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Gene Review

MAP3K7  -  mitogen-activated protein kinase kinase...

Homo sapiens

Synonyms: MEKK7, Mitogen-activated protein kinase kinase kinase 7, TAK1, TGF-beta-activated kinase 1, TGF1a, ...
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Disease relevance of MAP3K7

  • The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL-1 signalling pathway [1].
  • The TAK1-mediated antiapoptotic effects were also observed in human lung adenocarcinoma A549 cells [2].
  • In addition, as heterozygosity for mutations in endoglin and ALK1 lead to the human syndromes known as hereditary hemorrhagic telangiectasia 1 and 2, respectively, our results raise the possibility that mutations in human TAK1 might contribute to this disease [3].
  • The mechanism of TH and TRalpha1-specific hypertrophy is novel for a nuclear hormone receptor and involves the transforming growth factor beta-activated kinase (TAK1) and p38 [4].
  • In the present study, we investigated whether another downstream mediator, human TGF-beta-activated kinase 1 (hTAK1), also is altered in lung cancer [5].

High impact information on MAP3K7

  • TAB1 may function as an activator of the TAK1 MAPKKK in TGF-beta signal transduction [6].
  • To analyze the function of TAK1 in vivo, we have deleted the Tak1 gene in mice, with the resulting phenotype being early embryonic lethality [7].
  • The K377R mutation of RIP1 also prevents the recruitment of TAK1 and IKK complexes to TNF receptor [8].
  • TAK1 is in turn activated by TRAF6, a RING domain ubiquitin ligase that facilitates the synthesis of lysine 63-linked polyubiquitin chains [9].
  • We re-injected each patient with IIIIn-labelled TAK cells in order to visualise metastases [10].

Chemical compound and disease context of MAP3K7


Biological context of MAP3K7

  • Together, these results indicate that STAT3 enhances the efficiency of its own Ser-727 phosphorylation by acting as a scaffold for the TAK1-NLK kinases, specifically in the YXXQ motif-derived pathway [11].
  • IAP suppression of apoptosis involves distinct mechanisms: the TAK1/JNK1 signaling cascade and caspase inhibition [12].
  • We have previously described a new aspect of the Inhibitor of Apoptosis (IAP) family of proteins anti-apoptotic activity that involves the TAK1/JNK1 signal transduction pathway (1,2) [13].
  • Both the wild-type and a constitutively active mutant of TAK1 stimulated JNK in transient transfection assays [14].
  • In conclusion, our data provide evidence for the existence of a direct inhibitory effect of the IL-1beta-TAK1 pathway on SMAD3-mediated TGFbeta signaling, resulting in reduced TGFbeta target gene activation and restored proliferation of hematopoietic progenitors [15].

Anatomical context of MAP3K7


Associations of MAP3K7 with chemical compounds


Physical interactions of MAP3K7

  • Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex [23].
  • Nod2 appears to interact with TAK1 through its LRR region to exert its inhibitory effect on TAK1-induced NF-kappaB activation [24].
  • We believe that IHPK2-TRAF2 binding leads to attenuation of TAK1- and NF-kappaB-mediated signaling and is partially responsible for the apoptotic activity of IHPK2 [25].

