Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

J. Cell Biol. 185 (6): 949-957

Copyright © 2009 by the Rockefeller University Press.


Report

Acetylation and activation of STAT3 mediated by nuclear translocation of CD44

Jia-Lin Lee1, Mei-Jung Wang1, , and Jeou-Yuan Chen1,2

1 Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, Republic of China
2 Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan, Republic of China

Correspondence to Jeou-Yuan Chen: bmchen{at}ibms.sinica.edu.tw

Abstract: Expression of the type I transmembrane glycoprotein CD44 has recently been recognized as a signature for cancer stem cells. In this study, we demonstrate that CD44, once engaged, is internalized and translocated to the nucleus, where it binds to various promoters, including that of cyclin D1, leading to cell fate change through transcriptional reprogramming. In regulating cyclin D1 expression, the internalized CD44 forms a complex with STAT3 and p300 (acetyltransferase), eliciting STAT3 acetylation at lysine 685 and dimer formation in a cytokine- and growth factor–independent manner. A bipartite nuclear localization signal (NLS) was mapped to the cytoplasmic tail of CD44, which mediates its nuclear translocation. Expression of CD44(NLS) mutant sequesters STAT3 in cytosol. In the nucleus, the acetylated STAT3 dimer remains associated with CD44 and binds to the cyclin D1 promoter, leading to increased cyclin D1 expression and cell proliferation. This study describes a novel function for CD44 in transcriptional modulation through nuclear translocation of the internalized CD44 and complex formation with transcription factors.


Abbreviations used in this paper: ChIP, chromatin IP; EMSA, electrophoretic mobility shift assay; H-3, Hermes-3; IP, immunoprecipitation; OPN, osteopontin; shRNA, short hairpin RNA; STAT, signal transducer and activator of transcription; WT, wild type.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Mesenchymal CD44 Expression Contributes to the Acquisition of an Activated Fibroblast Phenotype via TWIST Activation in the Tumor Microenvironment.
E. L. Spaeth, A. M. Labaff, B. P. Toole, A. Klopp, M. Andreeff, and F. C. Marini (2013)
Cancer Res. 73, 5347-5359
   Abstract »    Full Text »    PDF »
The Hyaluronic Acid Receptor CD44 Coordinates Normal and Metaplastic Gastric Epithelial Progenitor Cell Proliferation.
S. S. Khurana, T. E. Riehl, B. D. Moore, M. Fassan, M. Rugge, J. Romero-Gallo, J. Noto, R. M. Peek Jr., W. F. Stenson, and J. C. Mills (2013)
J. Biol. Chem. 288, 16085-16097
   Abstract »    Full Text »    PDF »
Small-Molecule Inhibitors of Acetyltransferase p300 Identified by High-Throughput Screening Are Potent Anticancer Agents.
H. Yang, C. E. Pinello, J. Luo, D. Li, Y. Wang, L. Y. Zhao, S. C. Jahn, S. A. Saldanha, J. Planck, K. R. Geary, et al. (2013)
Mol. Cancer Ther. 12, 610-620
   Abstract »    Full Text »    PDF »
CD44 integrates signaling in normal stem cell, cancer stem cell and (pre)metastatic niches.
K. Williams, K. Motiani, P. V. Giridhar, and S. Kasper (2013)
Experimental Biology and Medicine 238, 324-338
   Abstract »    Full Text »    PDF »
Global Quantitative Phosphoproteome Analysis of Human Tumor Xenografts Treated with a CD44 Antagonist.
S. Weigand, F. Herting, D. Maisel, A. Nopora, E. Voss, C. Schaab, M. Klammer, and A. Tebbe (2012)
Cancer Res. 72, 4329-4339
   Abstract »    Full Text »    PDF »
Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies.
P. Sansone and J. Bromberg (2012)
J. Clin. Oncol. 30, 1005-1014
   Abstract »    Full Text »    PDF »
MT1-MMP regulates the PI3K{delta}{middle dot}Mi-2/NuRD-dependent control of macrophage immune function.
R. Shimizu-Hirota, W. Xiong, B. T. Baxter, S. L. Kunkel, I. Maillard, X.-W. Chen, F. Sabeh, R. Liu, X.-Y. Li, and S. J. Weiss (2012)
Genes & Dev. 26, 395-413
   Abstract »    Full Text »    PDF »
STAT3 Negatively Regulates Type I IFN-Mediated Antiviral Response.
W.-B. Wang, D. E. Levy, and C.-K. Lee (2011)
J. Immunol. 187, 2578-2585
   Abstract »    Full Text »    PDF »
Direct reprogramming of stem cell properties in colon cancer cells by CD44.
Y.-J. Su, H.-M. Lai, Y.-W. Chang, G.-Y. Chen, and J.-L. Lee (2011)
EMBO J. 30, 3186-3199
   Abstract »    Full Text »    PDF »
Negative Regulation of STAT3 Protein-mediated Cellular Respiration by SIRT1 Protein.
M. Bernier, R. K. Paul, A. Martin-Montalvo, M. Scheibye-Knudsen, S. Song, H.-J. He, S. M. Armour, B. P. Hubbard, V. A. Bohr, L. Wang, et al. (2011)
J. Biol. Chem. 286, 19270-19279
   Abstract »    Full Text »    PDF »
Transportin Regulates Nuclear Import of CD44.
M. Janiszewska, C. De Vito, M.-A. Le Bitoux, C. Fusco, and I. Stamenkovic (2010)
J. Biol. Chem. 285, 30548-30557
   Abstract »    Full Text »    PDF »
NCAM-Induced Neurite Outgrowth Depends on Binding of Calmodulin to NCAM and on Nuclear Import of NCAM and fak Fragments.
R. Kleene, M. Mzoughi, G. Joshi, I. Kalus, U. Bormann, C. Schulze, M.-F. Xiao, A. Dityatev, and M. Schachner (2010)
J. Neurosci. 30, 10784-10798
   Abstract »    Full Text »    PDF »
Regulation of Copper Transporter 2 Expression by Copper and Cisplatin in Human Ovarian Carcinoma Cells.
B. G. Blair, C. A. Larson, P. L. Adams, P. B. Abada, R. Safaei, and S. B. Howell (2010)
Mol. Pharmacol. 77, 912-921
   Abstract »    Full Text »    PDF »
Acetylation and activation of STAT3 mediated by nuclear translocation of CD44.
J.-L. Lee, M.-J. Wang, and J.-Y. Chen (2009)
J. Exp. Med. 206, i12
   Full Text »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882