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Molecular and Cellular Biology, December 2005, p. 10543-10555, Vol. 25, No. 23
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.23.10543-10555.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Regulation of Caspase 9 through Phosphorylation by Protein Kinase C Zeta in Response to Hyperosmotic Stress

Suzanne C. Brady,{dagger} Lindsey A. Allan, and Paul R. Clarke*

Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom

Received 6 May 2005/ Returned for modification 2 June 2005/ Accepted 19 September 2005

Caspase 9 is a critical component of the mitochondrial or intrinsic apoptotic pathway and is activated by Apaf-1 following release of cytochrome c from mitochondria in response to a variety of stimuli. Caspase 9 cleaves and activates effector caspases, mainly caspase 3, leading to the demise of the cell. Survival signaling pathways can impinge on this pathway to restrain apoptosis. Here, we have identified Ser144 of human caspase 9as an inhibitory site that is phosphorylated in a cell-free system and in cells in response to the protein phosphatase inhibitor okadaic acid. Inhibitor sensitivity and interactions with caspase 9 indicate that the predominant kinase that targets Ser144 is the atypical protein kinase C isoform zeta (PKC{zeta}). Prevention of Ser144 phosphorylation by inhibition of PKC{zeta} or mutation of caspase 9 promotes caspase 3 activation. Phosphorylation of serine 144 in cells is also induced by hyperosmotic stress, which activates PKC{zeta} and regulates its interaction with caspase 9, but not by growth factors, phorbol ester, or other cellular stresses. These results indicate that phosphorylation and inhibition of caspase 9 by PKC{zeta} restrain the intrinsic apoptotic pathway during hyperosmotic stress. This work provides further evidence that caspase 9 acts as a focal point for multiple protein kinase signaling pathways that regulate apoptosis.

* Corresponding author. Mailing address: Biomedical Research Centre, Level 5, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom. Phone: 44 (0) 1382 425580. Fax: 44 (0) 1382 669993. E-mail: paul.clarke{at}cancer.org.uk.

{dagger} Present address: Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, United Kingdom.

Molecular and Cellular Biology, December 2005, p. 10543-10555, Vol. 25, No. 23
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.23.10543-10555.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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