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

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.

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

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

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

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.