The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase.
Bone morphogenetic proteins (BMPs) are members of the TGF-beta 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-beta receptor serine/threonine kinases and undergo serine phosphorylation in response to receptor activation. Smad1 is regulated in this fashion by BMP receptors, and Smad2 and Smad3 by TGF-beta and activin receptors. Here, we report that BMP receptors phosphorylate and activate Smad1 directly. Phosphorylation of Smad1 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 Smad1 activation events, namely, Smad1 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 TGF-beta, indicating the generality of this process of Smad activation. As a direct physiological substrate of BMP receptors, Smad1 provides a link between receptor serine/threonine kinases and the nucleus.
Kretzschmar
M
M
Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Liu
F
F
Hata
A
A
Doody
J
J
Massagué
J
J
D029404:Activin Receptors; D030201:Activin Receptors, Type I; D000595:Amino Acid Sequence; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004847:Epithelial Cells; D008168:Lung; D008907:Mink; D008969:Molecular Sequence Data; D009154:Mutation; D010748:Phosphopeptides / Q000032:analysis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*
D004268:DNA-Binding Proteins; D010748:Phosphopeptides; D017978:Receptors, Growth Factor; D051785:Smad Proteins; D051899:Smad2 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D029404:Activin Receptors; D030201:Activin Receptors, Type I; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II