Mothers against dpp participates in a DPP/TGF-β responsive serine-threonine kinase signal transduction cascade

Mothers against dpp (Mad) is the prototype of a family of genes required for signaling by TGF-β related ligands. In Drosophila, Mad is specifically required in cells responding to Decapentaplegic (DPP) signals. We further specify the role of Mad in DPP-mediated signaling by utilizing tkv(Q199D), an activated form of the DPP type I receptor serine-threonine kinase thick veins (tkv). In the embryonic midgut, tkv(Q199D) mimics DPP-mediated inductive interactions. Homozygous Mad mutations block signaling by tkv(Q199D). Appropriate responses to signaling by tkv(Q199D) are restored by expression of MAD protein in DPP-target cells. Endogenous MAD is phosphorylated in a ligand-dependent manner in Drosophila cell culture. DPP overexpression in the embryonic midgut induces MAD nuclear accumulation; after withdrawal of the overexpressed DPP signal, MAD is detected only in the cytoplasm. However, in three different tissues and developmental stages actively responding to endogenous DPP, MAD protein is detected in the cytoplasm but not in the nucleus. From these observations, we discuss possible roles for MAD in a DPP-dependent serine-threonine kinase signal transduction cascade integral to the proper interpretation of DPP signals.