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Review
. 2009 Jan;19(1):71-88.
doi: 10.1038/cr.2008.302.

Signaling cross-talk between TGF-beta/BMP and other pathways

Xing Guo  1 , Xiao-Fan Wang
Affiliations
Review

Signaling cross-talk between TGF-beta/BMP and other pathways

Xing Guo et al. Cell Res. 2009 Jan.

Abstract

Transforming growth factor-beta (TGF-beta)/bone morphogenic protein (BMP) signaling is involved in the vast majority of cellular processes and is fundamentally important during the entire life of all metazoans. Deregulation of TGF-beta/BMP activity almost invariably leads to developmental defects and/or diseases, including cancer. The proper functioning of the TGF-beta/BMP pathway depends on its constitutive and extensive communication with other signaling pathways, leading to synergistic or antagonistic effects and eventually desirable biological outcomes. The nature of such signaling cross-talk is overwhelmingly complex and highly context-dependent. Here we review the different modes of cross-talk between TGF-beta/BMP and the signaling pathways of Mitogen-activated protein kinase, phosphatidylinositol-3 kinase/Akt, Wnt, Hedgehog, Notch, and the interleukin/interferon-gamma/tumor necrosis factor-alpha cytokines, with an emphasis on the underlying molecular mechanisms.

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Figures

Figure 1
Figure 1
Basic modes of signaling cross-talk. A cross-talk exists between pathways A and B when both of the following criteria are met. Functionally, the combinatorial signal from A and B must produce a different response than that triggered by A or B alone. Mechanistically, the A and B pathways must be connected in at least one of the three depicted ways: (a) components of the two pathways physically interact; (b) components of one pathway are enzymatic or transcriptional _targets of the other; and (c) one signal modulates or competes for a key modulator or mediator (“M”) of the other. In this scheme, A and B are interchangeable, and the arrows may represent either positive or negative regulations. Note that an altered response can arise from independent (non-cross-talk) inputs (d).
Figure 2
Figure 2
TGF-β/BMP and RTK/Ras-activated MAPK and PI3K/Akt pathways. The MAPK and PI3K/Akt pathways impinge on TGF-β/BMP signaling primarily by modulating Smad functions. MAPKs and Akt bind and/or phosphorylate R-Smads to control their intracellular distribution and transcriptional activity. MAPKs and Akt also phosphorylate and regulate a variety of Smad binding partners in the nucleus, indirectly affecting the Smads.
Figure 3
Figure 3
TGF-β/BMP and the Wnt pathway. The most common format of TGF-β/Wnt cross-talk occurs in the nucleus, where the Smad and Lef/β-catenin synergistically regulate a set of shared _target genes. TGF-β/BMP and Wnt can determine the ligand production of each other (see text and Figure 4). In addition, protein interactions in the cytoplasm (such as Smad7-Axin binding) also link the two pathways in various settings.
Figure 4
Figure 4
simplified and unified view of the multi-level cross-talk. TGF-β/BMP communicates with other signals at several levels. Physical interactions between pathway components, both in the cytoplasm and in the nucleus, can lead to protein redistribution and/or post-translational modifications, and eventually changes in _target gene expression. Often the ligands themselves, as well as certain extracellular regulators of the ligands, are transcriptional _targets of other pathways. All these events are context-dependent.
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References

    1. Massagué J. How cells read TGF-beta signals. Nat Rev Mol Cell Biol. 2000;1:169–178. - PubMed
    1. Gomis RR, Alarcon C, Nadal C, Van Poznak C, Massague J. C/EBPbeta at the core of the TGFbeta cytostatic response and its evasion in metastatic breast cancer cells. Cancer Cell. 2006;10:203–214. - PubMed
    1. Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685–700. - PubMed
    1. Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006;6:506–520. - PubMed
    1. Massagué J, Blain SW, Lo RS. TGFβ signaling in growth control, cancer, and heritable disorders. Cell. 2000;103:295–309. - PubMed

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