title: TAK1 control of cell death.
abstract: Programmed cell death, a physiologic process for removing cells, is critically important in normal development and for elimination of damaged cells. Conversely, unattended cell death contributes to a variety of human disease pathogenesis. Thus, precise understanding of molecular mechanisms underlying control of cell death is important and relevant to public health. Recent studies emphasize that transforming growth factor-β-activated kinase 1 (TAK1) is a central regulator of cell death and is activated through a diverse set of intra- and extracellular stimuli. The physiologic importance of TAK1 and TAK1-binding proteins in cell survival and death has been demonstrated using a number of genetically engineered mice. These studies uncover an indispensable role of TAK1 and its binding proteins for maintenance of cell viability and tissue homeostasis in a variety of organs. TAK1 is known to control cell viability and inflammation through activating downstream effectors such as NF-κB and mitogen-activated protein kinases (MAPKs). It is also emerging that TAK1 regulates cell survival not solely through NF-κB but also through NF-κB-independent pathways such as oxidative stress and receptor-interacting protein kinase 1 (RIPK1) kinase activity-dependent pathway. Moreover, recent studies have identified TAK1's seemingly paradoxical role to induce programmed necrosis, also referred to as necroptosis. This review summarizes the consequences of TAK1 deficiency in different cell and tissue types from the perspective of cell death and also focuses on the mechanism by which TAK1 complex inhibits or promotes programmed cell death. This review serves to synthesize our current understanding of TAK1 in cell survival and death to identify promising directions for future research and TAK1's potential relevance to human disease pathogenesis.
authors.affiliation: Department of Biological Sciences, North Carolina State University, Environmental and Molecular Toxicology, Raleigh, NC 27695-7633, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Mihaly
authors.affiliation: Department of Biological Sciences, North Carolina State University, Environmental and Molecular Toxicology, Raleigh, NC 27695-7633, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ninomiya-Tsuji
authors.affiliation: Department of Biological Sciences, North Carolina State University, Environmental and Molecular Toxicology, Raleigh, NC 27695-7633, USA.
authors.forename: S
authors.initials: S
authors.lastname: Morioka
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death; D002470:Cell Survival; D006706:Homeostasis; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis / Q000378:metabolism; D015398:Signal Transduction; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D000099151:MAP Kinase Kinase Kinase 7