Alternative titles; symbols
HGNC Approved Gene Symbol: MAP3K8
Cytogenetic location: 10p11.23 Genomic coordinates (GRCh38): 10:30,434,021-30,461,833 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p11.23 | Lung cancer, somatic | 211980 | 3 |
By transfecting the hamster embryonic cell line SHOK with DNA extracted from a human thyroid carcinoma cell line, Miyoshi et al. (1991) identified the transforming oncogene 'cancer Osaka thyroid' (COT). Sequence analysis revealed that COT is a serine-threonine protein kinase. The authors compared genomic clones of COT from transformed SHOK cells and from human placenta cells and found that the COT oncogene had undergone a rearrangement within the last coding exon, an event which probably occurred during the initial transfection experiment. The COT protooncogene contains 8 exons. Aoki et al. (1993) reported that the predicted normal COT protein has 467 amino acids. In the COT oncoprotein, the C-terminal 70 amino acids of normal COT are replaced by 18 novel residues. Cell fractionation and immunoprecipitation studies demonstrated that the COT protooncogene encodes 58- and 52-kD proteins that are located in the cytosol.
Chan et al. (1993) isolated a Ewing sarcoma (612219) cell line cDNA that transformed NIH 3T3 cells. They designated the gene EST for 'Ewing sarcoma transformant' and identified it as COT. Since the EST cDNA encodes the normal form of the COT protein, the authors concluded that the COT gene can be activated as an oncogene by overexpression as well as by gene rearrangement. Northern blot analysis revealed that COT is expressed as a 3.2-kb mRNA in human fibroblasts and epithelial cells. Treatment of a lung fibroblast cell line with the tumor promoter okadaic acid induced COT expression.
Ohara et al. (1993) reported the sequence of the mouse Cot protooncogene. Like human COT, the mouse Cot gene contains 8 exons, and the intron-exon borders are well-conserved between the 2 species. The predicted mouse and human COT proteins are 94% identical. Northern blot analysis revealed that Cot is expressed in many mouse tissues at various developmental stages.
Aoki et al. (1993) determined that the 2 COT isoforms have serine/threonine kinase activity and appear to result from the use of alternative translation initiation sites. The 58-kD isoform had stronger transforming activity than the 52-kD protein, although this activity was much weaker than that of the oncoprotein. Aoki et al. (1993) suggested that the N-terminal domain of COT may be necessary for cellular transformation, whereas the C-terminal domain may negatively regulate the transforming activity.
Interaction of TPL2 with NFKB1 p105 (164011) is required to maintain TPL2 metabolic stability and also negatively regulates TPL2 MEK (see 176872) kinase activity. By affinity purification in HeLa cells, Lang et al. (2004) identified ABIN2 (TNIP2; 610669) as a protein associated with p105. Cotransfection studies in HeLa cells showed that ABIN2 also interacted with TPL2 and preferentially formed a ternary complex with both proteins. In bone marrow-derived macrophages, a substantial fraction of endogenous ABIN2 was associated with both p105 and TPL2. Mutation and binding analysis showed that ABIN2 interacted with the death domain and PEST region of p105 and with the C terminus of TPL2. Depletion of ABIN2 by RNA interference in HeLa cells and human embryonic kidney cells dramatically reduced TPL2 protein levels, but did not alter TPL2 mRNA or p105 protein levels. ABIN2 increased the half-life of cotransfected TPL2 in human embryonic kidney cells. Lang et al. (2004) concluded that optimal TPL2 stability requires interaction with both ABIN2 and p105.
Channavajhala et al. (2003) showed that both full-length KSR2 (610737) and the C-terminal catalytic domain of KSR2 associated with COT. Cotransfection of KSR2 with COT in HEK-293T cells lead to reduced COT-mediated ERK activation in a dose-dependent manner; however, RAF (164760)-mediated ERK activation was not significantly attenuated by coexpression with KSR2, suggesting that the effect is selective. Luciferase reporter assays showed that KSR2 inhibited COT-induced NF-kappa-B (164011) activation but did not inhibit IKKB (603258)-mediated NF-kappa-B activation. In vitro kinase assays showed that KSR2 negatively regulated the kinase activity of COT. COT kinase activity regulated IL8 (146930) production in HeLa cells, and coexpression of KSR2 markedly reduced COT-induced IL8 production.
