Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases.
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.
Marais
R
R
Cancer Research Campaign Centre for Cell and Molecular Biology, Chester Beatty Laboratories, Institute of Cancer Research, London SW3 6JB, United Kingdom.
Light
Y
Y
Paterson
H F
HF
Mason
C S
CS
Marshall
C J
CJ
D000818:Animals; D001692:Biological Transport; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D006160:Guanosine Triphosphate / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf; D014443:Tyrosine / Q000378:metabolism
D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D006160:Guanosine Triphosphate; D011505:Protein-Tyrosine Kinases; D015688:Oncogene Protein pp60(v-src); D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D015689:Oncogene Protein p21(ras)