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Genes & Dev. 13 (7): 804-816

Copyright © 1999 by Cold Spring Harbor Laboratory Press.

Vol. 13, No. 7, pp. 804-816, April 1, 1999

RESEARCH PAPER
A mechanism of repression of TGFbeta / Smad signaling by oncogenic Ras

Marcus Kretzschmar,1,2 Jacqueline Doody,1 Inna Timokhina,1,2 and Joan Massagué1,3

1 Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 USA

TGFbeta can override the proliferative effects of EGF and other Ras-activating mitogens in normal epithelial cells. However, epithelial cells harboring oncogenic Ras mutations often show a loss of TGFbeta antimitogenic responses. Here we report that oncogenic Ras inhibits TGFbeta signaling in mammary and lung epithelial cells by negatively regulating the TGFbeta mediators Smad2 and Smad3. Oncogenically activated Ras inhibits the TGFbeta -induced nuclear accumulation of Smad2 and Smad3 and Smad-dependent transcription. Ras acting via Erk MAP kinases causes phosphorylation of Smad2 and Smad3 at specific sites in the region linking the DNA-binding domain and the transcriptional activation domain. These sites are separate from the TGFbeta receptor phosphorylation sites that activate Smad nuclear translocation. Mutation of these MAP kinase sites in Smad3 yields a Ras-resistant form that can rescue the growth inhibitory response to TGFbeta in Ras-transformed cells. EGF, which is weaker than oncogenic mutations at activating Ras, induces a less extensive phosphorylation and cytoplasmic retention of Smad2 and Smad3. Our results suggest a mechanism for the counterbalanced regulation of Smad2/Smad3 by TGFbeta and Ras signals in normal cells, and for the silencing of antimitogenic TGFbeta functions by hyperactive Ras in cancer cells.

[Key Words: Growth inhibition; MAP kinase; Ras; Smad; TGFbeta ]

GENES & DEVELOPMENT 13:804-816 © 1999 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/99 $5.00

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The Endogenous Ratio of Smad2 and Smad3 Influences the Cytostatic Function of Smad3.
S. G. Kim, H.-A. Kim, H.-S. Jong, J.-H. Park, N. K. Kim, S. H. Hong, T.-Y. Kim, and Y.-J. Bang (2005)
Mol. Biol. Cell 16, 4672-4683
   Abstract »    Full Text »    PDF »
Pathway- and Expression Level-Dependent Effects of Oncogenic N-Ras: p27Kip1 Mislocalization by the Ral-GEF Pathway and Erk-Mediated Interference with Smad Signaling.
S. Kfir, M. Ehrlich, A. Goldshmid, X. Liu, Y. Kloog, and Y. I. Henis (2005)
Mol. Cell. Biol. 25, 8239-8250
   Abstract »    Full Text »    PDF »
Asthmatic changes in mice lacking T-bet are mediated by IL-13.
S. Finotto, M. Hausding, A. Doganci, J. H. Maxeiner, H. A. Lehr, C. Luft, P. R. Galle, and L. H. Glimcher (2005)
Int. Immunol. 17, 993-1007
   Abstract »    Full Text »    PDF »
Inhibition of the Transforming Growth Factor {beta} (TGF{beta}) Pathway by Interleukin-1{beta} Is Mediated through TGF{beta}-activated Kinase 1 Phosphorylation of SMAD3.
G. F.J.D. Benus, A. T.J. Wierenga, D. J.J. de Gorter, J. J. Schuringa, A. M. van Bennekum, L. Drenth-Diephuis, E. Vellenga, and B. J.L. Eggen (2005)
Mol. Biol. Cell 16, 3501-3510
   Abstract »    Full Text »    PDF »
Characterization of a novel transcriptionally active domain in the transforming growth factor {beta}-regulated Smad3 protein.
V. Prokova, S. Mavridou, P. Papakosta, and D. Kardassis (2005)
Nucleic Acids Res. 33, 3708-3721
   Abstract »    Full Text »    PDF »
Retinal neurons regulate proliferation of postnatal progenitors and Muller glia in the rat retina via TGF{beta} signaling.
J. L. Close, B. Gumuscu, and T. A. Reh (2005)
Development 132, 3015-3026
   Abstract »    Full Text »    PDF »
TGF-{beta} signaling of human T cells is modulated by the ancillary TGF-{beta} receptor endoglin.
C. B. Schmidt-Weber, M. Letarte, S. Kunzmann, B. Ruckert, C. Bernabeu, and K. Blaser (2005)
Int. Immunol. 17, 921-930
   Abstract »    Full Text »    PDF »
High-Level Activation of Cyclic AMP Signaling Attenuates Bone Morphogenetic Protein 2-Induced Sympathoadrenal Lineage Development and Promotes Melanogenesis in Neural Crest Cultures.
M. Ji and O. M. Andrisani (2005)
Mol. Cell. Biol. 25, 5134-5145
   Abstract »    Full Text »    PDF »
Integration of Ras subeffector signaling in TGF-{beta} mediated late stage hepatocarcinogenesis.
A. N.M. Fischer, B. Herrera, M. Mikula, V. Proell, E. Fuchs, J. Gotzmann, R. Schulte-Hermann, H. Beug, and W. Mikulits (2005)
Carcinogenesis 26, 931-942
   Abstract »    Full Text »    PDF »
Transforming Growth Factor-{beta}, Smads, and Cancer.
W. M. Grady (2005)
Clin. Cancer Res. 11, 3151-3154
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Role of Transforming Growth Factor Beta in Human Cancer.
R. L. Elliott and G. C. Blobe (2005)
J. Clin. Oncol. 23, 2078-2093
   Abstract »    Full Text »    PDF »
Fibroblast Growth Factor Signaling during Early Vertebrate Development.
R. T. Bottcher and C. Niehrs (2005)
Endocr. Rev. 26, 63-77
   Abstract »    Full Text »    PDF »

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