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Molecular and Cellular Biology, November 2003, p. 7838-7848, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7838-7848.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Death Receptor-Induced Activation of Initiator Caspase 8 Is Antagonized by Serine/Threonine Kinase PAK4

Nerina Gnesutta{dagger} and Audrey Minden*

Biological Sciences, Columbia University, New York, New York 10027

Received 23 December 2002/ Returned for modification 12 March 2003/ Accepted 30 July 2003

Normal cell growth requires a precisely controlled balance between cell death and survival. This involves activation of different types of intracellular signaling cascades within the cell. While some types of signaling proteins regulate apoptosis, or programmed cell death, other proteins within the cell can promote survival. The serine/threonine kinase PAK4 can protect cells from apoptosis in response to several different types of stimuli. As is the case for other members of the p21-activated kinase (PAK) family, one way that PAK4 may promote cell survival is by phosphorylating and thereby inhibiting the proapoptotic protein Bad. This leads in turn to the inhibition of effector caspases such as caspase 3. Here we show that in response to cytokines which activate death domain-containing receptors, such as the tumor necrosis factor and Fas receptors, PAK4 can inhibit the death signal by a different mechanism. Under these conditions, PAK4 inhibits apoptosis early in the caspase cascade, antagonizing the activation of initiator caspase 8. This inhibition, which does not require PAK4's kinase activity, may involve inhibition of caspase 8 recruitment to the death domain receptors. This role in regulating initiator caspases is an entirely novel role for the PAK proteins and suggests a new mechanism by which these proteins promote cell survival.

* Corresponding author. Mailing address: Columbia University, Biological Sciences MC 2460, Sherman Fairchild Center, Room 813, 1212 Amsterdam Ave., New York, NY 10027. Phone: (212) 854-5632. Fax: (212) 854-1559. E-mail: agm24{at}columbia.edu.

{dagger} Present address: Università degli Studi di Milano, Dipartimento di Scienze Biomolecolari e Biotecnologie, Milan, Italy.

Molecular and Cellular Biology, November 2003, p. 7838-7848, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7838-7848.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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