Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1.
Apoptosis signal-regulating kinase (ASK) 1 is a mitogen-activated protein kinase kinase kinase (MAP3K) in the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase pathways that play multiple important roles in cytokine and stress responses. Here we show that ASK2, a highly related serine/threonine kinase to ASK1, also functions as a MAP3K only in a heteromeric complex with ASK1. We found that endogenous ASK2 was constitutively degraded in ASK1-deficient cells, suggesting that ASK1 is required for the stability of ASK2. ASK2 in a heteromeric complex with a kinase-negative mutant of ASK1 (ASK1-KN) effectively activated MAP2K and was more competent to respond to oxidative stress than ASK2 alone. Knockdown of ASK2 revealed that ASK2 was required for oxidative stress-induced JNK activation. These results suggest that ASK2 forms a functional MAP3K complex with ASK1, in which ASK1 supports the stability and the active configuration of ASK2. Moreover, ASK2 was found to activate ASK1 by direct phosphorylation, suggesting that ASK1 and ASK2 in a heteromeric complex facilitate their activities to each other by distinct mechanisms. Such a formation of functional heteromeric complex between different MAP3Ks may be advantageous for cells to cope with a wide variety of stimuli by fine regulation of cellular responses.
Takeda
Kohsuke
K
Graduate School of Pharmaceutical Sciences, The University of Tokyo, CREST, Japan Science and Technology Corporation, and Strategic Approach to Drug Discovery and Development in Pharmaceutical Sciences, Center of Excellence Program, Japan.
Shimozono
Rieko
R
Noguchi
Takuya
T
Umeda
Tsuyoshi
T
Morimoto
Yoshifumi
Y
Naguro
Isao
I
Tobiume
Kei
K
Saitoh
Masao
M
Matsuzawa
Atsushi
A
Ichijo
Hidenori
H
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis; D002478:Cells, Cultured; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000737:chemistry* / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D010766:Phosphorylation
D002352:Carrier Proteins; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C116394:MAP kinase kinase kinase 6; C482858:MAP3K5 protein, human; C482859:Map3k5 protein, mouse