Alternative titles; symbols
HGNC Approved Gene Symbol: MAP3K5
Cytogenetic location: 6q23.3 Genomic coordinates (GRCh38): 6:136,557,046-136,793,091 (from NCBI)
Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MAP2K, also called MKK or MEK), and MAPK kinase kinase (MAP3K, also called MAPKKK or MEKK). MAPKK kinase/MEKK, such as MAP3K5, phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. The kinases of these signaling cascades are highly conserved, and homologs exist in yeast, Drosophila, and mammalian cells (Wang et al., 1996).
Wang et al. (1996) used a degenerate polymerase chain reaction-based strategy to isolate a cDNA encoding a protein kinase, designated MAPKKK5, from a human macrophage library. The predicted protein contains 1,374 amino acids with all 11 kinase subdomains. Northern blot analysis shows that MAPKKK5 transcript is abundantly expressed in human heart and pancreas.
Ichijo et al. (1997) used a similar cloning strategy to identify a nearly identical MAPKKK cDNA, termed ASK1 for apoptosis signal-regulating kinase. The deduced protein contains 1,375 amino acids, and is most closely related to yeast SSK2 and SSK22, which are upstream regulators of yeast HOG1 MAPK.
Wang et al. (1996) showed that the MAPKKK5 protein phosphorylated and activated MKK4 (601335) in vitro and activated c-jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK; 601158) during transient expression in COS and 293 cells; MAPKKK5 did not activate MAPK/ERK.
Ichijo et al. (1997) found that ASK1 expression complemented a yeast mutant lacking functional SSK2 and SSK22. ASK1 also activated MKK3 (602315), MKK4 (SEK1), and MKK6 (601254). Overexpression of ASK1 induced apoptotic cell death, and ASK1 was activated in cells treated with tumor necrosis factor-alpha (TNFA; 191160).
Nishitoh et al. (1998) showed that ASK1 interacts with members of the TRAF family and is activated by TRAF2 (601895) in the TNF-signaling pathway. After activation by TRAF2, ASK1 activates MKK4, which in turn activates JNK. Thus, ASK1 is a mediator of TRAF2-induced JNK activation.
By yeast 2-hybrid analysis of a human brain cDNA library, Saitoh et al. (1998) identified thioredoxin (TXN; 187700) and ASK1 as interacting partners. TXN associated with the N-terminal portion of ASK1 in vitro and in vivo, and the interaction between TXN and ASK1 was highly dependent on the redox status of TXN. Expression of TXN inhibited ASK1 kinase activity and ASK1-dependent apoptosis. Inhibition of TXN resulted in activation of endogenous ASK1 activity. Saitoh et al. (1998) concluded that TXN is a physiologic inhibitor of ASK1 and may be involved in redox regulation of the apoptosis signal transduction pathway.
A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD protein that perturbs a multiplicity of signaling pathways. These include inhibition of the extracellular signal-regulated kinase ERK (600997), c-jun NH2-terminal kinase (JNK; see 601158), and p38 mitogen-activated protein kinase (600289) pathways and inhibition of the nuclear factor kappa B (NF-kappa-B; see 164011) pathway. The expression of YopJ has been correlated with the induction of apoptosis by Yersinia. Using a yeast 2-hybrid screen based on a LexA-YopJ fusion protein and a HeLa cDNA library, Orth et al. (1999) identified mammalian binding partners of YopJ. These included the fusion proteins of the GAL4 activation domain with MAPK kinases MKK1 (176872), MKK2 (601263), and MKK4/SEK1 (601335). YopJ was found to bind directly to MKKs in vitro, including MKK1, MKK3 (602315), MKK4, and MKK5. Binding of YopJ to the MKK blocked both phosphorylation and subsequent activation of the MKKs. These results explain the diverse activities of YopJ in inhibiting the ERK, JNK, p38, and NF-kappa-B signaling pathways, preventing cytokine synthesis and promoting apoptosis. YopJ-related proteins that are found in a number of bacterial pathogens of animals and plants may function to block MKKs so that host signaling responses can be modulated upon infection.
Using a yeast 2-hybrid screen, McDonald et al. (2000) identified JNK3 (602897) as a binding partner of beta-arrestin-2 (ARBB2; 107941). These results were confirmed by coimmunoprecipitation from mouse brain extracts and cotransfection in COS-7 cells. The upstream JNK activators ASK1 and MKK4 (601335) were also found in complex with ARBB2. Cellular transfection of ARBB2 caused cytosolic retention of JNK3 and enhanced JNK3 phosphorylation stimulated by ASK1. Moreover, stimulation of the angiotensin II type 1A receptor (AGTR1; 106165) activated JNK3 and triggered the colocalization of ARBB2 and active JNK3 to intracellular vesicles. Thus, McDonald et al. (2000) concluded that ARBB2 acts as a scaffold protein, which brings the spatial distribution and activity of this MAPK module under the control of a G protein-coupled receptor.
