Specificity, versatility, and control of TGF-β family signaling

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Science Signaling  26 Feb 2019:
Vol. 12, Issue 570, eaav5183
DOI: 10.1126/scisignal.aav5183


The transforming growth factor–β (TGF-β) family of secreted proteins is implicated in the control of widely diverse physiologies and its dysregulation with disease. In this review, which contains 7 figures and 343 references, we describe the exquisite nature of TGF-β family signaling in its roles in diverse and context-specific cellular behaviors. These pathways are far from linear and still far from being fully illuminated.


Encoded in mammalian cells by 33 genes, the transforming growth factor–β (TGF-β) family of secreted, homodimeric and heterodimeric proteins controls the differentiation of most, if not all, cell lineages and many aspects of cell and tissue physiology in multicellular eukaryotes. Deregulation of TGF-β family signaling leads to developmental anomalies and disease, whereas enhanced TGF-β signaling contributes to cancer and fibrosis. Here, we review the fundamentals of the signaling mechanisms that are initiated upon TGF-β ligand binding to its cell surface receptors and the dependence of the signaling responses on input from and cooperation with other signaling pathways. We discuss how cells exquisitely control the functional presentation and activation of heteromeric receptor complexes of transmembrane, dual-specificity kinases and, thus, define their context-dependent responsiveness to ligands. We also introduce the mechanisms through which proteins called Smads act as intracellular effectors of ligand-induced gene expression responses and show that the specificity and impressive versatility of Smad signaling depend on cross-talk from other pathways. Last, we discuss how non-Smad signaling mechanisms, initiated by distinct ligand-activated receptor complexes, complement Smad signaling and thus contribute to cellular responses.

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