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

被引：51

作者：

Herhaus, Lina ^{[1
]}

Al-Salihi, Mazin A. ^{[1
]}

Dingwell, Kevin S. ^{[2
]}

Cummins, Timothy D. ^{[1
]}

Wasmus, Lize ^{[1
]}

Vogt, Janis ^{[1
]}

Ewan, Richard ^{[1
]}

Bruce, David ^{[1
]}

Macartney, Thomas ^{[1
]}

Weidlich, Simone ^{[1
]}

Smith, James C. ^{[2
]}

Sapkota, Gopal P. ^{[1
]}

机构：

[1] Univ Dundee, MRC, Prot Phosphorylat & Ubiquitylat Unit, Dundee DD1 5EH, Scotland

[2] Natl Inst Med Res, MRC, Div Syst Biol, Mill Hill NW7 1AA, England

来源：

OPEN BIOLOGY | 2014年 / 4卷 / 05期

基金：

英国医学研究理事会;

关键词：

bone morphogenetic protein; deubiquitylation; USP15; ubiquitin; ALK3; SMAD; NEURAL INDUCTION; CELL-MEMBRANE; I RECEPTOR; BETA; BMP; DEGRADATION; SMAD6; ACTIVATION; LYSOSOMES; UBIQUITIN;

D O I：

10.1098/rsob.140065

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页数：13

共 49 条

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