Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1996 Nov;16(11):6132–6140. doi: 10.1128/mcb.16.11.6132

TC21 causes transformation by Raf-independent signaling pathways.

S M Graham 1, A B Vojtek 1, S Y Huff 1, A D Cox 1, G J Clark 1, J A Cooper 1, C J Der 1
PMCID: PMC231616  PMID: 8887643

Abstract

Although the Ras-related protein TC21/R-Ras2 has only 55% amino acid identity with Ras proteins, mutated forms of TC21 exhibit the same potent transforming activity as constitutively activated forms of Ras. Therefore, like Ras, TC21 may activate signaling pathways that control normal cell growth and differentiation. To address this possibility, we determined if regulators and effectors of Ras are also important for controlling TC21 activity. First, we determined that Ras guanine nucleotide exchange factors (SOS1 and RasGRF/CDC25) synergistically enhanced wild-type TC21 activity in vivo and that Ras GTPase-activating proteins (GAPs; p120-GAP and NF1-GAP) stimulated wild-type TC21 GTP hydrolysis in vitro. Thus, extracellular signals that activate Ras via SOS1 activation may cause coordinate activation of Ras and TC21. Second, we determined if Raf kinases were effectors for TC21 transformation. Unexpectedly, yeast two-hybrid binding analyses showed that although both Ras and TC21 could interact with the isolated Ras-binding domain of Raf-1, only Ras interacted with full-length Raf-1, A-Raf, or B-Raf. Consistent with this observation, we found that Ras- but not TC21-transformed NIH 3T3 cells possessed constitutively elevated Raf-1 and B-Raf kinase activity. Thus, Raf kinases are effectors for Ras, but not TC21, signaling and transformation. We conclude that common upstream signals cause activation of Ras and TC21, but activated TC21 controls cell growth via distinct Raf-independent downstream signaling pathways.

Full Text

The Full Text of this article is available as a PDF (606.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Basu T. N., Gutmann D. H., Fletcher J. A., Glover T. W., Collins F. S., Downward J. Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature. 1992 Apr 23;356(6371):713–715. doi: 10.1038/356713a0. [DOI] [PubMed] [Google Scholar]
  2. Boguski M. S., McCormick F. Proteins regulating Ras and its relatives. Nature. 1993 Dec 16;366(6456):643–654. doi: 10.1038/366643a0. [DOI] [PubMed] [Google Scholar]
  3. Bollag G., McCormick F. GTPase activating proteins. Semin Cancer Biol. 1992 Aug;3(4):199–208. [PubMed] [Google Scholar]
  4. Bollag G., McCormick F. Intrinsic and GTPase-activating protein-stimulated Ras GTPase assays. Methods Enzymol. 1995;255:161–170. doi: 10.1016/s0076-6879(95)55020-8. [DOI] [PubMed] [Google Scholar]
  5. Bourne H. R., Sanders D. A., McCormick F. The GTPase superfamily: conserved structure and molecular mechanism. Nature. 1991 Jan 10;349(6305):117–127. doi: 10.1038/349117a0. [DOI] [PubMed] [Google Scholar]
  6. Brtva T. R., Drugan J. K., Ghosh S., Terrell R. S., Campbell-Burk S., Bell R. M., Der C. J. Two distinct Raf domains mediate interaction with Ras. J Biol Chem. 1995 Apr 28;270(17):9809–9812. doi: 10.1074/jbc.270.17.9809. [DOI] [PubMed] [Google Scholar]
  7. Béranger F., Goud B., Tavitian A., de Gunzburg J. Association of the Ras-antagonistic Rap1/Krev-1 proteins with the Golgi complex. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1606–1610. doi: 10.1073/pnas.88.5.1606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carboni J. M., Yan N., Cox A. D., Bustelo X., Graham S. M., Lynch M. J., Weinmann R., Seizinger B. R., Der C. J., Barbacid M. Farnesyltransferase inhibitors are inhibitors of Ras but not R-Ras2/TC21, transformation. Oncogene. 1995 May 18;10(10):1905–1913. [PubMed] [Google Scholar]
  9. Cepko C. L., Roberts B. E., Mulligan R. C. Construction and applications of a highly transmissible murine retrovirus shuttle vector. Cell. 1984 Jul;37(3):1053–1062. doi: 10.1016/0092-8674(84)90440-9. [DOI] [PubMed] [Google Scholar]
