Editors' ChoiceDevelopment

Dual activator and inhibitor of TGF-β signaling

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Sci. Signal.  11 Aug 2015:
Vol. 8, Issue 389, pp. ec226
DOI: 10.1126/scisignal.aad1995

Many secreted proteins antagonize transforming growth factor–β (TGF-β) signaling by binding to these ligands and preventing them from activating their receptors. The secreted protein Coco (also known as Dand5, Cerberus 2, and Gremlin 3) inhibits bone morphogenetic protein (BMP) signaling in the context of metastatic breast cancer and inhibits signaling by several TGF-β superfamily members— including Activin, Nodal, and BMP4—during vertebrate embryonic development. Deglincerti et al. report that Coco can also promote signaling by TGF-β1, a different member of this superfamily. Knocking down Coco in cultured mouse myoblast C2C12 cells reduced nuclear accumulation of the transcription factors Smad2 and Smad4 and reduced expression of a TGF-β1–dependent reporter gene in response to TGF-β1. Conversely, overexpression of Coco or application of culture medium conditioned by Coco-overexpressing cells increased the TGF-β1–dependent nuclear accumulation of Smad4 and expression of endogenous TGF-β1–responsive target genes. In contrast, Coco inhibited BMP4 signaling in C2C12 cells. TGF-β1 inhibits the differentiation of C2C12 cells. Knockdown of Coco in these cells promoted myoblast differentiation, whereas overexpression of Coco prevented myoblast differentiation. Experiments in human embryonic RUES2 cells were consistent with Coco inhibiting signaling by Activin and Nodal but promoting signaling by TGF-β1. TGF-β1 coimmunoprecipitated with Coco in extracts from Xenopus laevis (frog) embryos expressing tagged versions of these proteins. Coimmunoprecipitation experiments also suggested that the presence of Coco enhanced the association of TGF-β1 with its receptor Alk5. Coinjecting increasing concentrations of coco mRNA along with TGF-β1 mRNA into Xenopus embryos dose-dependently enhanced expression of an endogenous TGF-β1 target gene and Coco synergized with TGF-β1 to induce ectopic cement glands. These findings showed that Coco can either inhibit or promote signaling by TGF-β superfamily ligands, depending on which ligand it binds.

A. Deglincerti, T. Haremaki, A. Warmflash, B. Sorre, A. H. Brivanlou, Coco is a dual activity modulator of TGFβ signaling. Development 142, 2678–2685 (2015). [PubMed]