5d7a | pdb_00005d7a

Crystal structure of the kinase domain of TRAF2 and NCK-interacting protein kinase with NCB-0846

Structural highlights

5d7a is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.9Å
Ligands:	58C, SO4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TNIK_HUMAN Serine/threonine kinase that acts as an essential activator of the Wnt signaling pathway. Recruited to promoters of Wnt target genes and required to activate their expression. May act by phosphorylating TCF4/TCF7L2. Appears to act upstream of the JUN N-terminal pathway. May play a role in the response to environmental stress. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. More generally, it may play a role in cytoskeletal rearrangements and regulate cell spreading. Phosphorylates SMAD1 on Thr-322.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Canonical Wnt/beta-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and beta-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik(-/-)/Apc(min/+) mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apc(min/+) mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach.

TNIK inhibition abrogates colorectal cancer stemness.,Masuda M, Uno Y, Ohbayashi N, Ohata H, Mimata A, Kukimoto-Niino M, Moriyama H, Kashimoto S, Inoue T, Goto N, Okamoto K, Shirouzu M, Sawa M, Yamada T Nat Commun. 2016 Aug 26;7:12586. doi: 10.1038/ncomms12586. PMID:27562646^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Fu CA, Shen M, Huang BC, Lasaga J, Payan DG, Luo Y. TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton. J Biol Chem. 1999 Oct 22;274(43):30729-37. PMID:10521462
↑ Taira K, Umikawa M, Takei K, Myagmar BE, Shinzato M, Machida N, Uezato H, Nonaka S, Kariya K. The Traf2- and Nck-interacting kinase as a putative effector of Rap2 to regulate actin cytoskeleton. J Biol Chem. 2004 Nov 19;279(47):49488-96. Epub 2004 Sep 1. PMID:15342639 doi:10.1074/jbc.M406370200
↑ Uechi Y, Bayarjargal M, Umikawa M, Oshiro M, Takei K, Yamashiro Y, Asato T, Endo S, Misaki R, Taguchi T, Kariya K. Rap2 function requires palmitoylation and recycling endosome localization. Biochem Biophys Res Commun. 2009 Jan 23;378(4):732-7. doi:, 10.1016/j.bbrc.2008.11.107. Epub 2008 Dec 4. PMID:19061864 doi:https://dx.doi.org/10.1016/j.bbrc.2008.11.107
↑ Mahmoudi T, Li VS, Ng SS, Taouatas N, Vries RG, Mohammed S, Heck AJ, Clevers H. The kinase TNIK is an essential activator of Wnt target genes. EMBO J. 2009 Nov 4;28(21):3329-40. doi: 10.1038/emboj.2009.285. Epub 2009 Oct 8. PMID:19816403 doi:https://dx.doi.org/10.1038/emboj.2009.285
↑ Kawabe H, Neeb A, Dimova K, Young SM Jr, Takeda M, Katsurabayashi S, Mitkovski M, Malakhova OA, Zhang DE, Umikawa M, Kariya K, Goebbels S, Nave KA, Rosenmund C, Jahn O, Rhee J, Brose N. Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development. Neuron. 2010 Feb 11;65(3):358-72. doi: 10.1016/j.neuron.2010.01.007. PMID:20159449 doi:10.1016/j.neuron.2010.01.007
↑ Kaneko S, Chen X, Lu P, Yao X, Wright TG, Rajurkar M, Kariya K, Mao J, Ip YT, Xu L. Smad inhibition by the Ste20 kinase Misshapen. Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11127-32. doi:, 10.1073/pnas.1104128108. Epub 2011 Jun 20. PMID:21690388 doi:https://dx.doi.org/10.1073/pnas.1104128108
↑ Masuda M, Uno Y, Ohbayashi N, Ohata H, Mimata A, Kukimoto-Niino M, Moriyama H, Kashimoto S, Inoue T, Goto N, Okamoto K, Shirouzu M, Sawa M, Yamada T. TNIK inhibition abrogates colorectal cancer stemness. Nat Commun. 2016 Aug 26;7:12586. doi: 10.1038/ncomms12586. PMID:27562646 doi:https://dx.doi.org/10.1038/ncomms12586

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OCA

[1] Fu CA, Shen M, Huang BC, Lasaga J, Payan DG, Luo Y. TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton. J Biol Chem. 1999 Oct 22;274(43):30729-37. PMID:10521462

[2] Taira K, Umikawa M, Takei K, Myagmar BE, Shinzato M, Machida N, Uezato H, Nonaka S, Kariya K. The Traf2- and Nck-interacting kinase as a putative effector of Rap2 to regulate actin cytoskeleton. J Biol Chem. 2004 Nov 19;279(47):49488-96. Epub 2004 Sep 1. PMID:15342639 doi:10.1074/jbc.M406370200

[3] Uechi Y, Bayarjargal M, Umikawa M, Oshiro M, Takei K, Yamashiro Y, Asato T, Endo S, Misaki R, Taguchi T, Kariya K. Rap2 function requires palmitoylation and recycling endosome localization. Biochem Biophys Res Commun. 2009 Jan 23;378(4):732-7. doi:, 10.1016/j.bbrc.2008.11.107. Epub 2008 Dec 4. PMID:19061864 doi:https://dx.doi.org/10.1016/j.bbrc.2008.11.107

[4] Mahmoudi T, Li VS, Ng SS, Taouatas N, Vries RG, Mohammed S, Heck AJ, Clevers H. The kinase TNIK is an essential activator of Wnt target genes. EMBO J. 2009 Nov 4;28(21):3329-40. doi: 10.1038/emboj.2009.285. Epub 2009 Oct 8. PMID:19816403 doi:https://dx.doi.org/10.1038/emboj.2009.285

[5] Kawabe H, Neeb A, Dimova K, Young SM Jr, Takeda M, Katsurabayashi S, Mitkovski M, Malakhova OA, Zhang DE, Umikawa M, Kariya K, Goebbels S, Nave KA, Rosenmund C, Jahn O, Rhee J, Brose N. Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development. Neuron. 2010 Feb 11;65(3):358-72. doi: 10.1016/j.neuron.2010.01.007. PMID:20159449 doi:10.1016/j.neuron.2010.01.007

[6] Kaneko S, Chen X, Lu P, Yao X, Wright TG, Rajurkar M, Kariya K, Mao J, Ip YT, Xu L. Smad inhibition by the Ste20 kinase Misshapen. Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11127-32. doi:, 10.1073/pnas.1104128108. Epub 2011 Jun 20. PMID:21690388 doi:https://dx.doi.org/10.1073/pnas.1104128108

[7] Masuda M, Uno Y, Ohbayashi N, Ohata H, Mimata A, Kukimoto-Niino M, Moriyama H, Kashimoto S, Inoue T, Goto N, Okamoto K, Shirouzu M, Sawa M, Yamada T. TNIK inhibition abrogates colorectal cancer stemness. Nat Commun. 2016 Aug 26;7:12586. doi: 10.1038/ncomms12586. PMID:27562646 doi:https://dx.doi.org/10.1038/ncomms12586

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5d7a | pdb_00005d7a

Crystal structure of the kinase domain of TRAF2 and NCK-interacting protein kinase with NCB-0846

Structural highlights

Function

Publication Abstract from PubMed

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References

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