  10. Chan A. M., Miki T., Meyers K. A., Aaronson S. A. A human oncogene of the RAS superfamily unmasked by expression cDNA cloning. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7558–7562. doi: 10.1073/pnas.91.16.7558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chang E. C., Barr M., Wang Y., Jung V., Xu H. P., Wigler M. H. Cooperative interaction of S. pombe proteins required for mating and morphogenesis. Cell. 1994 Oct 7;79(1):131–141. doi: 10.1016/0092-8674(94)90406-5. [DOI] [PubMed] [Google Scholar]
  12. Chen S. Y., Huff S. Y., Lai C. C., Der C. J., Powers S. Ras-15A protein shares highly similar dominant-negative biological properties with Ras-17N and forms a stable, guanine-nucleotide resistant complex with CDC25 exchange factor. Oncogene. 1994 Sep;9(9):2691–2698. [PubMed] [Google Scholar]
  13. Clark G. J., Cox A. D., Graham S. M., Der C. J. Biological assays for Ras transformation. Methods Enzymol. 1995;255:395–412. doi: 10.1016/s0076-6879(95)55042-9. [DOI] [PubMed] [Google Scholar]
  14. Clark G. J., Kinch M. S., Gilmer T. M., Burridge K., Der C. J. Overexpression of the Ras-related TC21/R-Ras2 protein may contribute to the development of human breast cancers. Oncogene. 1996 Jan 4;12(1):169–176. [PubMed] [Google Scholar]
  15. Cook S. J., Rubinfeld B., Albert I., McCormick F. RapV12 antagonizes Ras-dependent activation of ERK1 and ERK2 by LPA and EGF in Rat-1 fibroblasts. EMBO J. 1993 Sep;12(9):3475–3485. doi: 10.1002/j.1460-2075.1993.tb06022.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Cowley S., Paterson H., Kemp P., Marshall C. J. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell. 1994 Jun 17;77(6):841–852. doi: 10.1016/0092-8674(94)90133-3. [DOI] [PubMed] [Google Scholar]
  17. Cox A. D., Brtva T. R., Lowe D. G., Der C. J. R-Ras induces malignant, but not morphologic, transformation of NIH3T3 cells. Oncogene. 1994 Nov;9(11):3281–3288. [PubMed] [Google Scholar]
  18. Davis R. J. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993 Jul 15;268(20):14553–14556. [PubMed] [Google Scholar]
  19. DeClue J. E., Papageorge A. G., Fletcher J. A., Diehl S. R., Ratner N., Vass W. C., Lowy D. R. Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell. 1992 Apr 17;69(2):265–273. doi: 10.1016/0092-8674(92)90407-4. [DOI] [PubMed] [Google Scholar]
  20. Drugan J. K., Khosravi-Far R., White M. A., Der C. J., Sung Y. J., Hwang Y. W., Campbell S. L. Ras interaction with two distinct binding domains in Raf-1 may be required for Ras transformation. J Biol Chem. 1996 Jan 5;271(1):233–237. doi: 10.1074/jbc.271.1.233. [DOI] [PubMed] [Google Scholar]
  21. Egan S. E., Weinberg R. A. The pathway to signal achievement. Nature. 1993 Oct 28;365(6449):781–783. doi: 10.1038/365781a0. [DOI] [PubMed] [Google Scholar]
  22. Feig L. A., Cooper G. M. Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP. Mol Cell Biol. 1988 Aug;8(8):3235–3243. doi: 10.1128/mcb.8.8.3235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Feig L. A. The many roads that lead to Ras. Science. 1993 May 7;260(5109):767–768. doi: 10.1126/science.8484117. [DOI] [PubMed] [Google Scholar]
  24. Fields S., Song O. A novel genetic system to detect protein-protein interactions. Nature. 1989 Jul 20;340(6230):245–246. doi: 10.1038/340245a0. [DOI] [PubMed] [Google Scholar]
  25. Frech M., John J., Pizon V., Chardin P., Tavitian A., Clark R., McCormick F., Wittinghofer A. Inhibition of GTPase activating protein stimulation of Ras-p21 GTPase by the Krev-1 gene product. Science. 1990 Jul 13;249(4965):169–171. doi: 10.1126/science.2164710. [DOI] [PubMed] [Google Scholar]
  26. Furth M. E., Aldrich T. H., Cordon-Cardo C. Expression of ras proto-oncogene proteins in normal human tissues. Oncogene. 1987 Mar;1(1):47–58. [PubMed] [Google Scholar]
