Growth factor induced cell cycle progression and cell survival:
Role of targeting of Raf effector kinases

Rapp, U.R.

Institut für Medizinische Strahlenkunde und Zellforschung, Versbacher Str. 5, D-97078 Würzburg, Germany

Raf family protein serine/threonine kinases are critical elements of signal transduction cascades controlling growth, differentiation and cell survival. The first cascade that was elucidated, the Ras-Raf-MEK-MAPK cascade, is involved in regulation of cell cycle progression as well as differentiation. A critical event in linking this "classic" cascade to activated growth factor receptors in the plasma membrane is the transient membrane docking of Raf by Ras GTP. Recently, we have identified a novel cascade in which Raf functions to suppress apoptosis. In this case the shuttle protein is not Ras but bcl2 which targets Raf to the outer mitochondrial membrane where it phosphorylates a novel substrate, BAD. Data with dominant negative mutants of Raf indicate that Raf is a critical effector kinase of bcl2 and a yeast two hybrid screen has identified BAG-1 as a Raf kinase-interacting protein that may contribute to Raf activation in this environment.
Further evidence for a role of Raf kinases in suppression of apoptosis has recently been obtained by analysis of B-Raf -/- knockout mice. Mice with a targeted disruption in the Braf gene die of vascular defects during mid-gestation. Braf -/- embryos, unlike Araf -/- or Craf1 -/- embryos, show an increased number of endothelial precursor cells, dramatically enlarged blood vessels and apoptotic death of differentiated endothelial cells. These results establish Braf as a critical signalling factor in the formation of the vascular system and provide the first genetic evidence for an essential role of Raf gene in the regulation of programmed cell death.

Daum, G. et al. (1994) Trends in Biochem. Sci, 19: 474-480
Wang, H.-G. et al. (1996) PNAS, 93: 7063-7068
Wang, H.-G., Rapp, U.R., Reed, J.C. (1996) Cell, 87: 1-20

LOCATION DATE TIME
Lecture Hall II Tuesday, April 7 03:05 pm