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Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation

  1. Author:
    Yamashita, M.
    Ying, S. X.
    Zhang, G. M.
    Li, C. L.
    Cheng, S. Y.
    Deng, C. X.
    Zhang, Y. E.

  2. Author Address

    NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Lab Anim Sci Program, Frederick, MD 21702 USA. NIDDKD, Mammalian Genet Sect, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA Zhang, YE, NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA
    1. Year: 2005
    2. Date: APR 8
  2. Journal: Cell
    1. 121
    2. 1
    3. Pages: 101-113
  4. Type of Article: Article
  1. 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 TGF beta 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

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  2. DOI: 10.1016/j.cell.2005.01.035
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