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

Science 315 (5813): 840-843

Copyright © 2007 by the American Association for the Advancement of Science

Integration of TGF-ß and Ras/MAPK Signaling Through p53 Phosphorylation

Michelangelo Cordenonsi, Marco Montagner, Maddalena Adorno, Luca Zacchigna, Graziano Martello, Anant Mamidi, Sandra Soligo, Sirio Dupont, Stefano Piccolo*

Abstract: During development and tissue homeostasis, cells must integrate different signals. We investigated how cell behavior is controlled by the combined activity of transforming growth factor–ß (TGF-ß) and receptor tyrosine kinase (RTK) signaling, whose integration mechanism is unknown. We find that RTK/Ras/MAPK (mitogen-activated protein kinase) activity induces p53 N-terminal phosphorylation, enabling the interaction of p53 with the TGF-ß–activated Smads. This mechanism confines mesoderm specification in Xenopus embryos and promotes TGF-ß cytostasis in human cells. These data indicate a mechanism to allow extracellular cues to specify the TGF-ß gene-expression program.

Department of Medical Biotechnologies, Section of Histology and Embryology, University of Padua, Padua, Italy.

* To whom correspondence should be addressed. E-mail: piccolo{at}civ.bio.unipd.it


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
REG{gamma} deficiency promotes premature aging via the casein kinase 1 pathway.
L. Li, D. Zhao, H. Wei, L. Yao, Y. Dang, A. Amjad, J. Xu, J. Liu, L. Guo, D. Li, et al. (2013)
PNAS 110, 11005-11010
   Abstract »    Full Text »    PDF »
Inhibition of tumor growth and metastasis by a self-therapeutic nanoparticle.
R. R. Arvizo, S. Saha, E. Wang, J. D. Robertson, R. Bhattacharya, and P. Mukherjee (2013)
PNAS 110, 6700-6705
   Abstract »    Full Text »    PDF »
In Vivo Regulation of TGF-{beta} by R-Ras2 Revealed through Loss of the RasGAP Protein NF1.
D. M. Patmore, S. Welch, P. C. Fulkerson, J. Wu, K. Choi, D. Eaves, J. J. Kordich, M. H. Collins, T. P. Cripe, and N. Ratner (2012)
Cancer Res. 72, 5317-5327
   Abstract »    Full Text »    PDF »
p53 N-terminal phosphorylation: a defining layer of complex regulation.
L. M. M. Jenkins, S. R. Durell, S. J. Mazur, and E. Appella (2012)
Carcinogenesis 33, 1441-1449
   Abstract »    Full Text »    PDF »
Snail2 controls mesodermal BMP/Wnt induction of neural crest.
J. Shi, C. Severson, J. Yang, D. Wedlich, and M. W. Klymkowsky (2011)
Development 138, 3135-3145
   Abstract »    Full Text »    PDF »
The tumor suppressor gene Trp53 protects the mouse lens against posterior subcapsular cataracts and the BMP receptor Acvr1 acts as a tumor suppressor in the lens.
L. A. Wiley, R. Rajagopal, L. K. Dattilo, and D. C. Beebe (2011)
Dis. Model. Mech. 4, 484-495
   Abstract »    Full Text »    PDF »
Cancer early dissemination: cancerous epithelial-mesenchymal transdifferentiation and transforming growth factor {beta} signalling.
H. Sabe (2011)
J. Biochem. 149, 633-639
   Abstract »    Full Text »    PDF »
Cancer Susceptibility Polymorphism of p53 at Codon 72 Affects Phosphorylation and Degradation of p53 Protein.
C. Ozeki, Y. Sawai, T. Shibata, T. Kohno, K. Okamoto, J. Yokota, F. Tashiro, S.-i. Tanuma, R. Sakai, T. Kawase, et al. (2011)
J. Biol. Chem. 286, 18251-18260
   Abstract »    Full Text »    PDF »
A Novel p53 Phosphorylation Site within the MDM2 Ubiquitination Signal: I. PHOSPHORYLATION AT SER269 IN VIVO IS LINKED TO INACTIVATION OF p53 FUNCTION.
J. A. Fraser, B. Vojtesek, and T. R. Hupp (2010)
J. Biol. Chem. 285, 37762-37772
