Cdh1 Regulates Osteoblast Function through an APC/C-Independent Modulation of Smurf1

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. ► Cdh1 governs osteoblast differentiation via modulating the Smurf1 signaling pathway ► Cdh1 enhances Smurf1 activity independent of Cdh1's APC/C E3 ligase activity ► Smurf1 can form homodimers to suppress its own E3 ligase activity ► Cdh1 activates Smurf1 through disrupting homodimer-mediated Smurf1 autoinhibition