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Cell death by the process of apoptosis plays important roles in development, tissue homeostasis, diseases and drug responses. The cysteine aspartyl prote-ase caspase-9 plays a central role in the mitochondrial or intrinsic apoptotic pathway that is engaged in response to many apoptotic stimuli. | ỊFEBS Journal MINIREVIEW Apoptosis and autophagy Regulation of caspase-9 by phosphorylation Lindsey A. Allan and Paul R. Clarke BiomedicalResearch Institute Schoolof Medicine College of Medicine Dentistry and Nursing University of Dundee Ninewells Hospital and Medical School Dundee Scotland UK Keywords apoptosis caspase mitosis phosphorylation protein kinase Correspondence P. R. Clarke BiomedicalResearch Institute Level5 Ninewells Hospitaland Medical School Dundee DD1 9SY UK Fax 44 0 1382 669993 Tel 44 0 1382 425580 E-mail p.r.clarke@dundee.ac.uk Received 23 March 2009 revised 6 July 2009 accepted 13 August 2009 doi 10.1111 j.1742-4658.2009.07330.x Cell death by the process of apoptosis plays important roles in development tissue homeostasis diseases and drug responses. The cysteine aspartyl protease caspase-9 plays a central role in the mitochondrial or intrinsic apoptotic pathway that is engaged in response to many apoptotic stimuli. Caspase-9 is activated in a large multimeric complex the apoptosome which is formed with apoptotic peptidase activating factor 1 Apaf-1 in response to the release of cytochrome c from mitochondria. Once activated caspase-9 cleaves and activates the effector caspases 3 and 7 to bring about apoptosis. This pathway is tightly regulated at multiple steps including apoptosome formation and caspase-9 activation. Recent work has shown that caspase-9 is the direct target for regulatory phosphorylation by multiple protein kinases activated in response to extracellular growth survival factors osmotic stress or during mitosis. Here we review these advances and discuss the possible roles of caspase-9 phosphorylation in the regulation of apoptosis during development and in pathological states including cancer. Introduction Apoptosis is a controlled form of cell death that plays fundamental roles during embryonic development and in the maintenance of tissues. Defects in the regulation of apoptosis have been associated with the pathogenesis of .
