and is similar in affinity to a standard GGPT-1 substrate terminating in leucine. However, the catalytic efficiencies of these geranylgeranylation reactions are between 15- and 140-fold lower than the corresponding farnesylation reactions, largely reflecting differences in affinity. Carboxyl-terminal peptides account for many of the properties of the Ras proteins. One interesting exception is that, unlike the full-length N-Ras protein, a carboxyl-terminal N-Ras peptide is not a GGPT-1 substrate, raising the possibility that upstream sequences in this protein may play a role in its recognition by GGPT-1. Studies with various carboxyl-terminal peptides from Ki-Ras4B suggest that both the carboxyl-terminal methionine and the upstream polylysine region are important determinants for geranylgeranylation. Furthermore, it was found that full-length Ki-Ras4B, but not other Ras isoforms, can be geranylgeranylated in vitro by FPT. These findings suggest that the different distribution of Ras isoforms and the ability of cells to alternatively process these proteins may explain in part the resistance of some cell lines to FPT inhibitors.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1074/jbc.272.15.10232

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Preclinical excitement with farnesyltransferase inhibitors did not translate to clinical utility with multiple negative phase II and phase III studies, likely due to presence of bypass prenylation pathway by geranylgeranylation.

    “However, preclinical excitement did not transcribe to clinical utility with multiple negative phase II and phase III studies, likely due to presence of bypass prenylation pathway by geranylgeranylation [79].”

    From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [79]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 41

