title: Cdh1 regulates osteoblast function through an APC/C-independent modulation of Smurf1.
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.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wan
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zou
authors.forename: Daming
authors.initials: D
authors.lastname: Gao
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Fukushima
authors.forename: Anders H
authors.initials: AH
authors.lastname: Berg
authors.forename: Rebecca
authors.initials: R
authors.lastname: Drapp
authors.forename: Shavali
authors.initials: S
authors.lastname: Shaik
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hu
authors.forename: Chantel
authors.initials: C
authors.lastname: Lester
authors.forename: Manuel
authors.initials: M
authors.lastname: Eguren
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D006801:Humans; D048730:MAP Kinase Kinase Kinase 2 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; C577585:Fzr1 protein, mouse; D043743:Ubiquitin-Protein Ligase Complexes; C498342:SMURF1 protein, human; C492381:Smurf1 protein, mouse; D064173:Anaphase-Promoting Complex-Cyclosome; D044767:Ubiquitin-Protein Ligases; D048730:MAP Kinase Kinase Kinase 2