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.
Allan
Lindsey A
LA
Biomedical Research Institute, School of Medicine, College of Medicine, Dentistry and Nursing, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK.
Clarke
Paul R
PR
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