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PMID: 20194509 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

TAB2 scaffolds TAK1 and NLK in repressing canonical Wnt signaling.

The Journal of biological chemistry ·Vol. 285 ·No. 18 ·2010-04-30 ·Pages 13397-404

Li M, Wang H, Huang T, Wang J, Ding Y, Li Z, Zhang J, Li L

Abstract

The TAK1-NLK cascade is a mitogen-activated protein kinase-related pathway that plays an inhibitory role in canonical Wnt/beta-catenin signaling through regulating the LEF1/TCF family transcriptional factors. TAB2 (TAK1-binding protein 2) is a putative TAK1 interacting protein that is involved in the regulation of TAK1. Here, we found that TAB2 could directly interact with NLK and function as a scaffold protein to facilitate the interaction between TAK1 and NLK. Knocking down TAB2 using small interfering RNA abolished the interaction of TAK1 with NLK in mammalian cells. The intermediate region (residues 292-417) of TAB2 was mapped for its binding to NLK. TAB2-DeltaM, a TAB2 mutant lacking this region, showed a lower affinity for NLK and became defective in its scaffolding function. In addition, TAB2, but not TAB2-DeltaM, mediated TAK1-dependent activation of NLK and LEF1 polyubiquitylation, resulting in the inhibition of canonical Wnt signaling. Moreover, Wnt3a stimulation led to an increase in the interaction of TAB2 with NLK and the formation of a TAK1.TAB2.NLK complex, suggesting that this TAK1-TAB2-NLK pathway may constitute a negative feedback mechanism for canonical Wnt signaling.

