The Yes-associated protein controls the cell density regulation of Hedgehog signaling

被引:41
作者
Tariki, M. [1 ]
Dhanyamraju, P. K. [1 ]
Fendrich, V. [2 ]
Borggrefe, T. [3 ]
Feldmann, G. [4 ]
Lauth, M. [1 ]
机构
[1] Univ Marburg, Ctr Tumor & Immunol, Inst Mol Biol & Tumor Res IMT, D-35043 Marburg, Hesse, Germany
[2] Univ Marburg, Dept Surg, D-35043 Marburg, Hesse, Germany
[3] Univ Giessen, Inst Biochem, D-35390 Giessen, Germany
[4] Univ Bonn, Ctr Integrated Oncol Cologne Bonn, Bonn, Germany
关键词
HIPPO PATHWAY; TRANSCRIPTIONAL COACTIVATOR; ORGAN SIZE; YAP; GLI1; INHIBITION; MECHANISMS; TRANSDUCTION; REVEALS; GROWTH;
D O I
10.1038/oncsis.2014.27
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The evolutionarily conserved Hedgehog (Hh) signaling pathway is essential for correct embryogenesis and is misregulated in several malignancies. In cell culture, Hh-sensitive cells display a striking dependence on cell density with active Hh signaling requiring cell-to-cell contact. As the Hippo/YAP system is tightly linked to cell density control and contact inhibition, we investigated the cross-talk between the two pathways. Our data reveal that the suppression of Hh signaling in the absence of cellular contacts is independent of primary cilia and is mediated by the YAP oncogene. Overexpression of YAP blocks Hh signaling whereas RNA interference-mediated knockdown of YAP enhances Hh/GLI activity. Despite this negative regulation, Hh signaling promotes YAP activity through post-transcriptional mechanisms, resulting in a negative feedback loop. In vivo, we found strong nuclear YAP immunoreactivity restricted to compartments with low Hh pathway activity in human and mouse pancreatic cancer. Finally, we identified protease-activated receptors (PARs) as molecules being able to override the inverse Hippo/Hh regulation, potentially giving tumors a mechanism to utilize both oncogenic pathways in parallel.
引用
收藏
页码:e112 / e112
页数:8
相关论文
共 32 条
[1]   The Hippo superhighway: signaling crossroads converging on the Hippo/Yap pathway in stem cells and development [J].
Barry, Evan R. ;
Camargo, Fernando D. .
CURRENT OPINION IN CELL BIOLOGY, 2013, 25 (02) :247-253
[2]   The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma [J].
Bhat, Krishna P. L. ;
Salazar, Katrina L. ;
Balasubramaniyan, Veerakumar ;
Wani, Khalida ;
Heathcock, Lindsey ;
Hollingsworth, Faith ;
James, Johanna D. ;
Gumin, Joy ;
Diefes, Kristin L. ;
Kim, Se Hoon ;
Turski, Alice ;
Azodi, Yasaman ;
Yang, Yuhui ;
Doucette, Tiffany ;
Colman, Howard ;
Sulman, Erik P. ;
Lang, Frederick F. ;
Rao, Ganesh ;
Copray, Sjef ;
Vaillant, Brian D. ;
Aldape, Kenneth D. .
GENES & DEVELOPMENT, 2011, 25 (24) :2594-2609
[3]   The mechanisms of Hedgehog signalling and its roles in development and disease [J].
Briscoe, James ;
Therond, Pascal P. .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2013, 14 (07) :416-429
[4]   YAP1 increases organ size and expands undifferentiated progenitor cells [J].
Camargo, Fernando D. ;
Gokhale, Sumita ;
Johnnidis, Jonathan B. ;
Fu, Dongdong ;
Bell, George W. ;
Jaenisch, Rudolf ;
Brummelkamp, Thijn R. .
CURRENT BIOLOGY, 2007, 17 (23) :2054-2060
[5]   Small molecule modulation of Smoothened activity [J].
Chen, JK ;
Taipale, J ;
Young, KE ;
Maiti, T ;
Beachy, PA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (22) :14071-14076
[6]   The Hippo Transducer TAZ Confers Cancer Stem Cell-Related Traits on Breast Cancer Cells [J].
Cordenonsi, Michelangelo ;
Zanconato, Francesca ;
Azzolin, Luca ;
Forcato, Mattia ;
Rosato, Antonio ;
Frasson, Chiara ;
Inui, Masafumi ;
Montagner, Marco ;
Parenti, Anna R. ;
Poletti, Alessandro ;
Daidone, Maria Grazia ;
Dupont, Sirio ;
Basso, Giuseppe ;
Bicciato, Silvio ;
Piccolo, Stefano .
CELL, 2011, 147 (04) :759-772
[7]   The α Subunit of the G Protein G13 Regulates Activity of One or More Gli Transcription Factors Independently of Smoothened [J].
Douglas, Andrew E. ;
Heim, Jennifer A. ;
Shen, Feng ;
Almada, Luciana L. ;
Riobo, Natalia A. ;
Fernandez-Zapico, Martin E. ;
Manning, David R. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (35) :30714-30722
[8]   YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation [J].
Fernandez-L, Africa ;
Northcott, Paul A. ;
Dalton, James ;
Fraga, Charles ;
Ellison, David ;
Angers, Stephane ;
Taylor, Michael D. ;
Kenney, Anna Marie .
GENES & DEVELOPMENT, 2009, 23 (23) :2729-2741
[9]   Trp53R172H and KraSG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice [J].
Hingorani, SR ;
Wang, LF ;
Multani, AS ;
Combs, C ;
Deramaudt, TB ;
Hruban, RH ;
Rustgi, AK ;
Chang, S ;
Tuveson, DA .
CANCER CELL, 2005, 7 (05) :469-483
[10]   Genome-Wide RNAi Screen Reveals Disease-Associated Genes That Are Common to Hedgehog and Wnt Signaling [J].
Jacob, Leni S. ;
Wu, Xiaofeng ;
Dodge, Michael E. ;
Fan, Chih-Wei ;
Kulak, Ozlem ;
Chen, Baozhi ;
Tang, Wei ;
Wang, Baolin ;
Amatruda, James F. ;
Lum, Lawrence .
SCIENCE SIGNALING, 2011, 4 (157)