Browse > Article
http://dx.doi.org/10.5483/BMBRep.2015.48.8.225

An inhibitory role of NEK6 in TGFβ/Smad signaling pathway  

Zuo, Jie (State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University)
Ma, Haijie (Cell and Molecular Biology Laboratory, Zhoushan Hospital)
Cai, Hao (State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University)
Wu, Yanhua (State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University)
Jiang, Wei (State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University)
Yu, Long (State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University)
Publication Information
BMB Reports / v.48, no.8, 2015 , pp. 473-478 More about this Journal
Abstract
The NEK6 (NIMA-related kinases 6) is reported to play po-tential roles in tumorigenesis. Although it is suggested to function in several cellular pathways, the underlying mechanism in tumorigenesis is still largely unknown. In the present study, we discovered interaction of NEK6 with Smad4, a key member of transforming growth factor beta (TGFβ) pathway. Over-expression of NEK6 in hepatocellular carcinoma (HCC) cell lines suppresses TGFβ-mediated transcription activity in a kinase activity-dependent manner. In addition, NEK6 suppresses the cell growth arrest induced by TGFβ. Mechanically, NEK6 blocks nuclear translocation of Smad4, which is essential for TGFβ function. Moreover, we identified that NEK6 could be regulated by TGFβ and hypoxia. Our study sheds new light on the roles of NEK6 in canonical TGFβ/Smad pathway and tum-origenesis. [BMB Reports 2015; 48(8): 473-478]
Keywords
NEK6; Nuclear translocation; Smad4; TGFβ; Transcription;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Chen J, Li L, Zhang Y et al (2006) Interaction of Pin1 with Nek6 and characterization of their expression correlation in Chinese hepatocellular carcinoma patients. Biochem Biophys Res Commun 341, 1059-1065   DOI
2 Inman GJ (2011) Switching TGFbeta from a tumor suppressor to a tumor promoter. Curr Opin Genet Dev 21, 93-99   DOI
3 O'Regan L and Fry AM (2009) The Nek6 and Nek7 protein kinases are required for robust mitotic spindle formation and cytokinesis. Mol Cell Biol 29, 3975-3990   DOI
4 Barrios-Rodiles M, Brown KR, Ozdamar B et al (2005) High-throughput mapping of a dynamic signaling network in mammalian cells. Science 307, 1621-1625   DOI
5 Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S and Gauthier JM (1998) Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 17, 3091-3100   DOI
6 Lee KY and Bae SC (2002) TGF-beta-dependent cell growth arrest and apoptosis. J Biochem Mol Biol 35, 47-53   DOI
7 Zhang W, Ou J, Inagaki Y, Greenwel P and Ramirez F (2000) Synergistic cooperation between Sp1 and Smad3/Smad4 mediates transforming growth factor beta1 stimulation of alpha 2(I)-collagen (COL1A2) transcription. J Biol Chem 275, 39237-39245   DOI
8 Nakao A, Afrakhte M, Morén A et al (1997) Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 389, 631-635   DOI
9 Jeon YJ, Lee KY and Cho YY (2010) Role of NEK6 in tumor promoter-induced transformation in JB6 C141 mouse skin epidermal cells. J Biol Chem 285, 28126-28133   DOI
10 Massagué J (1996) TGFbeta signaling: receptors, transducers, and Mad proteins. Cell 85, 947-950   DOI
11 Höckel M and Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93, 266-276   DOI
12 O'Connell MJ, Krien MJ and Hunter T (2003) Never say never. The NIMA-related protein kinases in mitotic control. Trends Cell Biol 13, 221-228   DOI
13 Belham C, Roig J, Caldwell JA et al (2003) A mitotic cascade of NIMA family kinases. Nercc1/Nek9 activates the Nek6 and Nek7 kinases. J Biol Chem 278, 34897-34909   DOI
14 Lee MY, Kim HJ, Kim MA et al (2008) Nek6 is involved in G2/M phase cell cycle arrest through DNA damage-induced phosphorylation. Cell Cycle 7, 2705-2709   DOI
15 Jee HJ, Kim AJ, Song N et al (2010) Nek6 overexpression antagonizes p53-induced senescence in human cancer cells. Cell Cycle 9, 4703-4710   DOI
16 Nassirpour R, Shao L, Flanagan P et al (2010) Nek6 mediates human cancer cell transformation and is a potential cancer therapeutic target. Mol Cancer Res 8, 717-728   DOI
17 Jee HJ, Kim HJ, Kim AJ, Song N, Kim M and Yun J (2011) Nek6 suppresses the premature senescence of human cancer cells induced by camptothecin and doxorubicin treatment. Biochem Biophys Res Commun 408, 669-673   DOI
18 Takeno A, Takemasa I, Doki Y et al (2008) Integrative approach for differentially overexpressed genes in gastric cancer by combining large-scale gene expression profiling and network analysis. Br J Cancer 99, 1307-1315   DOI
19 Cao X, Xia Y, Yang J et al (2012) Clinical and biological significance of never in mitosis gene A-related kinase 6 (NEK6) expression in hepatic cell cancer. Pathol Oncol Res 18, 201-207   DOI