USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling

Lina Herhaus, Mazin A. Al-Salihi, Kevin S. Dingwell, Timothy D. Cummins, Lise Wasmus, Janis Vogt, Richard Ewan, David Bruce, Thomas Macartney, Simone Weidlich, James C. Smith, Gopal P. Sapkota (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    25 Citations (Scopus)
    162 Downloads (Pure)

    Abstract

    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.

    Original languageEnglish
    Article number140065
    Number of pages13
    JournalOpen Biology
    Volume4
    DOIs
    Publication statusPublished - 21 May 2014

    Fingerprint Dive into the research topics of 'USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling'. Together they form a unique fingerprint.

  • Profiles

    No photo of Gopal Sapkota

    Sapkota, Gopal

    • MRC PPU - Scientific Programme Leader (MRC)

    Person: Research

    Cite this

    Herhaus, L., Al-Salihi, M. A., Dingwell, K. S., Cummins, T. D., Wasmus, L., Vogt, J., Ewan, R., Bruce, D., Macartney, T., Weidlich, S., Smith, J. C., & Sapkota, G. P. (2014). USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling. Open Biology, 4, [140065]. https://doi.org/10.1098/rsob.140065