  1. [1]1. Barbacid, M. Annu. Rev. Biochem. 1987; 56:779-827 Google Scholar
  2. [2]2. Lowy, D.R. ∙ Willumsen, B.M. Annu. Rev. Biochem. 1993; 62:851-891 Scopus (1166) Google Scholar
  3. [3]3. Bos, J.L. Cancer Res. 1989; 49:4682-4689 Google Scholar
  4. [4]4. Clark, G.J. ∙ Cox, A.D. ∙ Graham, S.M. ... Methods Enzymol. 1995; 255:395-411 Google Scholar
  5. [5]5. Leon, J. ∙ Guerrero, I. ∙ Pellicer, A. Mol. Cell. Biol. 1987; 4:1493-1498 Google Scholar
  6. [6]6. Casey, P.J. ∙ Solski, P.A. ∙ Der, C.J. ... Proc. Natl. Acad. Sci. U. S. A. 1989; 86:8323-8327 Google Scholar
  7. [7]7. Hancock, J.F. ∙ Magee, A.I. ∙ Childs, J.E. ... Cell. 1989; 57:1167-1177 Google Scholar
  8. [8]8. Schafer, W.R. ∙ Kim, R. ∙ Sterne, R. ... Science. 1989; 245:379-385 Google Scholar
  9. [9]9. Reiss, Y. ∙ Goldstein, J.L. ∙ Seabra, M.C. ... Cell. 1990; 62:81-88 Google Scholar
  10. [10]10. Clarke, S. Annu. Rev. Biochem. 1992; 61:355-386 Google Scholar
  11. [11]11. Zhang, F.L. ∙ Casey, P.J. Annu. Rev. Biochem. 1996; 65:241-269 Google Scholar
  12. [12]12. Reiss, Y. ∙ Stradley, S.J. ∙ Gierasch, L.M. ... Proc. Natl. Acad. Sci. U. S. A. 1991; 88:732-736 Google Scholar
  13. [13]13. Casey, P.J. ∙ Thissen, J.A. ∙ Moomaw, J.F. Proc. Natl. Acad. Sci. U. S. A. 1991; 88:8631-8635 Google Scholar
  14. [14]14. Yokoyama, K. ∙ Goodwin, G.W. ∙ Ghomashchi, F. ... Proc. Natl. Acad. Sci. U. S. A. 1991; 88:5302-5306 Google Scholar
  15. [15]15. James, G.L. ∙ Goldstein, J.L. ∙ Brown, M.S. J. Biol. Chem. 1995; 270:6221-6226 Google Scholar
  16. [16]16. Armstrong, S.A. ∙ Hannah, V.C ∙ Goldstein, J.L. ... J. Biol. Chem. 1995; 270:7864-7868 Google Scholar
  17. [17]17. Hancock, J.F. ∙ Paterson, H. ∙ Marshall, C.J. Cell. 1990; 63:133-139 Google Scholar
  18. [18]18. Kato, K. ∙ Cox, A.D. ∙ Hisaka, M.M. ... Proc. Natl. Acad. Sci. U. S. A. 1992; 89:6403-6407 Google Scholar
  19. [19]19. Gibbs, J.B. ∙ Oliff, A. ∙ Kohl, N.E. Cell. 1994; 77:175-178 Google Scholar
  20. [20]20. Gibbs, J.B. ∙ Pompliano, D.L. ∙ Mosser, S.D. ... J. Biol. Chem. 1993; 268:7617-7620 Google Scholar
  21. [21]21. James, G.L. ∙ Goldstein, J.L. ∙ Brown, M.S. ... Science. 1993; 260:1937-1942 Google Scholar
  22. [22]22. Kohl, N.E. ∙ Mosser, S.D. ∙ deSolms, S.J. ... Science. 1993; 260:1934-1937 Google Scholar
  23. [23]23. Garcia, A.M. ∙ Rowell, C. ∙ Ackermann, K. ... J. Biol. Chem. 1993; 268:18415-18418 Google Scholar
  24. [24]24. Nigam, M. ∙ Seong, C-M. ∙ Qian, Y. ... J. Biol. Chem. 1993; 268:20695-20698 Google Scholar
  25. [25]25. Manne, V. ∙ Yan, N. ∙ Carboni, J.M. ... Oncogene. 1995; 10:1763-1779 Google Scholar
  26. [26]26. Bishop, W.R. ∙ Bond, R. ∙ Petrin, J. ... J. Biol. Chem. 1995; 270:30611-30618 Google Scholar
  27. [27]27. Kohl, N.E. ∙ Wilson, F.R. ∙ Mosser, S.D. ... Proc. Natl. Acad. Sci. U. S. A. 1994; 91:9141-9145 Google Scholar
  28. [28]28. Kohl, N.E. ∙ Omer, C.A. ∙ Conner, M.W. ... Nat. Med. 1995; 1:792-797 Google Scholar
  29. [29]29. Sepp-Lorenzino, L. ∙ Ma, Z. ∙ Rands, E. ... Cancer Res. 1995; 55:5302-5309 Google Scholar
  30. [30]30. Nagasu, T. ∙ Yoshimatsu, K. ∙ Rowell, C. ... Cancer Res. 1995; 55:5310-5314 Google Scholar
  31. [31]31. Chen, W-J. ∙ Moomaw, J.F. ∙ Overton, L. ... J. Biol. Chem. 1993; 268:9675-9680 Google Scholar
  32. [32]32. Campbell-Burk, S.L. ∙ Carpenter, J.W. Methods Enzymol. 1995; 255:3-12 Google Scholar
  33. [33]33. Zhang, F.L. ∙ Diehl, R.E. ∙ Kohl, N.E. ... J. Biol. Chem. 1994; 269:3175-3180 Google Scholar
  34. [35]35. Zhang, F.L. ∙ Moomaw, J.F. ∙ Casey, P.J. J. Biol. Chem. 1994; 269:23465-23470 Google Scholar
  35. [36]36. Zhang, F.L. ∙ Fu, H.-W. ∙ Casey, P.J. ... Biochemistry. 1996; 35:8166-8171 Google Scholar
  36. [37]37. Moomaw, J.F. ∙ Casey, P.J. J. Biol. Chem. 1992; 267:17438-17443 Google Scholar
  37. [38]38. Pompliano, D.L. ∙ Schaber, M.D. ∙ Mosser, S.D. ... Biochemistry. 1993; 32:8341-8347 Google Scholar
  38. [39]39. Pompliano, D.L. ∙ Rands, E. ∙ Schaber, M.D. ... Biochemistry. 1992; 31:3800-3807 Google Scholar
  39. [40]40. Omer, C.A. ∙ Kral, A.M. ∙ Diehl, R.E. ... Biochemistry. 1993; 32:5167-5176 Google Scholar
  40. [41]41. Kalman, V.K. ∙ Erdman, R.A. ∙ Maltese, W.A. ... J. Biol. Chem. 1995; 270:14835-14841 Google Scholar
  41. [42]42. Cox, A.D. ∙ Graham, S.M. ∙ Solski, P.A. ... J. Biol. Chem. 1993; 268:11548-11552 Google Scholar Figures (6) Article metrics Related Articles Advertisement Hide CaptionDownloadSee figure in Article Toggle Thumbstrip Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Download .PPT Home Access for Developing Countries Articles Papers in Press Current Volume Archive Editorials ASBMB Award Articles JBC Reviews Meeting Reports Thematic Series Virtual Issues Classics Reflections Editors' Picks JBC Communications eLetters Tabor Awards For Authors Information for Authors About Open Access Permissions Submit manuscript Submission Help Contact Us Contact Information Journal Info About the Journal Early Career Reviewers Editorial Board Image Gallery New Content Alerts All Topics Bioenergetics Cell Biology Computational Biology Developmental Biology DNA and Chromosomes Enzymology Gene Regulation Genomics and Proteomics Glycobiology and Extracellular Matrices Immunology Lipids Membrane Biology Metabolism

Cited by

Sorted by citations

Related

Authors
Zhang, F. L., Kirschmeier, P., Carr, D., James, L., Bond, R. W., Wang, L., Patton, R., Windsor, W. T., Syto, R., Zhang, R., & Bishop, W. R.
Corresponding author
Bishop, W. Robert
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1997-04
Volume
272
Issue
15
Pages
10232-10239
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.272.15.10232
OpenAlex
W2156654096
Cited by
197
References
41
Citations by year
2025: 2 · 2024: 2 · 2023: 6 · 2022: 2 · 2021: 6 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 4 · 2014: 2 · 2013: 4 · 2012: 7
FWCI
5.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
Keywords
Ras isoforms, Ha-ras, NRAS, farnesyltransferase, protein prenylation, geranylgeranylation, CAAX motif, substrate affinity, carboxyl-terminal peptide, polylysine, oncogenic Ras, cell transformation
MeSH terms
Benzazepines, Binding Sites, Enzyme Inhibitors, Humans, Kinetics, Methionine, Piperidines, Polylysine, Transferases, Protein Prenylation, ras Proteins, Alkyl and Aryl Transferases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review