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Inhibition of transforming growth factor-β/SMAD signalling by the interferon-γ/STAT pathway

Abstract

Transforming growth factor-β (TGF-β) and interferon-γ (IFN-γ) have opposite effects on diverse cellular functions1,2,3,4,5, but the basis for this antagonism is not known6. TGF-β signals through a receptor serine kinase that phosphorylates and activates the transcription factors Smads 2 and 3 (refs 7, 8), whereas the IFN-γ receptor and its associated protein tyrosine kinase Jak1 mediate phosphorylation and activation of the transcription factor Stat1 (refs 6, 9, 10). Here we present a basis for the integration of TGF-β and IFN-γ signals. IFN-γ inhibits the TGF β-induced phosphorylation of Smad3 and its attendant events, namely, the association of Smad3 with Smad4, the accumulation of Smad3 in the nucleus, and the activation of TGFβ-responsive genes. Acting through Jak1 and Stat1, IFN-γ induces the expression of Smad7, an antagonistic SMAD11,12, which prevents the interaction of Smad3 with the TGF-β receptor. The results indicate a mechanism of transmodulation between the STAT and SMAD signal-transduction pathways.

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Figure 1: Inhibition of SMAD activation and transcriptional responses by IFN-γ.
Figure 5: The IFN-γ/Jak1/Stat 1 pathway inhibits the TGF-β receptor through Smad7.
Figure 2: Erk phosphorylation is present but not required for Smad inhibition by IFN-γ in U4A/Jak1 cells.
Figure 3: Induction of an antagonistic SMAD by IFN-γ.
Figure 4: Inhibition of interactions between TGF-β receptors and Smad3 by IFN-γ.

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Acknowledgements

We thank G. Stark, I. Kerr, R. Flavel, C. H. Heldin, P. Ten Dijke, R. Derynck and M.Whitman for cell lines and vectors; A. Hata, F. Liu, A. Nieporent and J. Ihle for useful insights; and C.Zhang for technical assistance. This work was supported by an NIH grant to J.M. and a Cancer Center grant to the Memorial Sloan-Kettering Cancer Center. L.U. is a postdoctoral fellow of the International Human Frontier Organization Program. J.M. is an investigator of the Howard Hughes Medical Institute.

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Ulloa, L., Doody, J. & Massagué, J. Inhibition of transforming growth factor-β/SMAD signalling by the interferon-γ/STAT pathway. Nature 397, 710–713 (1999). https://doi.org/10.1038/17826

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