   Abstract »    Full Text »    PDF »
Transcriptional Pathway Signatures Predict MEK Addiction and Response to Selumetinib (AZD6244).
J. R. Dry, S. Pavey, C. A. Pratilas, C. Harbron, S. Runswick, D. Hodgson, C. Chresta, R. McCormack, N. Byrne, M. Cockerill, et al. (2010)
Cancer Res. 70, 2264-2273
   Abstract »    Full Text »    PDF »
Transcriptional regulation of the small GTPase RhoB gene by TGF{beta}-induced signaling pathways.
E. Vasilaki, E. Papadimitriou, V. Tajadura, A. J. Ridley, C. Stournaras, and D. Kardassis (2010)
FASEB J 24, 891-905
   Abstract »    Full Text »    PDF »
Posttranslational Modification of p53: Cooperative Integrators of Function.
D. W. Meek and C. W. Anderson (2009)
Cold Spring Harb Perspect Biol 1, a000950
   Abstract »    Full Text »    PDF »
The regulation of TGF{beta} signal transduction.
A. Moustakas and C.-H. Heldin (2009)
Development 136, 3699-3714
   Abstract »    Full Text »    PDF »
Nodal Morphogens.
A. F. Schier (2009)
Cold Spring Harb Perspect Biol 1, a003459
   Abstract »    Full Text »    PDF »
Bile acids: regulation of synthesis.
J. Y. L. Chiang (2009)
J. Lipid Res. 50, 1955-1966
   Abstract »    Full Text »    PDF »
EWS-FLI1 Suppresses NOTCH-Activated p53 in Ewing's Sarcoma.
J. Ban, I. M. Bennani-Baiti, M. Kauer, K.-L. Schaefer, C. Poremba, G. Jug, R. Schwentner, O. Smrzka, K. Muehlbacher, D. N.T. Aryee, et al. (2008)
Cancer Res. 68, 7100-7109
   Abstract »    Full Text »    PDF »
p53 Brings a New Twist to the Smad Signaling Network.
A. Atfi and R. Baron (2008)
Science Signaling 1, pe33
   Abstract »    Full Text »    PDF »
Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo.
C Brockschmidt, H Hirner, N Huber, T Eismann, A Hillenbrand, G Giamas, B Radunsky, O Ammerpohl, B Bohm, D Henne-Bruns, et al. (2008)
Gut 57, 799-806
   Abstract »    Full Text »    PDF »
Chromatin-Bound p53 Anchors Activated Smads and the mSin3A Corepressor To Confer Transforming Growth Factor {beta}-Mediated Transcription Repression.
D. S. Wilkinson, W.-W. Tsai, M. A. Schumacher, and M. C. Barton (2008)
Mol. Cell. Biol. 28, 1988-1998
   Abstract »    Full Text »    PDF »
Integration of Transforming Growth Factor {beta} and RAS Signaling Silences a RAB5 Guanine Nucleotide Exchange Factor and Enhances Growth Factor-Directed Cell Migration.
H. Hu, M. Milstein, J. M. Bliss, M. Thai, G. Malhotra, L. C. Huynh, and J. Colicelli (2008)
Mol. Cell. Biol. 28, 1573-1583
   Abstract »    Full Text »    PDF »
Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase C{alpha}.
H. J. Lee, Y. Ji, S. Paul, H. Maehr, M. Uskokovic, and N. Suh (2007)
Cancer Res. 67, 11840-11847
   Abstract »    Full Text »    PDF »
MAP-kinase activity necessary for TGFbeta1-stimulated mesangial cell type I collagen expression requires adhesion-dependent phosphorylation of FAK tyrosine 397.
T. Hayashida, M.-H. Wu, A. Pierce, A.-C. Poncelet, J. Varga, and H. W. Schnaper (2007)
J. Cell Sci. 120, 4230-4240
   Abstract »    Full Text »    PDF »
Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor {beta}1 (TGF-{beta}1) Signaling Pathway by Repressing the Expression of TGF-{beta} Receptor Type II.
E. Kalo, Y. Buganim, K. E. Shapira, H. Besserglick, N. Goldfinger, L. Weisz, P. Stambolsky, Y. I. Henis, and V. Rotter (2007)
Mol. Cell. Biol. 27, 8228-8242
   Abstract »    Full Text »    PDF »
TGF{beta} superfamily signaling: notes from the desert.
R. W. Padgett and M. Reiss (2007)
Development 134, 3565-3569
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


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