PubMed Journals: J Biol Chem

  Source:		PMID: 17210579

    		J Biol Chem. 2007 Mar 9;282(10):7522-31.
     		Epub 2007 Jan 8.

			Apoptosis signal-regulating kinase (ASK) 2
			functions as a mitogen-activated protein
			kinase kinase kinase in a heteromeric complex
			with ASK1.

			Takeda K(1), Shimozono R, Noguchi T, Umeda
			T, Morimoto Y, Naguro I, Tobiume K, Saitoh
			M, Matsuzawa A, Ichijo H.

			Author Information
			(1) 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.

			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.

			DOI: 10.1074/jbc.M607177200 PMID: 17210579
			[Indexed for MEDLINE]

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