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

Lina Herhaus; Mazin A. Al-Salihi; Kevin S. Dingwell; Timothy D. Cummins; Lise Wasmus; Janis Vogt; Richard Ewan; David Bruce; Thomas Macartney; Simone Weidlich; James C. Smith; Gopal P. Sapkota

doi:10.1098/rsob.140065

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

Lina Herhaus, Mazin A. Al-Salihi, Kevin S. Dingwell, Timothy D. Cummins, Lise Wasmus, Janis Vogt, Richard Ewan, David Bruce, Thomas Macartney, Simone Weidlich, James C. Smith, Gopal P. Sapkota (Lead / Corresponding author)

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Abstract

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.

Original language	English
Article number	140065
Number of pages	13
Journal	Open Biology
Volume	4
DOIs	https://doi.org/10.1098/rsob.140065
Publication status	Published - 21 May 2014

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10.1098/rsob.140065

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@article{028f79bf06a947f292a29b42d697eb86,

title = "USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling",

abstract = "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.",

author = "Lina Herhaus and Al-Salihi, {Mazin A.} and Dingwell, {Kevin S.} and Cummins, {Timothy D.} and Lise Wasmus and Janis Vogt and Richard Ewan and David Bruce and Thomas Macartney and Simone Weidlich and Smith, {James C.} and Sapkota, {Gopal P.}",

year = "2014",

month = may,

day = "21",

doi = "10.1098/rsob.140065",

language = "English",

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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.

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SN - 2046-2441

VL - 4

JO - Open Biology

JF - Open Biology

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

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

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