The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase

Genes Dev. 1997 Apr 15;11(8):984-95. doi: 10.1101/gad.11.8.984.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activin Receptors
  • Activin Receptors, Type I
  • Amino Acid Sequence
  • Animals
  • Bone Morphogenetic Protein Receptors, Type I
  • Bone Morphogenetic Protein Receptors, Type II
  • COS Cells
  • Cell Line
  • Cell Nucleus / metabolism
  • DNA-Binding Proteins / metabolism*
  • Epithelial Cells
  • Lung
  • Mink
  • Molecular Sequence Data
  • Mutation
  • Phosphopeptides / analysis
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptors, Growth Factor / metabolism*
  • Serine / metabolism
  • Signal Transduction / physiology*
  • Smad Proteins
  • Smad2 Protein
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / physiology*

Substances

  • DNA-Binding Proteins
  • Phosphopeptides
  • Receptors, Growth Factor
  • Smad Proteins
  • Smad2 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Serine
  • Protein-Serine-Threonine Kinases
  • Activin Receptors
  • Activin Receptors, Type I
  • Bone Morphogenetic Protein Receptors, Type I
  • Bone Morphogenetic Protein Receptors, Type II