MADR1, A MAD-RELATED PROTEIN THAT FUNCTIONS IN BMP2 SIGNALING PATHWAYS

Components of the signaling pathways that lie downstream of Ser/Thr ki nase receptors and are required for signaling by the TGF beta superfam ily have been poorly defined. The Drosophila gene Mothers against dpp (Mad) and the C. elegans sma genes are implicated in these signaling p athways. We show that MAD functions downstream of DPP receptors and is required for receptor signaling. Phosphorylation of MADR1, a human ho molog of MAD, is tightly regulated and rapidly induced by BMP2, but no t TGF beta or activin. This phosphorylation is necessary for function, since a point mutant that yields a null phenotype in Drosophila is no t phosphorylated. BMP2 treatment results in accumulation of MADR1 in t he nucleus. MAD proteins may thus define a novel class of signaling mo lecules with nuclear function in Ser/Thr kinase receptor signaling pat hways.