MAP3K7 (original) (raw)

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Protein-coding gene in the species Homo sapiens

MAP3K7
Available structuresPDBOrtholog search: PDBe RCSB List of PDB id codes2EVA, 2YIY, 4GS6, 4L3P, 4L52, 4L53, 4O91, 5JGD, 5JGA
Identifiers
Aliases MAP3K7, MEKK7, TAK1, TGF1a, mitogen-activated protein kinase kinase kinase 7, FMD2, CSCF
External IDs OMIM: 602614; MGI: 1346877; HomoloGene: 135715; GeneCards: MAP3K7; OMA:MAP3K7 - orthologs
Gene location (Human)Chromosome 6 (human)Chr.Chromosome 6 (human)[1]Chromosome 6 (human)Genomic location for MAP3K7Genomic location for MAP3K7Band6q15Start90,513,573 bp[1]End90,587,072 bp[1]
Gene location (Mouse)Chromosome 4 (mouse)Chr.Chromosome 4 (mouse)[2]Chromosome 4 (mouse)Genomic location for MAP3K7Genomic location for MAP3K7Band4|4 A5Start31,964,097 bp[2]End32,023,467 bp[2]
RNA expression patternBgeeHuman Mouse (ortholog)Top expressed intendon of biceps brachiicorpus epididymisinternal globus pallidusstromal cell of endometriumtail of epididymiscaput epididymisganglionic eminencecorpus callosumBrodmann area 23Achilles tendonTop expressed ingenital tubercletail of embryoPaneth cellmolaraortic valveventricular zonemaxillary prominencesomitevastus lateralis musclemandibular prominenceMore reference expression dataBioGPSMore reference expression data
Gene ontologyMolecular function transferase activity protein kinase activity nucleotide binding scaffold protein binding metal ion binding kinase activity protein serine/threonine kinase activity protein binding ATP binding magnesium ion binding MAP kinase kinase kinase activity identical protein binding receptor tyrosine kinase binding Cellular component cytosol membrane plasma membrane endosome membrane nucleus IkappaB kinase complex cytoplasm Biological process regulation of transcription, DNA-templated phosphorylation positive regulation of JUN kinase activity stimulatory C-type lectin receptor signaling pathway activation of NF-kappaB-inducing kinase activity I-kappaB phosphorylation MyD88-dependent toll-like receptor signaling pathway transcription, DNA-templated Fc-epsilon receptor signaling pathway protein phosphorylation JNK cascade positive regulation of T cell activation positive regulation of NF-kappaB transcription factor activity positive regulation of interleukin-2 production positive regulation of T cell cytokine production histone H3 acetylation positive regulation of I-kappaB kinase/NF-kappaB signaling I-kappaB kinase/NF-kappaB signaling transforming growth factor beta receptor signaling pathway T cell receptor signaling pathway nucleotide-binding oligomerization domain containing signaling pathway signal transduction apoptotic process Wnt signaling pathway, calcium modulating pathway stress-activated MAPK cascade positive regulation of macroautophagy protein deubiquitination anoikis MyD88-independent toll-like receptor signaling pathway viral process interleukin-1-mediated signaling pathway Sources:Amigo / QuickGO
OrthologsSpeciesHuman MouseEntrez688526409EnsemblENSG00000135341ENSMUSG00000028284UniProtO43318Q62073RefSeq (mRNA)NM_003188NM_145331NM_145332NM_145333NM_009316NM_172688RefSeq (protein)NP_003179NP_663304NP_663305NP_663306NP_033342NP_766276Location (UCSC)Chr 6: 90.51 – 90.59 MbChr 4: 31.96 – 32.02 MbPubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is an enzyme that in humans is encoded by the MAP3K7 gene.[5]

TAK1 is an evolutionarily conserved kinase in the MAP3 K family and clusters with the tyrosine-like and sterile kinase families. The protein structure of TAK1 contains an N (residues 1–104)- and C (residues 111–303)-terminus connected through the hinge region (Met 104-Ser 111). The ATP binding pocket is located in the hinge region of the kinase. Additionally, TAK1 has a catalytic lysine (Lys63) in the active site. Crystal structure of TAK1-ATP have shown that ATP forms two hydrogen bonds with residues Ala 107 and Glu 105. Further hydrogen bonding is observed to Asp 175, which is the leading residue of the DFG motif. This residue is thought to interact with Lys 63 through polar interactions and is catalytically important for phosphate transfer to substrate molecules. Critical for the TAK1-TAB1 complex is a helical loop around Phe 484, which provides extensive surface contact between the two proteins.

The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase mediates signal transduction induced by TGF beta and morphogenetic protein (BMP), and controls a variety of cell functions including transcription regulation and apoptosis. TAK1 is a central regulator of cell death and is activated through a diverse set of intra- and extracellular stimuli. TAK1 regulates cell survival not solely through NF-κB but also through NF-κB-independent pathways such as oxidative stress and receptor-interacting protein kinase 1 (RIPK1) kinase activity-dependent pathway.[6] In response to IL-1, this protein forms a kinase complex including TRAF6, MAP3K7P1/TAB1 and MAP3K7P2/TAB2; this complex is required for the activation of nuclear factor kappa B. This kinase can also activate MAPK8/JNK, MAP2K4/MKK4, and thus plays a role in the cell response to environmental stresses. Four alternatively spliced transcript variants encoding distinct isoforms have been reported.[7]]

In addition to IL-1 agonist activation, TAK1has been shown to be activated following TNF, TGFB, and LPS stimulation leading to the activation of pro-inflammatory pathways. Following TNF stimulation, TAK1 forms a ternary structure with TAB1 and TAB2/3 to form a fully activated TAK1 kinase. Following activation, TAK1 phosphorylates downstream effectors such as NFKB, p38 and cJUN leading the up-regulation of pro inflammatory pro survival genes.

