USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling.
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.
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dow St., Dundee DD1 5EH, UK.
Lina
L
Herhaus
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dow St., Dundee DD1 5EH, UK.
Mazin A
MA
Al-Salihi
Division of Systems Biology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill NW7 1AA, UK.
Kevin S
KS
Dingwell
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dow St., Dundee DD1 5EH, UK.
Timothy D
TD
Cummins
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dow St., Dundee DD1 5EH, UK.
Lize
L
Wasmus
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dow St., Dundee DD1 5EH, UK.
Janis
J
Vogt
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dow St., Dundee DD1 5EH, UK.
Richard
R
Ewan
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dow St., Dundee DD1 5EH, UK.
David
D
Bruce
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dow St., Dundee DD1 5EH, UK.
Thomas
T
Macartney
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dow St., Dundee DD1 5EH, UK.
Simone
S
Weidlich
Division of Systems Biology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill NW7 1AA, UK.
James C
JC
Smith
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dow St., Dundee DD1 5EH, UK g.sapkota@dundee.ac.uk.
Gopal P
GP
Sapkota
D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011719:Pyrazines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051898:Smad1 Protein / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*; D054875:Ubiquitination; D029867:Xenopus Proteins / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology*
D019485:Bone Morphogenetic Proteins; D001897:Boronic Acids; D011719:Pyrazines; D051898:Smad1 Protein; D029867:Xenopus Proteins; D000069286:Bortezomib; D052005:Bone Morphogenetic Protein Receptors, Type I; D064570:Ubiquitin-Specific Proteases
ALK3; SMAD; USP15; bone morphogenetic protein; deubiquitylation; ubiquitin