Differential Regulation of Raf-1, A-Raf, and B-Raf by Oncogenic Ras and Tyrosine Kinases*
- From the Cancer Research Campaign Centre for Cell and Molecular Biology, Chester Beatty Laboratories, Institute of Cancer Research, London SW3 6JB, United Kingdom
- ‡ Gibb Life Fellow of the Cancer Research Campaign. To whom correspondence should be addressed: 44-171-352-9772; Fax: 44-171-352-3299; E-mail: chrism{at}icr.ac.uk.
Abstract
It has previously been shown that maximal activation of Raf-1 is produced by synergistic signals from oncogenic Ras and activated tyrosine kinases. This synergy arises because Ras-GTP translocates Raf-1 to the plasma membrane where it becomes phosphorylated on tyrosine residues 340 and 341 by membrane-bound tyrosine kinases (Marais, R., Light, Y., Paterson, H. F., and Marshall, C. J. (1995) EMBO J. 14, 3136-3145). We have examined whether the other two members of the Raf family, A-Raf and B-Raf, are regulated in a similar way to Raf-1. A-Raf behaves like Raf-1, being weakly activated by oncogenic Ras more strongly activated by oncogenic Src, and these signals synergize to give maximal activation. B-Raf by contrast is strongly activated by oncogenic Ras alone and is not activated by oncogenic Src. These results show that maximal activation of B-Raf merely requires signals that generate Ras-GTP, whereas activation of Raf-1 and A-Raf requires Ras-GTP together with signals that lead to their tyrosine phosphorylation. B-Raf may therefore be the primary target of oncogenic Ras.
Footnotes
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↵* This work was supported in part by the Cancer Research Campaign. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 The abbreviations used are:
- Mek
-
mitogen-activated protein kinase kinase
- ERK
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Ras/extracellular signal-related kinase
- MAPK
-
mitogen-activated protein kinase
- MBP
-
myelin basic protein
- wt
-
wild type
- GST
-
glutathione S-transferase.
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↵2 M. Rosario and C. J. Marshall, unpublished data.
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- Received October 16, 1996.
- Revision received December 12, 1996.
- © 1997 by The American Society for Biochemistry and Molecular Biology, Inc.
