Components of the signaling pathways that lie downstream of Ser/Thr kinase receptors and are required for signaling by the TGFβ superfamily have been poorly defined. The Drosophila gene Mothers against dpp (Mad) and the C. elegans sma genes are implicated in these signaling pathways. We show that MAD functions downstream of DPP receptors and is required for receptor signaling. Phosphorylation of MADR1, a human homolog of MAD, is tightly regulated and rapidly induced by BMP2, but not TGFβ or activin. This phosphorylation is necessary for function, since a point mutant that yields a null phenotype in Drosophila is not phosphorylated. BMP2 treatment results in accumulation of MADR1 in the nucleus. MAD proteins may thus define a novel class of signaling molecules with nuclear function in Ser/Thr kinase receptor signaling pathways.
Bibliographical noteFunding Information:
Correspondence should be addressed to J. L. W. We thank P. ten Dijke, K. Miyazono, and C. H. Heldin for the ALK3 and ALK6 cDNA clones, J. Massagué for BMPR-II cDNA, V. Rosen (Genetics Institute) for recombinant BMP2, J. Aubin for MC3T3E1 cells, T. Yager for use of the microscope, M. Macias-Silva for discussions, and Goldi Gupta for excellent technical assistance. This work was supported by grants to J. L. W. from the Medical Research Council of Canada and the National Cancer Institute of Canada, with funds from the Terry Fox Run and Public Health Service grant GM47462 to M. B. O. T. H. is supported by the cancer research coordinating committee of the University of California, and J. L. W. and L. A. are Medical Research Council of Canada Scholars.