Role in autoimmune diseases

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This kinase has also been shown to regulate downstream cytokine expression such as TNF. Due to its regulation of TNF, TAK1 has become a novel target for the treatment of TNF mediated diseases such as auto immune disease ( Rheumatoid Arthritis, lupus, IBD) but also other cytokine mediated disorders such as chronic pain and cancer.[8][9] With the advent of novel selective TAK1 inhibitors, groups have explored the therapeutic potential of TAK1 targeted therapies. One group has shown that the selective TAK1 inhibitor, Takinib developed at Duke University attenuated rheumatoid arthritis like pathology in the CIA mouse model of human inflammatory arthritis.[10] Furthermore, pharmacological inhibition of TAK1 has shown to reduce inflammatory cytokines in particular TNF.[11]

A rare mutation in TAK1 in humans has been reported. The mutation leads to gain of function, and hyper activation of TAK1 signaling pathways. Patients with gain of function mutations often present with craniofacial abnormalities.

MAP3K7 has been shown to interact with:

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000135341 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028284 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  7. ^ "Entrez Gene: MAP3K7 mitogen-activated protein kinase kinase kinase 7".
  8. ^ Scarneo, Scott, Xin Zhang, Yaomin Wang, Jose Camacho-Domenech, Jennifer Ricano, Philip Hughes, Tim Haystead, and Andrea G. Nackley. "Transforming growth factor-β-activated kinase 1 (TAK1) mediates chronic pain and cytokine production in mouse models of inflammatory, neuropathic, and primary pain." The Journal of Pain (2023).
  9. ^ Scarneo, S. A., Yang, K. W., Roques, J. R., Dai, A., Eibschutz, L. S., Hughes, P., & Haystead, T. A. (2020). TAK1 regulates the tumor microenvironment through inflammatory, angiogenetic and apoptotic signaling cascades. Oncotarget, 11(21), 1961.
  10. ^ Scarneo, S. A., Eibschutz, L. S., Bendele, P. J., Yang, K. W., Totzke, J., Hughes, P., ... & Haystead, T. A. (2019). Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice. Arthritis Research & Therapy, 21(1), 1-10.
  11. ^ Scarneo, S. A., Mansourati, A., Eibschutz, L. S., Totzke, J., Roques, J. R., Loiselle, D., ... & Haystead, T. A. (2018). Genetic and pharmacological validation of TAK1 inhibition in macrophages as a therapeutic strategy to effectively inhibit TNF secretion. Scientific reports, 8(1), 1-11.
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  14. ^ Sakurai H, Miyoshi H, Toriumi W, Sugita T (April 1999). "Functional interactions of transforming growth factor beta-activated kinase 1 with IkappaB kinases to stimulate NF-kappaB activation". J. Biol. Chem. 274 (15): 10641–10648. doi:10.1074/jbc.274.15.10641. PMID 10187861.
  15. ^ a b Sakurai H, Miyoshi H, Mizukami J, Sugita T (June 2000). "Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1". FEBS Lett. 474 (2–3): 141–145. doi:10.1016/s0014-5793(00)01588-x. PMID 10838074. S2CID 30831863.
  16. ^ a b c Ishitani T, Takaesu G, Ninomiya-Tsuji J, Shibuya H, Gaynor RB, Matsumoto K (December 2003). "Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling". EMBO J. 22 (23): 6277–6288. doi:10.1093/emboj/cdg605. PMC 291846. PMID 14633987.
  17. ^ Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ (July 2001). "TAK1 is a ubiquitin-dependent kinase of MKK and IKK". Nature. 412 (6844): 346–351. Bibcode:2001Natur.412..346W. doi:10.1038/35085597. PMID 11460167. S2CID 9641806.
  18. ^ a b c Cheung PC, Nebreda AR, Cohen P (February 2004). "TAB3, a new binding partner of the protein kinase TAK1". Biochem. J. 378 (Pt 1): 27–34. doi:10.1042/BJ20031794. PMC 1223947. PMID 14670075.
  19. ^ Channavajhala PL, Wu L, Cuozzo JW, Hall JP, Liu W, Lin LL, Zhang Y (November 2003). "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 (47): 47089–47097. doi:10.1074/jbc.M306002200. PMID 12975377.
  20. ^ a b Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, Ninomiya-Tsuji J, Matsumoto K (April 2000). "TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway". Mol. Cell. 5 (4): 649–658. doi:10.1016/s1097-2765(00)80244-0. PMID 10882101.
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  22. ^ Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T (June 2000). "BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6". J. Biol. Chem. 275 (23): 17647–17652. doi:10.1074/jbc.M908622199. PMID 10748100.
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