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J Biol Chem, Vol. 275, Issue 13, 9106-9109, March 31, 2000
§¶,§,
, and
From the § Department of Pharmacology, University of
Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
The Ras oncogene regulates cellular
proliferation, differentiation, transformation, and survival through
multiple downstream signals. Ras signals through its effector
phosphoinositide 3 (PI3) kinase to the Pak protein kinase
(p65pak), but the steps from Ras to Pak remain
to be elucidated. PI3 kinase can stimulate the small G protein, Rac, a
direct activator of Pak, as well as the Akt proto-oncogene, a
serine-threonine protein kinase. We found that activated Akt stimulated
Pak, whereas a dominant negative Akt inhibited Ras activation of Pak in
transfection assays. Akt stimulation of Pak was not inhibited by
dominant negative mutants of either Rac or Cdc42 suggesting that Akt
activated Pak through a GTPase-independent mechanism. We also
developed a novel cell-free system to study Ras activation of Pak. In
this system Ras activated Pak only in the presence of a crude cell
extract but failed to activate Pak when Akt was immunodepleted from the extract. Akt protects cells from apoptosis through phosphorylation of
downstream targets such as the Bcl-2 family member, Bad. We found that
activated Pak decreased apoptosis and increased phosphorylation of Bad,
whereas dominant negative Pak increased apoptosis and decreased
phosphorylation of Bad. These studies define a new oncogene-mediated cell survival signal.
Contributed equally to this work.
¶
Present address: Dupont Pharmaceuticals Co., Glenolden Lab.,
Glenolden, PA 19036.
To whom correspondence may be addressed. Tel: 215-898-9736;
Fax: 215-573-2236; E-mail: pittman@pharm.med.upenn.edu.
**
To whom correspondence may be addressed. Tel.: 215-898-1912; Fax:
215-573-2236; E-mail: field@pharm.med.upenn.edu.
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