Cdh1 regulates osteoblast function through an APC/C-independent modulation of smurf1

Lixin Wan, Weiguo Zou, Daming Gao, Hiroyuki Inuzuka, Hidefumi Fukushima, Anders H. Berg, Rebecca Drapp, Shavali Shaik, Dorothy Hu, Chantel Lester, Manuel Eguren, Marcos Malumbres, Laurie H. Glimcher, Wenyi Wei

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

The APC/Cdh1 E3 ubiquitin ligase plays an essential role in both mitotic exit and G1/S transition by targeting key cell-cycle regulators for destruction. There is mounting evidence indicating that Cdh1 has other functions in addition to cell-cycle regulation. However, it remains unclear whether these additional functions depend on its E3 ligase activity. Here, we report that Cdh1, but not Cdc20, promotes the E3 ligase activity of Smurf1. This is mediated by disruption of an autoinhibitory Smurf1 homodimer and is independent of APC/Cdh1 E3 ligase activity. As a result, depletion of Cdh1 leads to reduced Smurf1 activity and subsequent activation of multiple downstream targets, including the MEKK2 signaling pathway, inducing osteoblast differentiation. Our studies uncover a cell-cycle-independent function of Cdh1, establishing Cdh1 as an upstream component that governs Smurf1 activity. They further suggest that modulation of Cdh1 is a potential therapeutic option for treatment of osteoporosis.

Original languageEnglish
Pages (from-to)721-733
Number of pages13
JournalMolecular Cell
Volume44
Issue number5
DOIs
Publication statusPublished - 2011 Dec 9

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Cdh1 regulates osteoblast function through an APC/C-independent modulation of smurf1'. Together they form a unique fingerprint.

  • Cite this

    Wan, L., Zou, W., Gao, D., Inuzuka, H., Fukushima, H., Berg, A. H., Drapp, R., Shaik, S., Hu, D., Lester, C., Eguren, M., Malumbres, M., Glimcher, L. H., & Wei, W. (2011). Cdh1 regulates osteoblast function through an APC/C-independent modulation of smurf1. Molecular Cell, 44(5), 721-733. https://doi.org/10.1016/j.molcel.2011.09.024