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. 2009 Apr 24:7:9.
doi: 10.1186/1478-811X-7-9.

The roles of ASK family proteins in stress responses and diseases

Kazuki Hattori  1 , Isao Naguro, Christopher Runchel, Hidenori Ichijo
Affiliations

The roles of ASK family proteins in stress responses and diseases

Kazuki Hattori et al. Cell Commun Signal. .

Abstract

Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase family, which activates c-Jun N-terminal kinase and p38 in response to a diverse array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. In the past decade, various regulatory mechanisms of ASK1 have been elucidated, including its oxidative stress-dependent activation. Recently, it has emerged that ASK family proteins play key roles in cancer, cardiovascular diseases and neurodegenerative diseases. In this review, we summarize the recent findings on ASK family proteins and their implications in various diseases.

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Figures

Figure 1
Figure 1
The mammalian MAP kinase cascade. ASK1 and ASK2 belong to the MAPKKK family, whose members respond to various external stimuli and initiate the MAPK cascade. There are at least 20 MAPKKKs in vertebrates that selectively phosphorylate and activate MAPKKs leading to a specific activation profile of MAPK family members. The ASK family can activate the JNK and p38 pathways but not the ERK pathway.
Figure 2
Figure 2
Schematic illustrations of ASK1 and ASK2. The domain structures of ASK1 and ASK2 are illustrated. The binding domains of Trx and TRAF exist in the N-terminus of ASK1. Two coiled-coil domains (NCC and CCC) are important for the homomeric interaction and the activation of ASK1. ASK2 associates with the ASK1 C-terminus, which is required to stabilize the ASK2 protein. In the lower part, highly conserved amino acid sequences around the activation loop of the kinase domains of the ASK family are aligned with orthologues of invertebrate ASK1 (DASK1: D. melanogaster, NSY-1: C. elegans). A phosphorylation site essential for ASK1 activation (Thr845 in mouse-ASK1) is shown in red and by a star (*). Three autophosphorylation sites identified in ASK1 are enclosed in squares.
Figure 3
Figure 3
Overview of signaling upstream of ASK1 and ASK2. Various stimuli activate ASK1 and ASK2. In some of these stimuli, ROS generation is required to activate the ASK family. The recruitment of TRAF2 and/or TRAF6 to ASK1 is also important in the activation. ASK1 and ASK2 can form a complex in the cell. For details, see text.
Figure 4
Figure 4
Proposed mechanisms of pathogenesis of ASK family-related diseases. ASK family proteins are involved in the pathogenesis of various diseases. Detailed roles of the ASK family in the development of individual diseases are described in the text.
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References

    1. Johnson GL, Dohlman HG, Graves LM. MAPK kinase kinases (MKKKs) as a target class for small-molecule inhibition to modulate signaling networks and gene expression. Curr Opin Chem Biol. 2005;9:325–331. doi: 10.1016/j.cbpa.2005.04.004. - DOI - PubMed
    1. Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 1997;275:90–94. doi: 10.1126/science.275.5296.90. - DOI - PubMed
    1. Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 1998;17:2596–2606. doi: 10.1093/emboj/17.9.2596. - DOI - PMC - PubMed
    1. Kuranaga E, Kanuka H, Igaki T, Sawamoto K, Ichijo H, Okano H, Miura M. Reaper-mediated inhibition of DIAP1-induced DTRAF1 degradation results in activation of JNK in Drosophila. Nat Cell Biol. 2002;4:705–710. doi: 10.1038/ncb842. - DOI - PubMed
    1. Sagasti A, Hisamoto N, Hyodo J, Tanaka-Hino M, Matsumoto K, Bargmann CI. The CaMKII UNC-43 activates the MAPKKK NSY-1 to execute a lateral signaling decision required for asymmetric olfactory neuron fates. Cell. 2001;105:221–232. doi: 10.1016/S0092-8674(01)00313-0. - DOI - PubMed