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J. Biol. Chem., Vol. 276, Issue 20, 16624-16634, May 18, 2001
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From the Department of Pharmacology and Toxicology, Medical College
of Wisconsin, Milwaukee, Wisconsin 53226
In response to stress stimulants, cells activate
opposing signaling pathways for cell survival and programmed cell
death. p21-activated protein kinase
p21-activated Protein Kinase
-PAK Suppresses Programmed Cell
Death of BALB3T3 Fibroblasts*
,
-PAK is involved in both cell
survival and cell death pathways. Many stress stimulants activate
-PAK as a full-length enzyme and as a proteolytic fragment.
Caspase-mediated proteolytic activation parallels cell death and
appears to be a pro-apoptotic factor in stress-induced cell death.
Here, we show that activation of full-length -PAK promotes cell
survival and suppresses stress-induced cell death. Expression of
constitutively active -PAK-T402E, which mimics activated full-length
-PAK, stimulates cell survival of BALB3T3 fibroblasts in response to tumor necrosis factor 
, growth factor withdrawal, and UVC light. This stimulation of cell survival is mainly due to protection of cells
from cell death rather than by stimulation of proliferation. Expression
of -PAK-T402E increases phosphorylation of the pro-apoptotic Bcl-2
family protein Bad and protects from cell death induced by ectopic
expression of Bad. In response to tumor necrosis factor , expression
of -PAK-T402E increases the early but reduces the late activation of
ERK, JNK, and p38. Our results indicate that the ubiquitous -PAK may
have a crucial function in cell survival by regulating the
pro-apoptotic activity of Bad and the stress-induced activation of ERK,
JNK, and p38 pathways.
*
This work was supported by American Cancer Society Grant ACS
IRG 170 and a Wisconsin Breast Cancer Showhouse Grant (to R. J.).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.
To whom correspondence should be addressed: Dept. of Pharmacology
and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd.,
Milwaukee, WI 53226. Tel.: 414-456-4969; Fax: 414-456-6545; E-mail:
rjakobi@mcw.edu.
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