  27. Graham S. M., Cox A. D., Drivas G., Rush M. G., D'Eustachio P., Der C. J. Aberrant function of the Ras-related protein TC21/R-Ras2 triggers malignant transformation. Mol Cell Biol. 1994 Jun;14(6):4108–4115. doi: 10.1128/mcb.14.6.4108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Han L., Colicelli J. A human protein selected for interference with Ras function interacts directly with Ras and competes with Raf1. Mol Cell Biol. 1995 Mar;15(3):1318–1323. doi: 10.1128/mcb.15.3.1318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Hariharan I. K., Carthew R. W., Rubin G. M. The Drosophila roughened mutation: activation of a rap homolog disrupts eye development and interferes with cell determination. Cell. 1991 Nov 15;67(4):717–722. doi: 10.1016/0092-8674(91)90066-8. [DOI] [PubMed] [Google Scholar]
  30. Hata Y., Kikuchi A., Sasaki T., Schaber M. D., Gibbs J. B., Takai Y. Inhibition of the ras p21 GTPase-activating protein-stimulated GTPase activity of c-Ha-ras p21 by smg p21 having the same putative effector domain as ras p21s. J Biol Chem. 1990 May 5;265(13):7104–7107. [PubMed] [Google Scholar]
  31. Hauser C. A., Westwick J. K., Quilliam L. A. Ras-mediated transcription activation: analysis by transient cotransfection assays. Methods Enzymol. 1995;255:412–426. doi: 10.1016/s0076-6879(95)55043-7. [DOI] [PubMed] [Google Scholar]
  32. Hofer F., Fields S., Schneider C., Martin G. S. Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11089–11093. doi: 10.1073/pnas.91.23.11089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Joneson T., White M. A., Wigler M. H., Bar-Sagi D. Stimulation of membrane ruffling and MAP kinase activation by distinct effectors of RAS. Science. 1996 Feb 9;271(5250):810–812. doi: 10.1126/science.271.5250.810. [DOI] [PubMed] [Google Scholar]
  34. Jung V., Wei W., Ballester R., Camonis J., Mi S., Van Aelst L., Wigler M., Broek D. Two types of RAS mutants that dominantly interfere with activators of RAS. Mol Cell Biol. 1994 Jun;14(6):3707–3718. doi: 10.1128/mcb.14.6.3707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Khosravi-Far R., Der C. J. The Ras signal transduction pathway. Cancer Metastasis Rev. 1994 Mar;13(1):67–89. doi: 10.1007/BF00690419. [DOI] [PubMed] [Google Scholar]
  36. Khosravi-Far R., Solski P. A., Clark G. J., Kinch M. S., Der C. J. Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation. Mol Cell Biol. 1995 Nov;15(11):6443–6453. doi: 10.1128/mcb.15.11.6443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Khosravi-Far R., White M. A., Westwick J. K., Solski P. A., Chrzanowska-Wodnicka M., Van Aelst L., Wigler M. H., Der C. J. Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol Cell Biol. 1996 Jul;16(7):3923–3933. doi: 10.1128/mcb.16.7.3923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kikuchi A., Demo S. D., Ye Z. H., Chen Y. W., Williams L. T. ralGDS family members interact with the effector loop of ras p21. Mol Cell Biol. 1994 Nov;14(11):7483–7491. doi: 10.1128/mcb.14.11.7483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Kitayama H., Matsuzaki T., Ikawa Y., Noda M. Genetic analysis of the Kirsten-ras-revertant 1 gene: potentiation of its tumor suppressor activity by specific point mutations. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4284–4288. doi: 10.1073/pnas.87.11.4284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Kitayama H., Sugimoto Y., Matsuzaki T., Ikawa Y., Noda M. A ras-related gene with transformation suppressor activity. Cell. 1989 Jan 13;56(1):77–84. doi: 10.1016/0092-8674(89)90985-9. [DOI] [PubMed] [Google Scholar]
  41. Kolch W., Heidecker G., Lloyd P., Rapp U. R. Raf-1 protein kinase is required for growth of induced NIH/3T3 cells. Nature. 1991 Jan 31;349(6308):426–428. doi: 10.1038/349426a0. [DOI] [PubMed] [Google Scholar]
  42. Krengel U., Schlichting I., Scherer A., Schumann R., Frech M., John J., Kabsch W., Pai E. F., Wittinghofer A. Three-dimensional structures of H-ras p21 mutants: molecular basis for their inability to function as signal switch molecules. Cell. 1990 Aug 10;62(3):539–548. doi: 10.1016/0092-8674(90)90018-a. [DOI] [PubMed] [Google Scholar]
