Abstract

Bone morphogenetic proteins (BMPs) play vital roles in regulating stemcell maintenance and differentiation. BMPs can induce osteogenesis and inhibit myogenesis of mesenchymalstem cells. Canonical BMPsignaling is stringently controlled through reversible phosphorylation and nucleocytoplasmic shuttling of Smad1, Smad5 and Smad8 (Smad1/5/8). However, how nuclearexport of Smad1/5/8 is regulated remains unclear. Here we report that Ran-binding protein RanBP3L acts as a nuclearexport factor for Smad1/5/8. RanBP3L directly recognizes dephosphorylated Smad1/5/8 and mediates their nuclearexport in a Ran-dependent manner. Increased expression of RanBP3L blocks BMP-induced osteogenesis of mouse bone marrow derived mesenchymalstem cells and promotes myogenic induction of C2C12 mouse myoblasts, whereas depletion of RanBP3L expression enhances BMP-dependent stemcelldifferentiation 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 BMPsignaling and regulating mesenchymalstemcelldifferentiation.

Text link: http://mcb.asm.org/content/early/2015/03/03/MCB.00121-15.long