title: TAK1 regulates autophagic cell death by suppressing the phosphorylation of p70 S6 kinase 1.
abstract: There is growing interest in identifying regulators of autophagy. The molecular mechanism underlying transforming growth factor-β activated kinase 1 (TAK1)-induced autophagy is poorly understood. We found that TAK1 inhibits p70 S6 kinase1 (S6K1) phosphorylation by interfering interaction of raptor with S6K1, thus inducing autophagy. The factors that determine whether autophagy is cytoprotective or cytotoxic have not been fully elucidated. In Drosophila, TAK1 overexpression leads to an impaired eye phenotype despite inhibition of apoptosis, indicating that the phenotype was mainly due to autophagy. Also, TAK1 overexpression increases lactate dehydrogenase (LDH) level in mammalian cells. When treated with autophagy inhibitors, the level of TAK1-induced cytotoxicity or cell death was significantly attenuated, indicating that TAK1 induces cytotoxic autophagic cell death. This study provides the first in vitro and in vivo evidence of TAK1-induced autophagy and we believe that our findings significantly contribute to the understanding of the mechanisms underlying the induction of autophagy.
authors.affiliation: Department of Biological Sciences, KAIST, 373-1 Guseong-dong, Yuseong-gu, Daejeon, 305-701, Republic of Korea.
authors.forename: Ju Hyun
authors.initials: JH
authors.lastname: Shin
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Min
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Young-Il
authors.initials: YI
authors.lastname: Kim
authors.forename: Junsoo
authors.initials: J
authors.lastname: Park
authors.forename: Heung Kyu
authors.initials: HK
authors.lastname: Lee
authors.forename: Ook Joon
authors.initials: OJ
authors.lastname: Yoo
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000096:biosynthesis / Q000378:metabolism*; D010766:Phosphorylation; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013217:Starvation / Q000503:physiopathology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D000099151:MAP Kinase Kinase Kinase 7; C518293:raptor protein, Drosophila