The BRAF mutation V600E (164757.0001) is frequently seen in melanoma. While clinical trials found that treatment with RAF-inhibiting drugs was initially successful, acquired resistance quickly and almost invariably led to relapse. Johannessen et al. (2010) identified MAP3K8 as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting.
By analysis of somatic cell hybrids and by fluorescence in situ hybridization, Chan et al. (1993) mapped the MAP3K8 gene to chromosome 10p11.2.
Using a molecular probe for the analysis of an interspecific backcross between C57BL/6J and Mus spretus, Justice et al. (1992) mapped the tumor progression locus-2 to mouse chromosome 18.
Clark et al. (2004) identified MAP3K8 as a transforming gene from a human lung adenocarcinoma and characterized a 3-prime end mutation in the cDNA. In addition, they confirmed that the mutation was present in the original lung tumor and screened a series of lung cancer cell lines to determine whether the MAP3K8 mutation is a common occurrence in lung tumorigenesis. The mutation was localized to MAP3K8 exon 8 and confirmed in the primary tumor DNA. Both wildtype and mutant MAP3K8 cDNAs transformed NIH 3T3 cells, but the transforming activity of the mutant was much greater than that of the wildtype. Clark et al. (2004) stated that this was the first report of a mutation in the MAP3K8 gene occurring in a primary tumor, but concluded that mutational activation of the gene is a rare event in lung cancer.
Dumitru et al. (2000) generated Tpl2 knockout mice. The Tpl2 -/- animals produced low levels of tumor necrosis factor-alpha (TNFA; 191160) when exposed to lipopolysaccharide (LPS), and they were resistant to LPS/D-galactosamine-induced pathology. LPS stimulation of peritoneal macrophages from these mice did not activate MEK1 (176872), ERK1 (601795), or ERK2 (176948), but did activate JNK (601158), p38 MAPK (600289), and nuclear factor kappa-B (NFKB; see 164011). The block in ERK1 and ERK2 activation was causally linked to the defect in TNFA induction by experiments showing that normal murine macrophages treated with the MEK inhibitor PD98059 exhibited a similar defect. Deletion of the AU-rich motif in the TNFA mRNA minimized the effect of Tpl2 inactivation on the induction of TNFA. Subcellular fractionation of LPS-stimulated macrophages revealed that LPS signals transduced by Tpl2 specifically promoted the transport of TNFA mRNA from the nucleus to the cytoplasm.
Sugimoto et al. (2004) demonstrated that peritoneal macrophages and bone marrow-derived dendritic cells from Tpl2-null mice produced significantly more interleukin-12 (IL12; 161561) in response to CG-rich bacterial DNA than those from wildtype mice. Enhanced IL12 production in Tpl2 -/- macrophages was regulated in part at the transcriptional level, and the elevated IL12 mRNA level in Tpl2 -/- macrophages was accompanied by decreased amounts of IL12 repressors. Tpl2-null mice consistently showed Th1-skewed antigen-specific immune responses upon OVA immunization and Leishmania major infection in vivo. Sugimoto et al. (2004) concluded that TPL2 is an important negative regulator of Th1-type adaptive immunity and that it achieves this regulation by inhibiting IL12 production from accessory cells.
Van Acker et al. (2007) examined pancreatitis-associated Tpl2 effects in wildtype and Tpl2 -/- mice subjected to either secretagogue- or bile salt-induced pancreatitis. Tpl2 ablation markedly reduced pancreatic and lung inflammation in both models of pancreatitis, but did not alter pancreatic injury or necrosis. The reduction in secretagogue-induced inflammation was dependent upon Tpl2 ablation in nonmyeloid cells, possibly pancreatic acinar cells, and was associated in vivo and in vitro with inhibition of Mek, Jnk, and Ap1 (165160) activation and expression of Mcp1 (CCL2; 158105), Mip2 (CXCL2; 139110), and interleukin-6 (IL6; 147620). Van Acker et al. (2007) concluded that TPL2 regulates pancreatitis-associated inflammation by inducing chemoattracting chemokines.