Enzymatic interactions of MAP3K7


Regulatory relationships of MAP3K7


Other interactions of MAP3K7


Analytical, diagnostic and therapeutic context of MAP3K7


  1. The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL-1 signalling pathway. Thiefes, A., Wolf, A., Doerrie, A., Grassl, G.A., Matsumoto, K., Autenrieth, I., Bohn, E., Sakurai, H., Niedenthal, R., Resch, K., Kracht, M. EMBO Rep. (2006) [Pubmed]
  2. Blockade of transforming growth factor-{beta}-activated kinase 1 activity enhances TRAIL-induced apoptosis through activation of a caspase cascade. Choo, M.K., Kawasaki, N., Singhirunnusorn, P., Koizumi, K., Sato, S., Akira, S., Saiki, I., Sakurai, H. Mol. Cancer Ther. (2006) [Pubmed]
  3. The TGF{beta} activated kinase TAK1 regulates vascular development in vivo. Jadrich, J.L., O'connor, M.B., Coucouvanis, E. Development (2006) [Pubmed]
  4. Thyroid hormone induces cardiac myocyte hypertrophy in a thyroid hormone receptor alpha1-specific manner that requires TAK1 and p38 mitogen-activated protein kinase. Kinugawa, K., Jeong, M.Y., Bristow, M.R., Long, C.S. Mol. Endocrinol. (2005) [Pubmed]
  5. Molecular cloning of human TAK1 and its mutational analysis in human lung cancer. Kondo, M., Osada, H., Uchida, K., Yanagisawa, K., Masuda, A., Takagi, K., Takahashi, T., Takahashi, T. Int. J. Cancer (1998) [Pubmed]
  6. TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction. Shibuya, H., Yamaguchi, K., Shirakabe, K., Tonegawa, A., Gotoh, Y., Ueno, N., Irie, K., Nishida, E., Matsumoto, K. Science (1996) [Pubmed]
  7. TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Shim, J.H., Xiao, C., Paschal, A.E., Bailey, S.T., Rao, P., Hayden, M.S., Lee, K.Y., Bussey, C., Steckel, M., Tanaka, N., Yamada, G., Akira, S., Matsumoto, K., Ghosh, S. Genes Dev. (2005) [Pubmed]
  8. Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Ea, C.K., Deng, L., Xia, Z.P., Pineda, G., Chen, Z.J. Mol. Cell (2006) [Pubmed]
  9. TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. Kanayama, A., Seth, R.B., Sun, L., Ea, C.K., Hong, M., Shaito, A., Chiu, Y.H., Deng, L., Chen, Z.J. Mol. Cell (2004) [Pubmed]
  10. Imaging of metastatic colorectal cancer with tumour-activated killer lymphocytes. Swift, R.I., Danpure, H.J., Osman, S., Gaer, J., Tsikos, C., Peters, A.M., Lavender, J.P., Tebbut, S., Habib, N.A., Wood, C.B. Lancet (1991) [Pubmed]
  11. STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFbeta-activated kinase 1 for STAT3 Ser-727 phosphorylation. Kojima, H., Sasaki, T., Ishitani, T., Iemura, S., Zhao, H., Kaneko, S., Kunimoto, H., Natsume, T., Matsumoto, K., Nakajima, K. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  12. IAP suppression of apoptosis involves distinct mechanisms: the TAK1/JNK1 signaling cascade and caspase inhibition. Sanna, M.G., da Silva Correia, J., Ducrey, O., Lee, J., Nomoto, K., Schrantz, N., Deveraux, Q.L., Ulevitch, R.J. Mol. Cell. Biol. (2002) [Pubmed]
  13. ILPIP, a novel anti-apoptotic protein that enhances XIAP-mediated activation of JNK1 and protection against apoptosis. Sanna, M.G., da Silva Correia, J., Luo, Y., Chuang, B., Paulson, L.M., Nguyen, B., Deveraux, Q.L., Ulevitch, R.J. J. Biol. Chem. (2002) [Pubmed]
  14. Activation of the hematopoietic progenitor kinase-1 (HPK1)-dependent, stress-activated c-Jun N-terminal kinase (JNK) pathway by transforming growth factor beta (TGF-beta)-activated kinase (TAK1), a kinase mediator of TGF beta signal transduction. Wang, W., Zhou, G., Hu, M.C., Yao, Z., Tan, T.H. J. Biol. Chem. (1997) [Pubmed]
  15. Inhibition of the transforming growth factor beta (TGFbeta) pathway by interleukin-1beta is mediated through TGFbeta-activated kinase 1 phosphorylation of SMAD3. Benus, G.F., Wierenga, A.T., de Gorter, D.J., Schuringa, J.J., van Bennekum, A.M., Drenth-Diephuis, L., Vellenga, E., Eggen, B.J. Mol. Biol. Cell (2005) [Pubmed]
  16. Activation of NF-kappa B by XIAP, the X chromosome-linked inhibitor of apoptosis, in endothelial cells involves TAK1. Hofer-Warbinek, R., Schmid, J.A., Stehlik, C., Binder, B.R., Lipp, J., de Martin, R. J. Biol. Chem. (2000) [Pubmed]
  17. TAK1-mediated transcriptional activation of CD28-responsive element and AP-1-binding site within the IL-2 promoter in Jurkat T cells. Sakurai, H., Singhirunnusorn, P., Shimotabira, E., Chino, A., Suzuki, S., Koizumi, K., Saiki, I. FEBS Lett. (2005) [Pubmed]