MeSH Terms
Adaptor Proteins, Signal Transducing/genetics,metabolism Animals Cell Line Gene Knockdown Techniques Humans MAP Kinase Kinase Kinases/genetics,metabolism Mice Mitogen-Activated Protein Kinases/genetics,metabolism Multiprotein Complexes/genetics,metabolism Mutation Protein Serine-Threonine Kinases Signal Transduction/physiology Wnt Proteins/genetics,metabolism Wnt3 Protein Wnt3A Protein beta Catenin/genetics,metabolism
Chemicals
Adaptor Proteins, Signal Transducing Multiprotein Complexes Tab2 protein, mouse WNT3A protein, human Wnt Proteins Wnt3 Protein Wnt3A Protein Wnt3a protein, mouse beta Catenin Nlk protein, mouse Protein Serine-Threonine Kinases Mitogen-Activated Protein Kinases MAP Kinase Kinase Kinases MAP kinase kinase kinase 7
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Li Meng
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Wang He
Huang Tao
Wang Jiyong
Ding Yu
Li Zhenfei
Zhang Jinkuo
Li Lin
References (52)
52 references, click to expand
  1. TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway.
    Mol Cell. 2000 Apr;5(4):649-58 PMID: 10882101
  2. Nlk is a murine protein kinase related to Erk/MAP kinases and localized in the nucleus.
    Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):963-8 PMID: 9448268
  3. TAK1 mediates an activation signal from toll-like receptor(s) to nuclear factor-kappaB in lipopolysaccharide-stimulated macrophages.
    FEBS Lett. 2000 Feb 11;467(2-3):160-4 PMID: 10675530
  4. Gene profiling during neural induction in Xenopus laevis: regulation of BMP signaling by post-transcriptional mechanisms and TAB3, a novel TAK1-binding protein.
    Development. 2002 Dec;129(23):5529-40 PMID: 12403722
  5. Elevated expression of axin2 and hnkd mRNA provides evidence that Wnt/beta -catenin signaling is activated in human colon tumors.
    Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14973-8 PMID: 11752446
  6. Identification of zinc-finger BED domain-containing 3 (Zbed3) as a novel Axin-interacting protein that activates Wnt/beta-catenin signaling.
    J Biol Chem. 2009 Mar 13;284(11):6683-9 PMID: 19141611
  7. nemo-like kinase is an essential co-activator of Wnt signaling during early zebrafish development.
    Development. 2004 Jun;131(12):2899-909 PMID: 15151990
  8. The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway.
    Nature. 1999 Mar 18;398(6724):252-6 PMID: 10094049
  9. Atypical mitogen-activated protein kinases: structure, regulation and functions.
    Biochim Biophys Acta. 2007 Aug;1773(8):1376-87 PMID: 17161475
  10. The Wnt signaling pathway in development and disease.
    Annu Rev Cell Dev Biol. 2004;20:781-810 PMID: 15473860
  11. Role of the TAK1-NLK-STAT3 pathway in TGF-beta-mediated mesoderm induction.
    Genes Dev. 2004 Feb 15;18(4):381-6 PMID: 15004007
  12. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling.
    Dev Cell. 2003 Sep;5(3):367-77 PMID: 12967557
  13. Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK.
    Genes Dev. 2004 Apr 1;18(7):816-29 PMID: 15082531
  14. Wnt/beta-catenin signaling in development and disease.
    Cell. 2006 Nov 3;127(3):469-80 PMID: 17081971
  15. TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains.
    Mol Cell. 2004 Aug 27;15(4):535-48 PMID: 15327770
  16. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors.
    J Biol Chem. 2006 Aug 11;281(32):22429-33 PMID: 16793760
  17. WNT and beta-catenin signalling: diseases and therapies.
    Nat Rev Genet. 2004 Sep;5(9):691-701 PMID: 15372092
  18. Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling.
    EMBO J. 2003 Dec 1;22(23):6277-88 PMID: 14633987
  19. NARF, an nemo-like kinase (NLK)-associated ring finger protein regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF).
    J Biol Chem. 2006 Jul 28;281(30):20749-20760 PMID: 16714285
  20. Involvement of NLK and Sox11 in neural induction in Xenopus development.
    Genes Cells. 2002 May;7(5):487-96 PMID: 12047350
  21. Wnt activates the Tak1/Nemo-like kinase pathway.
    J Biol Chem. 2004 Apr 23;279(17):17232-40 PMID: 14960582
  22. TAK1-dependent signaling requires functional interaction with TAB2/TAB3.
    J Biol Chem. 2007 Feb 9;282(6):3918-28 PMID: 17158449
  23. Transcription under the control of nuclear Arm/beta-catenin.
    Curr Biol. 2006 May 23;16(10):R378-85 PMID: 16713950
  24. Direct activation of protein kinases by unanchored polyubiquitin chains.
    Nature. 2009 Sep 3;461(7260):114-9 PMID: 19675569
  25. Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO.
    Mol Cell. 2006 Apr 21;22(2):245-57 PMID: 16603398
  26. RelA suppresses the Wnt/beta-catenin pathway without exerting trans-acting transcriptional ability.
    Int J Mol Med. 2002 May;9(5):489-93 PMID: 11956654
  27. Nemo-like kinase (NLK) acts downstream of Notch/Delta signalling to downregulate TCF during mesoderm induction in the sea urchin embryo.
    Development. 2006 Nov;133(21):4341-53 PMID: 17038519
  28. STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFbeta-activated kinase 1 for STAT3 Ser-727 phosphorylation.
    Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4524-9 PMID: 15764709
  29. Cross-regulation of the Wnt signalling pathway: a role of MAP kinases.
    J Cell Sci. 2000 Mar;113 ( Pt 6):911-9 PMID: 10683140
  30. An evolutionarily conserved motif in the TAB1 C-terminal region is necessary for interaction with and activation of TAK1 MAPKKK.
    J Biol Chem. 2001 Jun 29;276(26):24396-400 PMID: 11323434
  31. TAK1 is a ubiquitin-dependent kinase of MKK and IKK.
    Nature. 2001 Jul 19;412(6844):346-51 PMID: 11460167
  32. The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF.
    Nature. 1999 Jun 24;399(6738):798-802 PMID: 10391247
  33. A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation.
    Nat Cell Biol. 2007 Nov;9(11):1273-85 PMID: 17952062
  34. Interleukin-1 (IL-1) receptor-associated kinase leads to activation of TAK1 by inducing TAB2 translocation in the IL-1 signaling pathway.
    Mol Cell Biol. 2001 Apr;21(7):2475-84 PMID: 11259596
  35. Regulation of MAP kinase signaling modules by scaffold proteins in mammals.
    Annu Rev Cell Dev Biol. 2003;19:91-118 PMID: 14570565
  36. Nemo is an inducible antagonist of Wingless signaling during Drosophila wing development.
    Development. 2004 Jun;131(12):2911-20 PMID: 15169756
  37. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction.
    Science. 1995 Dec 22;270(5244):2008-11 PMID: 8533096
  38. The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling.
    Mol Cell Biol. 2003 Jan;23(1):131-9 PMID: 12482967
  39. TAB3, a new binding partner of the protein kinase TAK1.
    Biochem J. 2004 Feb 15;378(Pt 1):27-34 PMID: 14670075
  40. Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling.
    Nat Genet. 2000 Oct;26(2):146-7 PMID: 11017067
  41. Wnt signalling in stem cells and cancer.
    Nature. 2005 Apr 14;434(7035):843-50 PMID: 15829953
  42. Wnt signaling inside the nucleus.
    Cancer Sci. 2008 Apr;99(4):631-7 PMID: 18177486
  43. Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphorylation in Wnt/beta-catenin signaling.
    Mol Cell Biol. 2003 Feb;23(4):1379-89 PMID: 12556497
  44. Interaction between TAK1-TAB1-TAB2 and RCAN1-calcineurin defines a signalling nodal control point.
    Nat Cell Biol. 2009 Feb;11(2):154-61 PMID: 19136967
  45. Nuclear Dvl, c-Jun, beta-catenin, and TCF form a complex leading to stabilization of beta-catenin-TCF interaction.
    J Cell Biol. 2008 Mar 24;180(6):1087-100 PMID: 18347071
  46. Scaffold proteins of MAP-kinase modules.
    Oncogene. 2007 May 14;26(22):3185-202 PMID: 17496915
  47. MOM-4, a MAP kinase kinase kinase-related protein, activates WRM-1/LIT-1 kinase to transduce anterior/posterior polarity signals in C. elegans.
    Mol Cell. 1999 Aug;4(2):275-80 PMID: 10488343
  48. Scaffold proteins in MAP kinase signaling: more than simple passive activating platforms.
    Bioessays. 2006 Feb;28(2):146-56 PMID: 16435292
  49. Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway.
    Mol Cell Biol. 2002 Feb;22(4):1172-83 PMID: 11809808
  50. Identification of a human NF-kappaB-activating protein, TAB3.
    Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2028-33 PMID: 14766965
  51. TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction.
    Science. 1996 May 24;272(5265):1179-82 PMID: 8638164
  52. MAP kinase and Wnt pathways converge to downregulate an HMG-domain repressor in Caenorhabditis elegans.
    Nature. 1999 Jun 24;399(6738):793-7 PMID: 10391246
Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M109.083246
Published
2010-04-30
Epub
2010-00-01
Pages
13397-404
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2859499
Subset
IM
External Links
PubMed source DOI: 10.1074/jbc.M109.083246 PMC Full Text View journal details
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