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

TY - JOUR

T1 - USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling

AU - Herhaus, Lina

AU - Al-Salihi, Mazin A.

AU - Dingwell, Kevin S.

AU - Cummins, Timothy D.

AU - Wasmus, Lise

AU - Vogt, Janis

AU - Ewan, Richard

AU - Bruce, David

AU - Macartney, Thomas

AU - Weidlich, Simone

AU - Smith, James C.

AU - Sapkota, Gopal P.

PY - 2014/5/21

Y1 - 2014/5/21

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84902386193

U2 - 10.1098/rsob.140065

DO - 10.1098/rsob.140065

M3 - Article

C2 - 24850914

AN - SCOPUS:84902386193

SN - 2046-2441

VL - 4

JO - Open Biology

JF - Open Biology

M1 - 140065

ER -