Apoptosis and autophagy: Regulation of caspase-9 by phosphorylation.
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.
Biomedical Research Institute, School of Medicine, College of Medicine, Dentistry and Nursing, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK.
Lindsey A
LA
Allan
Paul R
PR
Clarke
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D016203:CDC2 Protein Kinase / Q000502:physiology; D053453:Caspase 9 / Q000737:chemistry / Q000378:metabolism*; D061945:Caspase Inhibitors; D019926:Cyclin B / Q000502:physiology; D056744:Cyclin B1; D004249:DNA Damage; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
C534699:CCNB1 protein, human; D061945:Caspase Inhibitors; D019926:Cyclin B; D056744:Cyclin B1; D016203:CDC2 Protein Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053453:Caspase 9