biostudies-literatureHerhaus LMedical Research Council140065https://www.ebi.ac.uk/biostudies/studies/S-EPMC4042855biostudies-literatureUnknown4(5)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, Open biologyUSP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling.PMC4042855U117597140MC_U127092717MC_U117597140MC_UU_12016/3Cummins TDSapkota GPWasmus LEwan RBruce DHerhaus LVogt JAl-Salihi MADingwell KSMacartney TSmith JCWeidlich SfalseUSP15 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, 2014-01-01T00:00:00Z2014 May2025-04-21T20:06:07.671Z2019-03-27T01:29:22ZS-EPMC40428552485091410.1098/rsob.140065