p21-activated Kinase 1 (Pak1)-dependent phosphorylation of Raf-1 regulates its mitochondrial localization, phosphorylation of BAD, and Bcl-2 association.

Raf-1 protects cells from apoptosis, independently of its signals to MEK and ERK, by translocating to the mitochondria where it binds Bcl-2 and displaces BAD. However, the answer to the question of how Raf-1 is normally lured to the mitochondria and becomes activated remains elusive. p21-activated protein kinases (Paks) are ...
serine/threonine protein kinases that phosphorylate Raf-1 at Ser-338 and Ser-339. Here we elucidate the molecular mechanism through which Pak1 signals to BAD through a Raf-1-activated pathway. Upon phosphorylation by Pak1, Raf-1 translocates to mitochondria and phosphorylates BAD at Ser-112. Moreover, the mitochondrial translocation of Raf-1 and the interaction between Raf-1 and Bcl-2 are regulated by Raf-1 phosphorylation at Ser-338/Ser-339. Notably, we show that formation of a Raf-1-Bcl-2 complex coincides with loss of an interaction between Bcl-2 and BAD. These signals are specific for Pak1, because Src-activated Raf-1 only stimulates the MAP kinase cascade. Thus, our data identify the molecular connections of a Pak1-Raf-1-BAD pathway that is involved in cell survival signaling.
Mesh Terms:
Animals, Apoptosis, Carrier Proteins, Cell Line, Cell Survival, Humans, Immunoblotting, Immunoprecipitation, MAP Kinase Signaling System, Mice, Microscopy, Fluorescence, Mitochondria, Models, Biological, NIH 3T3 Cells, Peptides, Phosphorylation, Plasmids, Protein Binding, Protein Transport, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-raf, Serine, Signal Transduction, Subcellular Fractions, Transfection, bcl-Associated Death Protein, p21-Activated Kinases
J. Biol. Chem.
Date: Jul. 01, 2005
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