title: Nuclear Export of Smads by RanBP3L Regulates Bone Morphogenetic Protein Signaling and Mesenchymal Stem Cell Differentiation.
abstract: Bone morphogenetic proteins (BMPs) play vital roles in regulating stem cell maintenance and differentiation. BMPs can induce osteogenesis and inhibit myogenesis of mesenchymal stem cells. Canonical BMP signaling is stringently controlled through reversible phosphorylation and nucleocytoplasmic shuttling of Smad1, Smad5, and Smad8 (Smad1/5/8). However, how the nuclear export of Smad1/5/8 is regulated remains unclear. Here we report that the Ran-binding protein RanBP3L acts as a nuclear export factor for Smad1/5/8. RanBP3L directly recognizes dephosphorylated Smad1/5/8 and mediates their nuclear export in a Ran-dependent manner. Increased expression of RanBP3L blocks BMP-induced osteogenesis of mouse bone marrow-derived mesenchymal stem cells and promotes myogenic induction of C2C12 mouse myoblasts, whereas depletion of RanBP3L expression enhances BMP-dependent stem cell differentiation activity and transcriptional responses. In conclusion, our results demonstrate that RanBP3L, as a nuclear exporter for BMP-specific Smads, plays a critical role in terminating BMP signaling and regulating mesenchymal stem cell differentiation.
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Fenfang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Michael E. DeBakey Department of Surgery and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Lin
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Pinglong
authors.initials: P
authors.lastname: Xu
authors.affiliation: Michael E. DeBakey Department of Surgery and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Yanzhen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology and Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian, China.
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Mu
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China Michael E. DeBakey Department of Surgery and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA xfeng@bcm.edu.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000166:cytology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000378:metabolism*; D010012:Osteogenesis; D010766:Phosphorylation; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; C000599195:RanBP3L protein, human; C000599196:RanBP3L protein, mouse; D051785:Smad Proteins