RECEPTOR-ASSOCIATED MAD HOMOLOGS SYNERGIZE AS EFFECTORS OF THE TGF-BETA RESPONSE

TRANSFORMING growth factor-beta TGP-Beta is the prototype for a family of extracellular proteins that affect cell proliferation and tissue d ifferentiation(1-3). TGF-beta-related factors, including BMP-2/4, Dpp and activin, act through two types of serine/threonine kinase receptor s which can form a heteromeric complex(3,4). However, the mechanism of signal transduction by these receptors is largely unknown. In Drosoph ila, Mad is required for signalling by Dpp(5). We have isolated comple mentary DNAs for four human Mad homologues, one of which, hMAD-4, is i dentical to DPC-4, a candidate tumour suppressor(6). hMAD-3 and -4 syn ergized to induce strong ligand-independent TGF-beta-like responses. W hen truncated at their carboxy termini, hMAD-3 and -4 act as dominant- negative inhibitors of the normal TGF-beta response. The activity of h MAD-3 and -4 was regulated by the TGF-beta receptors, and hMAD-3 but n ot hMAD-4 was phosphorylated and associated with the ligand-bound rece ptor complex. These results define hMAD-3 and -4 as effecters of the T GF-beta response and demonstrate a function for DPC-4/hMAD-4 as a tumo ur suppressor.