Tumor Biology

, Volume 36, Issue 10, pp 7873–7879 | Cite as

LATS2 inhibits the activity of NF-κ B signaling by disrupting the interaction between TAK1 and IKKβ

  • Feng Yao
  • Weizheng Zhou
  • Chenxi Zhong
  • Wentao Fang
Research Article


NF-κB signaling plays very important role in the tumorigenesis of nonsmall cell lung cancer (NSCLC). However, the molecular mechanisms for the dysregulation of NF-κB signaling in NSCLC have not been fully understood. In the previous reports, we have showed that large tumor suppressor gene 2 (LATS2) inhibited NF-κB signaling in NSCLC cells, whereas the details for the mechanism remain unknown. Here, we reported that LATS2 is a suppressor of tumor necrosis factor (TNF-α)-induced NF-κB signaling by inhibiting the interaction between TAK1 and IKKβ. Overexpression of LATS2 largely blocked TNF-α-induced NF-κB activation and IκBα degradation, whereas knockdown of LATS2 showed the opposing results. Mechanistically, we identified that LATS2 interacted with IKKβ and blocked the interaction between IKKβ and TAK1. Our results indicate that LATS2 functions as a pivotal negative regulator in TNF-α-induced activation of NF-κB via disrupting the interaction of TAK1 with IKKβ.


Nonsmall cell lung cancer NF-κB signaling LATS2 IKK complex TAK1 TNF-α 



This work was supported by the National Natural Science Foundation of China (81201840), the Natural Science Foundation of Shanghai (13ZR1461300), the Health Bureau Foundation of Shanghai (20124Y152), and Chenxing Young Scholarship of Shanghai Jiaotong University.

Conflict of interest



  1. 1.
    Nair VS, Gevaert O, Davidzon G, Plevritis SK, West R. NF-kappaB protein expression associates with (18)F-FDG PET tumor uptake in non-small cell lung cancer: a radiogenomics validation study to understand tumor metabolism. Lung Cancer. 2014;83(2):189–96.CrossRefPubMedGoogle Scholar
  2. 2.
    Zhou B, Zuo Y, Li B, et al. Deubiquitinase inhibition of 19S regulatory particles by 4-arylidene curcumin analog AC17 causes NF-kappaB inhibition and p53 reactivation in human lung cancer cells. Mol Cancer Ther. 2012;12(8):1381–92.CrossRefGoogle Scholar
  3. 3.
    Palkowitsch L, Leidner J, Ghosh S, Marienfeld RB. Phosphorylation of serine 68 in the IkappaB kinase (IKK)-binding domain of NEMO interferes with the structure of the IKK complex and tumor necrosis factor-alpha-induced NF-kappaB activity. J Biol Chem. 2008;283(1):76–86.CrossRefPubMedGoogle Scholar
  4. 4.
    Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M. The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell. 1997;91(2):243–52.CrossRefPubMedGoogle Scholar
  5. 5.
    Wuerzberger-Davis SM, Miyamoto S. TAK-ling IKK activation: "Ub" the judge. Sci Signal. 2012;3(105):pe3.Google Scholar
  6. 6.
    Shinohara H, Yasuda T, Aiba Y, et al. PKC beta regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1. J Exp Med. 2005;202(10):1423–31.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Dan HC, Cooper MJ, Cogswell PC, Duncan JA, Ting JP, Baldwin AS. Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. Genes Dev. 2008;22(11):1490–500.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Factor V, Oliver AL, Panta GR, Thorgeirsson SS, Sonenshein GE, Arsura M. Roles of Akt/PKB and IKK complex in constitutive induction of NF-kappaB in hepatocellular carcinomas of transforming growth factor alpha/c-myc transgenic mice. Hepatology. 2001;34(1):32–41.CrossRefPubMedGoogle Scholar
  9. 9.
    Xu C, Shen G, Chen C, Gelinas C, Kong AN. Suppression of NF-kappaB and NF-kappaB-regulated gene expression by sulforaphane and PEITC through IkappaBalpha, IKK pathway in human prostate cancer PC-3 cells. Oncogene. 2005;24(28):4486–95.CrossRefPubMedGoogle Scholar
  10. 10.
    Gasparian AV, Yao YJ, Lu J, et al. Selenium compounds inhibit I kappa B kinase (IKK) and nuclear factor-kappa B (NF-kappa B) in prostate cancer cells. Mol Cancer Ther. 2002;1(12):1079–87.PubMedGoogle Scholar
  11. 11.
    Yao F, Liu H, Li Z, Zhong C, Fang W (2014) Down-regulation of LATS2 in non-small cell lung cancer promoted the growth and motility of cancer cells. Tumour Biol.Google Scholar
  12. 12.
    Gulen ST, Karadag F, Karul AB, et al. Adipokines and systemic inflammation in weight-losing lung cancer patients. Lung. 2012;190(3):327–32.CrossRefPubMedGoogle Scholar
  13. 13.
    Op den Kamp CM, Langen RC, Minnaard R, et al. Pre-cachexia in patients with stages I-III non-small cell lung cancer: systemic inflammation and functional impairment without activation of skeletal muscle ubiquitin proteasome system. Lung Cancer. 2013;76(1):112–7.CrossRefGoogle Scholar
  14. 14.
    Shiels MS, Engels EA, Shi J, et al. Genetic variation in innate immunity and inflammation pathways associated with lung cancer risk. Cancer. 2013;118(22):5630–6.CrossRefGoogle Scholar
  15. 15.
    Lau A, Kollara A, St John E, et al. Altered expression of inflammation-associated genes in oviductal cells following follicular fluid exposure: implications for ovarian carcinogenesis. Exp Biol Med (Maywood). 2013;239(1):24–32.CrossRefGoogle Scholar
  16. 16.
    Wang W, Li X, Zheng D, et al. Dynamic changes of peritoneal macrophages and subpopulations during ulcerative colitis to metastasis of colorectal carcinoma in a mouse model. Inflamm Res. 2014;62(7):669–80.CrossRefGoogle Scholar
  17. 17.
    Chakilam S, Gandesiri M, Rau TT, et al. Death-associated protein kinase controls STAT3 activity in intestinal epithelial cells. Am J Pathol. 2013;182(3):1005–20.CrossRefPubMedGoogle Scholar
  18. 18.
    Han J, Soletti RC, Sadarangani A, et al. Nuclear expression of beta-catenin promotes RB stability and resistance to TNF-induced apoptosis in colon cancer cells. Mol Cancer Res. 2013;11(3):207–18.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Yu FX, Mo JS, Guan KL. Upstream regulators of the Hippo pathway. Cell Cycle. 2012;11(22):4097–8.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Liu AM, Wong KF, Jiang X, Qiao Y, Luk JM. Regulators of mammalian Hippo pathway in cancer. Biochim Biophys Acta. 2012;1826(2):357–64.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Thoracic Surgery, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiChina
  2. 2.Department of Cardiothoracic Surgery, Changhai HospitalSecond Military Medical UniversityShanghaiChina

Personalised recommendations