Ubiquitin Ligase Smurf1 Controls Osteoblast Activity and Bone Homeostasis by Targeting MEKK2 for Degradation

Cell. 2005 Apr 8;121(1):101-13. doi: 10.1016/j.cell.2005.01.035.

Abstract

Bone is constantly resorbed and formed throughout life by coordinated actions of osteoclasts and osteoblasts. Here we show that Smurf1, a HECT domain ubiquitin ligase, has a specific physiological role in suppressing the osteogenic activity of osteoblasts. Smurf1-deficient mice are born normal but exhibit an age-dependent increase of bone mass. The cause of this increase can be traced to enhanced activities of osteoblasts, which become sensitized to bone morphogenesis protein (BMP) in the absence of Smurf1. However, loss of Smurf1 does not affect the canonical Smad-mediated intracellular TGFbeta or BMP signaling; instead, it leads to accumulation of phosphorylated MEKK2 and activation of the downstream JNK signaling cascade. We demonstrate that Smurf1 physically interacts with MEKK2 and promotes the ubiquitination and turnover of MEKK2. These results indicate that Smurf1 negatively regulates osteoblast activity and response to BMP through controlling MEKK2 degradation.

MeSH terms

  • Animals
  • Bone Density / genetics
  • Bone Density / physiology*
  • Bone Morphogenetic Proteins / metabolism
  • Bone and Bones / cytology
  • Bone and Bones / metabolism*
  • Cells, Cultured
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase Kinase 2 / metabolism*
  • Mice
  • Mice, Knockout
  • Osteoblasts / cytology
  • Osteoblasts / metabolism*
  • Phosphorylation
  • Protein Binding
  • Signal Transduction / physiology
  • Transforming Growth Factor beta / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Bone Morphogenetic Proteins
  • Transforming Growth Factor beta
  • Smurf1 protein, mouse
  • Ubiquitin-Protein Ligases
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 2