  43. Leevers S. J., Marshall C. J. MAP kinase regulation--the oncogene connection. Trends Cell Biol. 1992 Oct;2(10):283–286. doi: 10.1016/0962-8924(92)90105-v. [DOI] [PubMed] [Google Scholar]
  44. Mansour S. J., Matten W. T., Hermann A. S., Candia J. M., Rong S., Fukasawa K., Vande Woude G. F., Ahn N. G. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science. 1994 Aug 12;265(5174):966–970. doi: 10.1126/science.8052857. [DOI] [PubMed] [Google Scholar]
  45. Marais R., Wynne J., Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell. 1993 Apr 23;73(2):381–393. doi: 10.1016/0092-8674(93)90237-k. [DOI] [PubMed] [Google Scholar]
  46. Marshall M. S. The effector interactions of p21ras. Trends Biochem Sci. 1993 Jul;18(7):250–254. doi: 10.1016/0968-0004(93)90175-m. [DOI] [PubMed] [Google Scholar]
  47. Milburn M. V., Tong L., deVos A. M., Brünger A., Yamaizumi Z., Nishimura S., Kim S. H. Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science. 1990 Feb 23;247(4945):939–945. doi: 10.1126/science.2406906. [DOI] [PubMed] [Google Scholar]
  48. Mosteller R. D., Han J., Broek D. Identification of residues of the H-ras protein critical for functional interaction with guanine nucleotide exchange factors. Mol Cell Biol. 1994 Feb;14(2):1104–1112. doi: 10.1128/mcb.14.2.1104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Oldham S. M., Clark G. J., Gangarosa L. M., Coffey R. J., Jr, Der C. J. Activation of the Raf-1/MAP kinase cascade is not sufficient for Ras transformation of RIE-1 epithelial cells. Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):6924–6928. doi: 10.1073/pnas.93.14.6924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Polakis P., McCormick F. Structural requirements for the interaction of p21ras with GAP, exchange factors, and its biological effector target. J Biol Chem. 1993 May 5;268(13):9157–9160. [PubMed] [Google Scholar]
  51. Prendergast G. C., Gibbs J. B. Pathways of Ras function: connections to the actin cytoskeleton. Adv Cancer Res. 1993;62:19–64. doi: 10.1016/s0065-230x(08)60314-0. [DOI] [PubMed] [Google Scholar]
  52. Prendergast G. C., Khosravi-Far R., Solski P. A., Kurzawa H., Lebowitz P. F., Der C. J. Critical role of Rho in cell transformation by oncogenic Ras. Oncogene. 1995 Jun 15;10(12):2289–2296. [PubMed] [Google Scholar]
  53. Qiu R. G., Chen J., Kirn D., McCormick F., Symons M. An essential role for Rac in Ras transformation. Nature. 1995 Mar 30;374(6521):457–459. doi: 10.1038/374457a0. [DOI] [PubMed] [Google Scholar]
  54. Qiu R. G., Chen J., McCormick F., Symons M. A role for Rho in Ras transformation. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11781–11785. doi: 10.1073/pnas.92.25.11781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Quilliam L. A., Hisaka M. M., Zhong S., Lowry A., Mosteller R. D., Han J., Drugan J. K., Broek D., Campbell S. L., Der C. J. Involvement of the switch 2 domain of Ras in its interaction with guanine nucleotide exchange factors. J Biol Chem. 1996 May 10;271(19):11076–11082. doi: 10.1074/jbc.271.19.11076. [DOI] [PubMed] [Google Scholar]
  56. Quilliam L. A., Huff S. Y., Rabun K. M., Wei W., Park W., Broek D., Der C. J. Membrane-targeting potentiates guanine nucleotide exchange factor CDC25 and SOS1 activation of Ras transforming activity. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8512–8516. doi: 10.1073/pnas.91.18.8512. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Quilliam L. A., Kato K., Rabun K. M., Hisaka M. M., Huff S. Y., Campbell-Burk S., Der C. J. Identification of residues critical for Ras(17N) growth-inhibitory phenotype and for Ras interaction with guanine nucleotide exchange factors. Mol Cell Biol. 1994 Feb;14(2):1113–1121. doi: 10.1128/mcb.14.2.1113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Quilliam L. A., Khosravi-Far R., Huff S. Y., Der C. J. Guanine nucleotide exchange factors: activators of the Ras superfamily of proteins. Bioessays. 1995 May;17(5):395–404. doi: 10.1002/bies.950170507. [DOI] [PubMed] [Google Scholar]