The HIV-1 Nef protein induces the expression of FAS ligand (TNFSF6; 134638) on infected cells, thereby inducing apoptosis in neighboring cells, including HIV-1 specific cytotoxic T lymphocytes (Xu et al., 1997). By capturing cellular proteins interacting with a GST fusion protein containing HIV-1 Nef, followed by micropeptide sequence and immunoblot analyses, Geleziunas et al. (2001) identified a 160-kD protein identical to ASK1. Immunoprecipitation analysis showed that Nef interacts with ASK1 but not MAP3K3 (602539). Transfection and immunoprecipitation analyses indicated that wildtype, but not an N-terminal myristylation or an R106A mutant, Nef inhibits ASK1-, FAS- (134637), and TNFA-induced, but not MAP3K1- 600982 induced, activation of JNK-mediated apoptosis. Nef inhibits TNFA-induced dissociation of ASK1 from TXN, an inhibitor of ASK1 catalytic activity. Infection with ASK1-binding wildtype, but not ASK1-binding R106A Nef mutant, HIV strains also inhibited TNFA- and anti-FAS-induced apoptosis. Immunoblot analysis showed that only wildtype Nef inhibited the expression of the catalytic, apoptosis-inducing form of ASK1. Geleziunas et al. (2001) concluded that HIV-1 Nef enhances the resistance of infected cells to FAS- and TNFA-induced apoptosis, allowing host cells to survive and produce new infectious virions, by mimicking the action of TXN or 14-3-3 proteins (see YWHAE, 605066) in preventing ASK1 activation.
Using immunoprecipitation-kinase analysis, Chang et al. (1998) showed that activity of ASK1, but not of TAK1 (MAP3K7; 602614) or an ASK1 lys709-to-arg mutant, is potentiated by coexpression with DAXX (603186) or the JNK activation domain (amino acids 501 to 625) of DAXX. FAS activation was found to enhance endogenous ASK1 activity. Yeast 2-hybrid analysis established that ASK1 interacts directly with DAXX but not FAS, indicating that DAXX acts as a bridge between FAS and ASK1. Chang et al. (1998) concluded that the DAXX-ASK1 connection provides a mechanism for caspase-independent activation of JNK by FAS and perhaps other stimuli.
Raoul et al. (2002) showed that Fas triggers cell death specifically in motor neurons by transcriptional upregulation of neuronal nitric oxide synthase (nNOS; 163731) mediated by p38 kinase. ASK1 and Daxx act upstream of p38 in the Fas signaling pathway. The authors also showed that synergistic activation of the NO pathway and the classic FADD (602457)/caspase-8 (601763) pathway were needed for motor neuron cell death. No evidence for involvement of the Fas/NO pathway was found in other cell types. Motor neurons from transgenic mice expressing amyotrophic lateral sclerosis (ALS; 105400)-linked SOD1 (147450) mutations displayed increased susceptibility to activation of the Fas/NO pathway. Raoul et al. (2002) emphasized that this signaling pathway was unique to motor neurons and suggested that these cell death pathways may contribute to motor neuron loss in ALS.
Saito et al. (2007) found that expression of mouse Pp2ce (PPM1L; 611931) in HEK293 human embryonic kidney cells inhibited Ask1-induced activation of an AP1 (165160) reporter gene. Conversely, a dominant-negative Pp2ce mutant enhanced AP1 activity. Mouse Pp2ce and Ask1 interacted in HEK293 cells under nonstressed conditions, and Pp2ce inactivated Ask1 by decreasing thr845 phosphorylation in the cell system and also in vitro. The association of Pp2ce and Ask1 was also observed in mouse brain extracts. In contrast with PP5 (PPP5C; 600658), Pp2ce transiently dissociated from Ask1 within cells upon peroxide treatment. Saito et al. (2007) concluded that PP2CE maintains ASK1 in an inactive state by dephosphorylation in quiescent cells.
Takeda et al. (2009) found that PGAM5 (614939) interacted with and activated ASK1 by threonine dephosphorylation, resulting in downstream activation of JNK and p38. Overexpression and knockdown studies revealed that the Drosophila and C. elegans orthologs of PGAM5 also exhibited specific ser/thr phosphatase activity and activated the Drosophila and C. elegans orthologs of ASK1.
By radiation hybrid mapping, Rampoldi et al. (1997) localized the MAP3K5 gene to chromosome 6q22.33.
Stark et al. (2012) sequenced 8 melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, Stark et al. (2012) found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9 (600136). Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggested that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W33X variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.
