Visit our Expo - Redox and Inflammation signaling 2012

Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting
MEKK2-JNK pathway
Ying E. Zhang 1 , Motozo Yamashita 1 , Sai-Xia Ying 1 , Cuiling Li 2 , Chuxia Deng 2 , and
Steven Y. Cheng 1
1 Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National
Cancer Institute, National Institutes of Health, Bethesda, MD 20892
2 Genetics of Development and Disease Branch, National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
Smad ubiquitin regulatory factor (Smurf), a HECT domain ubiquitin ligase, was previously
identified as E3 ligase targeting TGF-beta/BMP pathway through in vitro biochemical
experiments. To investigate the physiological function of Smurf1, we disrupted the mouse
Smurf1 allele through homologous recombination. Smurf1-deficient mice are born normal,
fertile and have normal life span. Given the fact that members of the TGF-#eta/BMP
superfamily are crucial inductive signals during embryonic development, the seemingly
normal development of Smurf1 -/- mice and the concurrent increase of the Smurf2 transcript
in Smurf1 -/- suggest that the loss of Smurf1 function might have been compensated for, at
least in part, by the elevated Smurf2. Despite of no phenotypic developmental abnormalities
or health problems, Smurf1 -/- mice displayed 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. Surprisingly, this
skeletal abnormality is not due to alteration in the Smad-mediated canonical TGF-beta or
BMP signaling. Instead, loss of Smurf1 leads to accumulation of phosphorylated MEKK2
and activation of the downstream JNK signaling cascade. We found that Smurf1 physically
interacts with MEKK2 and promotes the ubiquitination and turn-over of phosphorylated
MEKK2, which resulted in downregulation of osteoblast activity and response to BMP.
These results reveal a novel function of Smurf1 in the regulation of bone homeostasis through
directly targeting MAPK signaling pathway, thereby regulating the biological response of the
TGF-beta superfamily signaling.
Selected Recent Publications from My Group:
Yu, L., Hebert, M. and Zhang, Y. E.: TGF-beta receptor-activated p38 MAP kinase mediates
Smad-independent TGF-beta responses. EMBO J. 21: 3749-3759, 2002.
Ying, S.-X., Zareena J. H., and Zhang, Y. E.: Smurf1 facilitates myogenic
differentiation and antagonizes the Bone Morphogenetic Protein-2-induced osteoblast
conversion by targeting Smad5 for degradation. J. Biol. Chem. 278: 39029-39036, 2003.
Derynck, R. and Zhang, Y. E.: TGF-beta family signaling: Smad-dependent and
Smad independent pathways. Nature 425: 577-584, 2003.
Yamashita, M., Ying, S.-X., Zhang, G.-M., Li, C., Cheng, S. Y., Deng, C.-X., and
Zhang, Y. E.: Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by
targeting MEKK2 for degradation. Cell 121: 101-113, 2005
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