Encyclopedia of Signaling Molecules

2012 Edition
| Editors: Sangdun Choi

RAF-1 (C-RAF)

  • Andrea Varga
  • Manuela Baccarini
Reference work entry
DOI: https://doi.org/10.1007/978-1-4419-0461-4_591

Synonyms

Historical Background

Raf-1, also known as C-Raf-1 or C-Raf, was identified about 30 years ago as the oncogene ( v-raf) in the murine sarcoma virus 3611 (3611-MSV) and, in parallel, in the naturally occurring avian retrovirus Mill Hill 2 (MH2). The gene was named after its enhancing effect on fibrosarcoma induction in newborn mice: Rapidly accelerated fibrosarcoma, or Raf. The sequences of the oncogenes, v-raf (derived from 3611-MSV) and v-mil (derived from MH2), were found to encode a serine/threonine protein kinase containing the catalytic, but not the N-terminal regulatory domain of the enzyme. This deletion rendered the protein constitutively active and was responsible for its transforming effect, making Raf the first oncogenic serine/threonine kinase discovered. A pseudogene ( c-raf-2) and two...
This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

The authors wish to thank all the members of the Baccarini group for helpful discussions. Dr. Andrea Varga is supported by a FEBS long term fellowship. Work in the Baccarini lab is supported by funds of the Austrian National Research Fund (FWF), the Austrian Society for the Advancement of Research (FFG), the Obermann Foundation, and the European Community.

References

  1. Alavi AS, Acevedo L, Min W, Cheresh DA. Chemoresistance of endothelial cells induced by basic fibroblast growth factor depends on Raf-1-mediated inhibition of the proapoptotic kinase, ASK1. Cancer Res. 2007;67:2766–72.PubMedCrossRefGoogle Scholar
  2. Arkenau HT, Kefford R, Long GV. Targeting BRAF for patients with melanoma. Br J Cancer. 2011;104:392–8.PubMedCrossRefGoogle Scholar
  3. Baccarini M. Second nature: biological functions of the Raf-1 “kinase”. FEBS Lett. 2005;579:3271–7.PubMedCrossRefGoogle Scholar
  4. Chen J, Fujii K, Zhang L, Roberts T, Fu H. Raf-1 promotes cell survival by antagonizing apoptosis signal- regulating kinase 1 through a MEK-ERK independent mechanism. Proc Natl Acad Sci USA. 2001;98:7783–8.PubMedCrossRefGoogle Scholar
  5. Cichowski K, Janne PA. Drug discovery: inhibitors that activate. Nature. 2010;464:358–9.PubMedCrossRefGoogle Scholar
  6. Ehrenreiter K, Piazzolla D, Velamoor V, Sobczak I, Small JV, Takeda J, et al. Raf-1 regulates Rho signaling and cell migration. J Cell Biol. 2005;168:955–64.PubMedCrossRefGoogle Scholar
  7. Ehrenreiter K, Kern F, Velamoor V, Meissl K, Galabova-Kovacs G, Sibilia M, et al. Raf-1 addiction in Ras-induced skin carcinogenesis. Cancer Cell. 2009;16:149–60.PubMedCrossRefGoogle Scholar
  8. Emerson SD, Madison VS, Palermo RE, Waugh DS, Scheffler JE, Tsao KL, et al. Solution structure of the Ras-binding domain of c-Raf-1 and identification of its Ras interaction surface. Biochemistry. 1995;34:6911–18.PubMedCrossRefGoogle Scholar
  9. Galabova-Kovacs G, Kolbus A, Matzen D, Meissl K, Piazzolla D, Rubiolo C, et al. ERK and beyond: insights from B-Raf and Raf-1 conditional knockouts. Cell Cycle. 2006;5:1514–18.PubMedCrossRefGoogle Scholar
  10. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431–5.PubMedCrossRefGoogle Scholar
  11. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209–21.PubMedCrossRefGoogle Scholar
  12. Kern F, Niault T, Baccarini M. Ras and Raf pathways in epidermis development and carcinogenesis. Br J Cancer. 2011;104:229–34.PubMedCrossRefGoogle Scholar
  13. King AJ, Patrick DR, Batorsky RS, Ho ML, Do HT, Zhang SY, et al. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res. 2006;66:11100–5.PubMedCrossRefGoogle Scholar
  14. Kolch W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol. 2005;6:827–37.PubMedCrossRefGoogle Scholar
  15. Maurer G, Tarkowski B, Baccarini M. Raf kinases in cancer – roles and therapeutic opportunities. Oncogene. 2011; in press.Google Scholar
  16. McKay MM, Morrison DK. Integrating signals from RTKs to ERK/MAPK. Oncogene. 2007;26:3113–21.PubMedCrossRefGoogle Scholar
  17. Mercer K, Giblett S, Oakden A, Brown J, Marais R, Pritchard C. A-Raf and Raf-1 work together to influence transient ERK phosphorylation and Gl/S cell cycle progression. Oncogene. 2005;24:5207–17.PubMedCrossRefGoogle Scholar
  18. Mott HR, Carpenter JW, Zhong S, Ghosh S, Bell RM, Campbell SL. The solution structure of the Raf-1 cysteine-rich domain: a novel ras and phospholipid binding site. Proc Natl Acad Sci USA. 1996;93:8312–17.PubMedCrossRefGoogle Scholar
  19. Niault TS, Baccarini M. Targets of Raf in tumorigenesis. Carcinogenesis. 2010;31:1165–74.PubMedCrossRefGoogle Scholar
  20. Niault T, Sobczak I, Meissl K, Weitsman G, Piazzolla D, Maurer G, et al. From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-alpha kinase activity. J Cell Biol. 2009;187:335–42.PubMedCrossRefGoogle Scholar
  21. O’Neill E, Rushworth L, Baccarini M, Kolch W. Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science. 2004;306:2267–70.PubMedCrossRefGoogle Scholar
  22. Pan D. The hippo signaling pathway in development and cancer. Dev Cell. 2010;19:491–505.PubMedCrossRefGoogle Scholar
  23. Piazzolla D, Meissl K, Kucerova L, Rubiolo C, Baccarini M. Raf-1 sets the threshold of Fas sensitivity by modulating Rok-{alpha} signaling. J Cell Biol. 2005;171:1013–22.PubMedCrossRefGoogle Scholar
  24. Romano D, Matallanas D, Weitsman G, Preisinger C, Ng T, Kolch W. Proapoptotic kinase MST2 coordinates signaling crosstalk between RASSF1A, Raf-1, and Akt. Cancer Res. 2010;70:1195–203.PubMedCrossRefGoogle Scholar
  25. Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol. 2004;5:875–85.PubMedCrossRefGoogle Scholar
  26. Wimmer R, Baccarini M. Partner exchange: protein-protein interactions in the Raf pathway. Trends Biochem Sci. 2010;35:660–8.PubMedCrossRefGoogle Scholar
  27. Yamaguchi O, Watanabe T, Nishida K, Kashiwase K, Higuchi Y, Takeda T, et al. Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. J Clin Invest. 2004;114:937–43.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Microbiology and Immunobiology, Center for Molecular BiologyUniversity of Vienna, Max F. Perutz LaboratoriesViennaAustria