Using a forward genetic screen of C. elegans mutants, Kim et al. (2002) showed that viable worms lacking esp2 and esp8, homologs of the mammalian MAP kinases SEK1 and ASK1, were highly susceptible to and died more rapidly from both a gram-negative bacterium, P. aeruginosa, and a gram-positive organism, E. faecalis, than wildtype worms. RNA-interference and biochemical analyses likewise implicated the p38 MAP kinase homolog, pmk1, in susceptibility to these pathogens. Kim et al. (2002) concluded that MAP kinase signaling, which is also involved in plant pathogen resistance, is a conserved element in innate metazoan immunity to diverse pathogens.
Left ventricular (LV) cardiac remodeling that occurs after myocardial infarction and pressure overload is generally accepted as a determinant of the clinical course of heart failure, and it has been suggested that the remodeling is associated with increased apoptosis in the myocardium. In mouse models of LV remodeling induced by left coronary artery ligation or pressure overload, Yamaguchi et al. (2003) found that Ask1 knockout mice had significantly smaller increases in LV dimensions and smaller decreases in fractional shortening compared with wildtype mice, as well as a reduction in apoptotic cardiac myocytes. In the wildtype hearts, there was a significant increase in Ask1 activity, accompanied by an increase in Jnk (MAPK8; 601158) phosphorylation. The authors concluded that ASK1 plays a critical role in the stress-induced apoptotic pathway in LV remodeling.
In male Sprague-Dawley rats, Izumi et al. (2003) observed a rapid and dramatic increase in arterial Ask1 activity after balloon injury. Gene transfer of a dominant-negative mutant of Ask1 significantly prevented neointimal formation at 14 days after injury; bromodeoxyuridine labeling revealed that dominant-negative Ask1 suppressed vascular smooth muscle cell (VSMC) proliferation in both the intima and media at 7 days. Infection of cultured rat VSMCs with dominant-negative Ask1 significantly attenuated serum-induced VSMC proliferation and migration. In Ask1-null mice, there was attenuation both of neointimal formation after cuff injury and of proliferation and migration of VSMCs compared to wildtype mice. Izumi et al. (2003) concluded that ASK1 activation plays a key role in vascular intimal hyperplasia.
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Geleziunas, R., Xu, W., Takeda, K., Ichijo, H., Greene, W. C. HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell. Nature 410: 834-838, 2001. [PubMed: 11298454] [Full Text: https://doi.org/10.1038/35071111]
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McDonald, P. H., Chow, C.-W., Miller, W. E., Laporte, S. A., Field, M. E., Lin, F.-T., Davis, R. J., Lefkowitz, R. J. Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290: 1574-1577, 2000. [PubMed: 11090355] [Full Text: https://doi.org/10.1126/science.290.5496.1574]
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Rampoldi, L., Zimbello, R., Bortoluzzi, S., Tiso, N., Valle, G., Lanfranchi, G., Danieli, G. A. Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5. Cytogenet. Cell Genet. 78: 301-303, 1997. [PubMed: 9465908] [Full Text: https://doi.org/10.1159/000134677]
Raoul, C., Estevez, A. G., Nishimune, H., Cleveland, D. W., deLapeyriere, O., Henderson, C. E., Hasse, G., Pettmann, B. Motoneuron death triggered by a specific pathway downstream of Fas: potentiation by ALS-linked SOD1 mutations. Neuron 35: 1067-1083, 2002. [PubMed: 12354397] [Full Text: https://doi.org/10.1016/s0896-6273(02)00905-4]
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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. 17: 2596-2606, 1998. [PubMed: 9564042] [Full Text: https://doi.org/10.1093/emboj/17.9.2596]
Stark, M. S., Woods, S. L., Gartside, M. G., Bonazzi, V. F., Dutton-Regester, K., Aoude, L. G., Chow, D., Sereduk, C., Niemi, N. M., Tang, N., Ellis, J. J., Reid, J., and 18 others. Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing. Nature Genet. 44: 165-169, 2012. [PubMed: 22197930] [Full Text: https://doi.org/10.1038/ng.1041]
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Yamaguchi, O., Higuchi, Y., Hirotani, S., Kashiwase, K., Nakayama, H., Hikoso, S., Takeda, T., Watanabe, T., Asahi, M., Taniike, M., Matsumura, Y., Tsujimoto, I., Hongo, K., Kusakari, Y., Kurihara, S., Nishida, K., Ichijo, H., Hori, M., Otsu, K. Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling. Proc. Nat. Acad. Sci. 100: 15883-15888, 2003. [PubMed: 14665690] [Full Text: https://doi.org/10.1073/pnas.2136717100]