MAP3K5

MAP3K5 Background

The MAP3K5 gene encodes the mitogen-activated protein kinase kinase kinase 5, an enzyme also known as apoptosis signal-regulating kinase 1 (ASK1). Under nonstressed conditions, MAP3K5/ASK1 forms a high molecular mass complex, designated as the ASK1 signalosome ^[1]. In the signalosome, ASK1 is homo-oligomerized through the C-terminal coiled-coil domain (CCC). Following hydrogen peroxide stimulation, ASK1 undergoes autophosphorylation, leading to ASK1 activation ^[2][3]. MAP3K5/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. These protein kinases are sequentially activated, such that the MAPK kinase kinase (MAPKKK) phosphorylates and activates the MAPK kinase (MAPKK), which in turn phosphorylates and activates the MAPK, eventually inducing proliferation, differentiation, migration, and apoptosis ^[4]. Besides, MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Furthermore, overexpression of ASK1 wild-type or a constitutively active mutant induced apoptosis in a fetal lung cell line ^[5][6]. ASK1 is involved in cancer, diabetes, rheumatoid arthritis, cardiovascular and neurodegenerative diseases ^[7][8].

[1] Noguchi T, Takeda K, et al. Recruitment of tumor necrosis factor receptor-associated factor family proteins to apoptosis signal-regulating kinase 1 signalosome is essential for oxidative stress-induced cell death [J]. J Biol Chem. 2005, 280: 37033-37040.
[2] Liu H, Nishitoh H, et al. Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin [J]. Mol Cell Biol. 2000, 20: 2198-2208.
[3] Fujino G, Noguchi T, et al. Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1 [J]. Mol Cell Biol. 2007, 27: 8152-8163.
[4] Nagai H, Noguchi T, et al. Pathophysiological roles of ASK1-MAP kinase signaling pathways [J]. J Biochem Mol Biol. 2007 Jan 31;40(1):1-6.
[5] Johnson GL, Dohlman HG, et al. MAPK kinase kinases (MKKKs) as a target class for small-molecule inhibition to modulate signaling networks and gene expression [J]. Curr Opin Chem Biol. 2005, 9: 325-331.
[6] Ichijo H, Nishida E, et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways [J]. Science. 1997, 275: 90-94.
[7] Hattori K, Naguro I, et al. The roles of ASK family proteins in stress responses and diseases [J]. Cell Communication and Signaling. 2009, 7: 9.
[8] Nygaard G, Di Paolo JA, et al. Regulation and function of apoptosis signal-regulating kinase 1 in rheumatoid arthritis [J]. Biochemical Pharmacology. 2008, 151: 282–290.