Receptor-associated Mad homologues synergize as effectors of the TGF-β response

Abstract

TRANSFORMING growth factor-β TGF-β is the prototype for a family of extracellular proteins that affect cell proliferation and tissue differentiation1–3. TGF-β-related factors, including BMP-2/4, Dpp and activin, act through two types of serine/threonine kinase receptors which can form a heteromeric complex3,4. However, the mechanism of signal transduction by these receptors is largely unknown. In Drosophila, Mad is required for signalling by Dpp5. We have isolated complementary DNAs for four human Mad homologues, one of which, hMAD-4, is identical to DPC-4, a candidate tumour suppressor6. hMAD-3 and -4 synergized to induce strong ligand-independent TGF-β-like responses. When truncated at their carboxy termini, hMAD-3 and -4 act as dominant-negative inhibitors of the normal TGF-β response. The activity of hMAD-3 and -4 was regulated by the TGF-β receptors, and hMAD-3 but not hMAD-4 was phosphorylated and associated with the ligand-bound receptor complex. These results define hMAD-3 and -4 as effectors of the TGF-β response and demonstrate a function for DPC-4/hMAD-4 as a tumour suppressor.

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Zhang, Y., Feng, X., Wu, R. et al. Receptor-associated Mad homologues synergize as effectors of the TGF-β response. Nature 383, 168–172 (1996). https://doi.org/10.1038/383168a0

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