Aoki, M., Hamada, F., Sugimoto, T., Sumida, S., Akiyama, T., Toyoshima, K. The human cot proto-oncogene encodes two protein serine/threonine kinases with different transforming activities by alternative initiation of translation. J. Biol. Chem. 268: 22723-22732, 1993. [PubMed: 8226782]
Chan, A. M.-L., Chedid, M., McGovern, E. S., Popescu, N. C., Miki, T., Aaronson, S. A. Expression cDNA cloning of a serine kinase transforming gene. Oncogene 8: 1329-1333, 1993. [PubMed: 8479752]
Channavajhala, P. L., Wu, L., Cuozzo, J. W., Hall, J. P., Liu, W., Lin, L. L., Zhang, Y. Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling. J. Biol. Chem. 278: 47089-47097, 2003. [PubMed: 12975377] [Full Text: https://doi.org/10.1074/jbc.M306002200]
Clark, A. M., Reynolds, S. H., Anderson, M., Wiest, J. S. Mutational activation of the MAP3K8 protooncogene in lung cancer. Genes Chromosomes Cancer 41: 99-108, 2004. [PubMed: 15287022] [Full Text: https://doi.org/10.1002/gcc.20069]
Dumitru, C. D., Ceci, J. D., Tsatsanis, C., Kontoyiannis, D., Stamatakis, K., Lin, J.-H., Patriotis, C., Jenkins, N. A., Copeland, N. G., Kollias, G., Tsichlis, P. N. TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103: 1071-1083, 2000. [PubMed: 11163183] [Full Text: https://doi.org/10.1016/s0092-8674(00)00210-5]
Johannessen, C. M., Boehm, J. S., Kim, S. Y., Thomas, S. R., Wardwell, L., Johnson, L. A., Emery, C. M., Stransky, N., Cogdill, A. P., Barretina, J., Caponigro, G., Hieronymus, H., and 23 others. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468: 968-972, 2010. [PubMed: 21107320] [Full Text: https://doi.org/10.1038/nature09627]
Justice, M. J., Gilbert, D. J., Kinzler, K. W., Vogelstein, B., Buchberg, A. M., Ceci, J. D., Matsuda, Y., Chapman, V. M., Patriotis, C., Makris, A., Tsichlis, P. N., Jenkins, N. A., Copeland, N. G. A molecular genetic linkage map of mouse chromosome 18 reveals extensive linkage conservation with human chromosomes 5 and 18. Genomics 13: 1281-1288, 1992. [PubMed: 1354644] [Full Text: https://doi.org/10.1016/0888-7543(92)90047-v]
Lang, V., Symons, A., Watton, S. J., Janzen, J., Soneji, Y., Beinke, S., Howell, S., Ley, S. C. ABIN-2 forms a ternary complex with TPL-2 and NF-kappa-B1 p105 and is essential for TPL-2 protein stability. Molec. Cell. Biol. 24: 5235-5248, 2004. [PubMed: 15169888] [Full Text: https://doi.org/10.1128/MCB.24.12.5235-5248.2004]
Miyoshi, J., Higashi, T., Mukai, H., Ohuchi, T., Kakunaga, T. Structure and transforming potential of the human cot oncogene encoding a putative protein kinase. Molec. Cell. Biol. 11: 4088-4096, 1991. [PubMed: 2072910] [Full Text: https://doi.org/10.1128/mcb.11.8.4088-4096.1991]
Ohara, R., Miyoshi, J., Aoki, M., Toyoshima, K. The murine cot proto-oncogene: genome structure and tissue-specific expression. Jpn. J. Cancer Res. 84: 518-525, 1993. [PubMed: 8320169] [Full Text: https://doi.org/10.1111/j.1349-7006.1993.tb00170.x]
Sugimoto, K., Ohata, M., Miyoshi, J., Ishizaki, H., Tsuboi, N., Masuda, A., Yoshikai, Y., Takamoto, M., Sugane, K., Matsuo, S., Shimada, Y., Matsuguchi, T. A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL-12 production and Th cell differentiation. J. Clin. Invest. 114: 857-866, 2004. [PubMed: 15372110] [Full Text: https://doi.org/10.1172/JCI20014]
Van Acker, G. J. D., Perides, G., Weiss, E. R., Das, S., Tsichlis, P. N., Steer, M. L. Tumor progression locus-2 is a critical regulator of pancreatic and lung inflammation during acute pancreatitis. J. Biol. Chem. 282: 22140-22149, 2007. [PubMed: 17537724] [Full Text: https://doi.org/10.1074/jbc.M702225200]