Bone morphogenetic proteins (BMPs) are members of the TGF-~ family that regulate cell proliferation, apoptosis, and differentiation, and participate in the development of most tissues and organs in vertebrates. Smad proteins function downstream of TGF-[~ receptor serine/threonine kinases and undergo serine phosphorylation in response to receptor activation. Smadl is regulated in this fashion by BMP receptors, and Smad2 and Smad3 by TGF-[~ and activin receptors. Here, we report that BMP

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... phosphorylate and activate Smadl directly. Phosphorylation of Smadl in vivo involves serines in the carboxy-terminal motif SSXS. These residues are phosphorylated directly by a BMP type I receptor in vitro. Mutation of these carboxy-terminal serines prevents several Smadl activation events, namely, Smadl association with the related protein DPC4, accumulation in the nucleus, and gain of transcriptional activity. Similar carboxy-terminal serines in Smad2 are required for its phosphorylation and association with DPC4 in response to TGFq3, indicating the generality of this process of Smad activation. As a direct physiological substrate of BMP receptors, Smadl provides a link between receptor serine/threonine kinases and the nucleus. [