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Open Biol May 1, 2014; 4 (5): 140065.

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

Herhaus L , Al-Salihi MA , Dingwell KS , Cummins TD , Wasmus L , Vogt J , Ewan R , Bruce D , Macartney T , Weidlich S , Smith JC , Sapkota GP .

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.

PubMed ID: 24850914
PMC ID: PMC4042855
Article link: Open Biol
Grant support: MC_U117597140 Medical Research Council , U117597140 Medical Research Council , MC_U127092717 Medical Research Council , MC_UU_12016/3 Medical Research Council , MRC_MC_U117597140 Medical Research Council , MRC_MC_U127092717 Medical Research Council , MRC_MC_UU_12016/3 Medical Research Council

Genes referenced: acvr1 bmp2 bmpr1a bmpr1b foxo4 gapdh isyna1 lmna prss1 smad1 smad6 tgfbr1 usp15

Morpholinos referenced: usp15 MO1

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Al-Salihi, 2012, Pubmed [+]

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