  18. Nemo-like kinase (NLK) acts downstream of Notch/Delta signalling to downregulate TCF during mesoderm induction in the sea urchin embryo. R??ttinger, E., Croce, J., Lhomond, G., Besnardeau, L., Gache, C., Lepage, T. Development (2006) [Pubmed]
  19. MyD88 and TNF receptor-associated factor 6 are critical signal transducers in Helicobacter pylori-infected human epithelial cells. Hirata, Y., Ohmae, T., Shibata, W., Maeda, S., Ogura, K., Yoshida, H., Kawabe, T., Omata, M. J. Immunol. (2006) [Pubmed]
  20. TAK1 regulates multiple protein kinase cascades activated by bacterial lipopolysaccharide. Lee, J., Mira-Arbibe, L., Ulevitch, R.J. J. Leukoc. Biol. (2000) [Pubmed]
  21. Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha. Cheung, P.C., Campbell, D.G., Nebreda, A.R., Cohen, P. EMBO J. (2003) [Pubmed]
  22. 15S-Lipoxygenase-2 mediates arachidonic acid-stimulated adhesion of human breast carcinoma cells through the activation of TAK1, MKK6, and p38 MAPK. Nony, P.A., Kennett, S.B., Glasgow, W.C., Olden, K., Roberts, J.D. J. Biol. Chem. (2005) [Pubmed]
  23. Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex. Frobøse, H., Rønn, S.G., Heding, P.E., Mendoza, H., Cohen, P., Mandrup-Poulsen, T., Billestrup, N. Mol. Endocrinol. (2006) [Pubmed]
  24. Reciprocal cross-talk between Nod2 and TAK1 signaling pathways. Chen, C.M., Gong, Y., Zhang, M., Chen, J.J. J. Biol. Chem. (2004) [Pubmed]
  25. Effect of inositol hexakisphosphate kinase 2 on transforming growth factor beta-activated kinase 1 and NF-kappaB activation. Morrison, B.H., Bauer, J.A., Lupica, J.A., Tang, Z., Schmidt, H., DiDonato, J.A., Lindner, D.J. J. Biol. Chem. (2007) [Pubmed]
  26. TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop. Kishimoto, K., Matsumoto, K., Ninomiya-Tsuji, J. J. Biol. Chem. (2000) [Pubmed]
  27. TAK1 MAPK Kinase Kinase Mediates Transforming Growth Factor-beta Signaling by Targeting SnoN Oncoprotein for Degradation. Kajino, T., Omori, E., Ishii, S., Matsumoto, K., Ninomiya-Tsuji, J. J. Biol. Chem. (2007) [Pubmed]
  28. TGF-beta-activated kinase 1 stimulates NF-kappa B activation by an NF-kappa B-inducing kinase-independent mechanism. Sakurai, H., Shigemori, N., Hasegawa, K., Sugita, T. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  29. Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1. Sakurai, H., Miyoshi, H., Mizukami, J., Sugita, T. FEBS Lett. (2000) [Pubmed]
  30. Regulation of the TAK1 signaling pathway by protein phosphatase 2C. Hanada, M., Ninomiya-Tsuji, J., Komaki , K., Ohnishi, M., Katsura, K., Kanamaru, R., Matsumoto, K., Tamura, S. J. Biol. Chem. (2001) [Pubmed]
  31. Constitutive activation of TAK1 by HTLV-1 tax-dependent overexpression of TAB2 induces activation of JNK-ATF2 but not IKK-NF-kappaB. Suzuki, S., Singhirunnusorn, P., Mori, A., Yamaoka, S., Kitajima, I., Saiki, I., Sakurai, H. J. Biol. Chem. (2007) [Pubmed]
  32. TAB4 stimulates TAK1-TAB1 phosphorylation and binds polyubiquitin to direct signaling to NF-kappaB. Prickett, T.D., Ninomiya-Tsuji, J., Broglie, P., Muratore-Schroeder, T.L., Shabanowitz, J., Hunt, D.F., Brautigan, D.L. J. Biol. Chem. (2008) [Pubmed]
  33. Raf kinase inhibitor protein interacts with NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation. Yeung, K.C., Rose, D.W., Dhillon, A.S., Yaros, D., Gustafsson, M., Chatterjee, D., McFerran, B., Wyche, J., Kolch, W., Sedivy, J.M. Mol. Cell. Biol. (2001) [Pubmed]
  34. A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. Moriguchi, T., Kuroyanagi, N., Yamaguchi, K., Gotoh, Y., Irie, K., Kano, T., Shirakabe, K., Muro, Y., Shibuya, H., Matsumoto, K., Nishida, E., Hagiwara, M. J. Biol. Chem. (1996) [Pubmed]
  35. TAK1: Another mesh in the NF-κB - JNK controlled network causing hepatocellular carcinoma. Greten, F.R. J. Hepatol. (2011) [Pubmed]
  36. Regulation of c-Jun N-terminal kinase by MEKK-2 and mitogen-activated protein kinase kinase kinases in rheumatoid arthritis. Hammaker, D.R., Boyle, D.L., Chabaud-Riou, M., Firestein, G.S. J. Immunol. (2004) [Pubmed]
  37. TAK1 downregulation reduces IL-1beta induced expression of MMP13, MMP1 and TNF-alpha. Klatt, A.R., Klinger, G., Neumüller, O., Eidenmüller, B., Wagner, I., Achenbach, T., Aigner, T., Bartnik, E. Biomed. Pharmacother. (2006) [Pubmed]
  38. TIP27: a novel repressor of the nuclear orphan receptor TAK1/TR4. Nakajima, T., Fujino, S., Nakanishi, G., Kim, Y.S., Jetten, A.M. Nucleic Acids Res. (2004) [Pubmed]
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