title: Negative control of apoptosis signal-regulating kinase 1 through phosphorylation of Ser-1034.
abstract: Apoptosis signal-regulating kinase 1 (ASK1) is a serine/threonine kinase that mediates cell stress signaling initiated by diverse stimuli, such as H(2)O(2) and TNF alpha. Owing to its critical role in promoting apoptosis, ASK1 activity is highly controlled in cells. Phosphorylation of ASK1 at Thr-845 has been correlated with its activation, while phosphorylation at Ser-967 negatively controls its death promoting activity. Here, we report the identification of a novel phosphorylation site at Ser-1034 in the C-terminal regulatory domain of ASK1. Mutating Ser-1034 to an unphosphorylatable Ala led to increased catalytic activity of ASK1 and enhanced proapoptotic function of ASK1. Thus, the proapoptotic function of ASK1 is suppressed in part by phosphorylation at its C-terminal regulatory domain, which may couple upstream survival kinases to the death regulatory machinery.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta GA 30322, USA.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Fujii
authors.forename: Erinn Hoag
authors.initials: EH
authors.lastname: Goldman
authors.forename: Hae Ryoun
authors.initials: HR
authors.lastname: Park
authors.forename: Lixin
authors.initials: L
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
mesh_terms: D017209:Apoptosis; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D012045:Regulatory Sequences, Nucleic Acid; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D012694:Serine; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human