Open AccessUSP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling
Author(s) -
Lina Herhaus,
Mazin A. Al-Salihi,
Kevin S. Dingwell,
Timothy D. Cummins,
Lize Wasmus,
J. Vogt,
Richard Ewan,
David L. Bruce,
Thomas Macartney,
Simone Weidlich,
James C. Smith,
Gopal P. Sapkota
Publication year - 2014
Publication title -
open biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.078
H-Index - 53
ISSN - 2046-2441
DOI - 10.1098/rsob.140065
Subject(s) - biology , bone morphogenetic protein , microbiology and biotechnology , bmpr2 , signalling , bone morphogenetic protein 4 , hedgehog signaling pathway , signal transduction , bone morphogenetic protein receptor , bone morphogenetic protein 2 , genetics , in vitro , gene
Protein kinase ALK3/BMPR1A mediates bone morphogenetic protein (BMP) signalling through phosphorylation and activation of SMADs 1/5/8. SMAD6, a transcriptional target of BMP, negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin-mediated degradation. Here, we identify a deubiquitylating enzyme USP15 as an interactor of SMAD6 and ALK3. We show that USP15 enhances BMP-induced phosphorylation of SMAD1 by interacting with and deubiquitylating ALK3. RNAi -mediated depletion of USP15 increases ALK3 K48-linked polyubiquitylation, and reduces both BMP-induced SMAD1 phosphorylation and transcription of BMP target genes. We also show that loss of USP15 expression from mouse myoblast cells inhibits BMP-induced osteoblast differentiation. Furthermore, USP15 modulates BMP-induced phosphorylation of SMAD1 and transcription during Xenopus embryogenesis.
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