  59. Reuter C. W., Catling A. D., Weber M. J. Immune complex kinase assays for mitogen-activated protein kinase and MEK. Methods Enzymol. 1995;255:245–256. doi: 10.1016/s0076-6879(95)55027-5. [DOI] [PubMed] [Google Scholar]
  60. Rodriguez-Viciana P., Warne P. H., Dhand R., Vanhaesebroeck B., Gout I., Fry M. J., Waterfield M. D., Downward J. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994 Aug 18;370(6490):527–532. doi: 10.1038/370527a0. [DOI] [PubMed] [Google Scholar]
  61. Russell M., Lange-Carter C. A., Johnson G. L. Direct interaction between Ras and the kinase domain of mitogen-activated protein kinase kinase kinase (MEKK1). J Biol Chem. 1995 May 19;270(20):11757–11760. doi: 10.1074/jbc.270.20.11757. [DOI] [PubMed] [Google Scholar]
  62. Sato K. Y., Polakis P. G., Haubruck H., Fasching C. L., McCormick F., Stanbridge E. J. Analysis of the tumor suppressor activity of the K-rev-1 gene in human tumor cell lines. Cancer Res. 1994 Jan 15;54(2):552–559. [PubMed] [Google Scholar]
  63. Schlessinger J. How receptor tyrosine kinases activate Ras. Trends Biochem Sci. 1993 Aug;18(8):273–275. doi: 10.1016/0968-0004(93)90031-h. [DOI] [PubMed] [Google Scholar]
  64. Schweighoffer F., Cai H., Chevallier-Multon M. C., Fath I., Cooper G., Tocque B. The Saccharomyces cerevisiae SDC25 C-domain gene product overcomes the dominant inhibitory activity of Ha-Ras Asn-17. Mol Cell Biol. 1993 Jan;13(1):39–43. doi: 10.1128/mcb.13.1.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Smith D. B., Johnson K. S. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene. 1988 Jul 15;67(1):31–40. doi: 10.1016/0378-1119(88)90005-4. [DOI] [PubMed] [Google Scholar]
  66. Spaargaren M., Bischoff J. R. Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12609–12613. doi: 10.1073/pnas.91.26.12609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Umanoff H., Edelmann W., Pellicer A., Kucherlapati R. The murine N-ras gene is not essential for growth and development. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1709–1713. doi: 10.1073/pnas.92.5.1709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Van Aelst L., Barr M., Marcus S., Polverino A., Wigler M. Complex formation between RAS and RAF and other protein kinases. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6213–6217. doi: 10.1073/pnas.90.13.6213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Van Aelst L., White M. A., Wigler M. H. Ras partners. Cold Spring Harb Symp Quant Biol. 1994;59:181–186. doi: 10.1101/sqb.1994.059.01.022. [DOI] [PubMed] [Google Scholar]
  70. Vojtek A. B., Hollenberg S. M., Cooper J. A. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell. 1993 Jul 16;74(1):205–214. doi: 10.1016/0092-8674(93)90307-c. [DOI] [PubMed] [Google Scholar]
  71. White M. A., Nicolette C., Minden A., Polverino A., Van Aelst L., Karin M., Wigler M. H. Multiple Ras functions can contribute to mammalian cell transformation. Cell. 1995 Feb 24;80(4):533–541. doi: 10.1016/0092-8674(95)90507-3. [DOI] [PubMed] [Google Scholar]
  72. Wu J., Harrison J. K., Dent P., Lynch K. R., Weber M. J., Sturgill T. W. Identification and characterization of a new mammalian mitogen-activated protein kinase kinase, MKK2. Mol Cell Biol. 1993 Aug;13(8):4539–4548. doi: 10.1128/mcb.13.8.4539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Zhang X. F., Settleman J., Kyriakis J. M., Takeuchi-Suzuki E., Elledge S. J., Marshall M. S., Bruder J. T., Rapp U. R., Avruch J. Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature. 1993 Jul 22;364(6435):308–313. doi: 10.1038/364308a0. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES