Journal
OPEN BIOLOGY
Volume 4, Issue 5, Pages -Publisher
ROYAL SOC
DOI: 10.1098/rsob.140065
Keywords
bone morphogenetic protein; deubiquitylation; USP15; ubiquitin; ALK3; SMAD
Categories
Funding
- Medical Research Council [U117597140]
- AstraZeneca
- Boehringer-Ingelheim
- GlaxoSmithKline
- Merck-Serono
- Pfizer
- Johnson Johnson
- Medical Research Council [MC_U127092717, MC_UU_12016/3, MC_U117597140] Funding Source: researchfish
- MRC [MC_UU_12016/3, MC_U127092717, MC_U117597140] Funding Source: UKRI
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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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