The MAPK Erk5 is necessary for proper skeletogenesis involving a smurf-smad-Sox9 molecular axis

Takashi Iezaki; Kazuya Fukasawa; Tetsuhiro Horie; Gyujin Park; Samuel Robinson; Michio Nakaya; Hiroyuki Fujita; Yuki Onishi; Kakeru Ozaki; Takashi Kanayama; Manami Hiraiwa; Yuka Kitaguchi; Katsuyuki Kaneda; Yukio Yoneda; Takeshi Takarada; X. Edward Guo; Hitoshi Kurose; Eiichi Hinoi

doi:10.1242/dev.164004

The MAPK Erk5 is necessary for proper skeletogenesis involving a smurf-smad-Sox9 molecular axis

Takashi Iezaki, Kazuya Fukasawa, Tetsuhiro Horie, Gyujin Park, Samuel Robinson, Michio Nakaya, Hiroyuki Fujita, Yuki Onishi, Kakeru Ozaki, Takashi Kanayama, Manami Hiraiwa, Yuka Kitaguchi, Katsuyuki Kaneda, Yukio Yoneda, Takeshi Takarada, X. Edward Guo, Hitoshi Kurose, Eiichi Hinoi

Pharmaceutical Health Care and Sciences Faculty

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

Abstract

Erk5 belongs to the mitogen-activated protein kinase (MAPK) family. Following its phosphorylation by Mek5, Erk5 modulates several signaling pathways in a number of cell types. In this study, we demonstrated that Erk5 inactivation in mesenchymal cells causes abnormalities in skeletal development by inducing Sox9, an important transcription factor of skeletogenesis. We further demonstrate that Erk5 directly phosphorylates and activates Smurf2 (a ubiquitin E3 ligase) at Thr²⁴⁹, which promotes the proteasomal degradation of Smad proteins and phosphorylates Smad1 at Ser²⁰⁶ in the linker region known to trigger its proteasomal degradation by Smurf1. Smads transcriptionally activated the expression of Sox9 in mesenchymal cells. Accordingly, removal of one Sox9 allele in mesenchymal cells fromErk5-deficient mice rescued some abnormalities of skeletogenesis. These findings highlight the importance of the Mek5-Erk5-Smurf-Smad-Sox9 axis in mammalian skeletogenesis.

Original language	English
Article number	dev164004
Journal	Development (Cambridge)
Volume	145
Issue number	14
DOIs	https://doi.org/10.1242/dev.164004
Publication status	Published - Jul 15 2018

All Science Journal Classification (ASJC) codes

Molecular Biology
Developmental Biology

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Iezaki, T., Fukasawa, K., Horie, T., Park, G., Robinson, S., Nakaya, M., Fujita, H., Onishi, Y., Ozaki, K., Kanayama, T., Hiraiwa, M., Kitaguchi, Y., Kaneda, K., Yoneda, Y., Takarada, T., Guo, X. E., Kurose, H., & Hinoi, E. (2018). The MAPK Erk5 is necessary for proper skeletogenesis involving a smurf-smad-Sox9 molecular axis. Development (Cambridge), 145(14), [dev164004]. https://doi.org/10.1242/dev.164004

Iezaki, T, Fukasawa, K, Horie, T, Park, G, Robinson, S, Nakaya, M, Fujita, H, Onishi, Y, Ozaki, K, Kanayama, T, Hiraiwa, M, Kitaguchi, Y, Kaneda, K, Yoneda, Y, Takarada, T, Guo, XE, Kurose, H & Hinoi, E 2018, 'The MAPK Erk5 is necessary for proper skeletogenesis involving a smurf-smad-Sox9 molecular axis', Development (Cambridge), vol. 145, no. 14, dev164004. https://doi.org/10.1242/dev.164004

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title = "The MAPK Erk5 is necessary for proper skeletogenesis involving a smurf-smad-Sox9 molecular axis",

abstract = "Erk5 belongs to the mitogen-activated protein kinase (MAPK) family. Following its phosphorylation by Mek5, Erk5 modulates several signaling pathways in a number of cell types. In this study, we demonstrated that Erk5 inactivation in mesenchymal cells causes abnormalities in skeletal development by inducing Sox9, an important transcription factor of skeletogenesis. We further demonstrate that Erk5 directly phosphorylates and activates Smurf2 (a ubiquitin E3 ligase) at Thr249, which promotes the proteasomal degradation of Smad proteins and phosphorylates Smad1 at Ser206 in the linker region known to trigger its proteasomal degradation by Smurf1. Smads transcriptionally activated the expression of Sox9 in mesenchymal cells. Accordingly, removal of one Sox9 allele in mesenchymal cells fromErk5-deficient mice rescued some abnormalities of skeletogenesis. These findings highlight the importance of the Mek5-Erk5-Smurf-Smad-Sox9 axis in mammalian skeletogenesis.",

author = "Takashi Iezaki and Kazuya Fukasawa and Tetsuhiro Horie and Gyujin Park and Samuel Robinson and Michio Nakaya and Hiroyuki Fujita and Yuki Onishi and Kakeru Ozaki and Takashi Kanayama and Manami Hiraiwa and Yuka Kitaguchi and Katsuyuki Kaneda and Yukio Yoneda and Takeshi Takarada and Guo, {X. Edward} and Hitoshi Kurose and Eiichi Hinoi",

note = "Funding Information: This work was supported in part by the Japan Society for the Promotion of Science (16H05131, 17KT0051 and 18H04971 to E.H.); and the Japan Agency for Medical Research and Development (17824969 to E.H.). Publisher Copyright: {\textcopyright} 2018. Published by The Company of Biologists Ltd.",

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AU - Iezaki, Takashi

AU - Fukasawa, Kazuya

AU - Horie, Tetsuhiro

AU - Park, Gyujin

AU - Robinson, Samuel

AU - Nakaya, Michio

AU - Fujita, Hiroyuki

AU - Onishi, Yuki

AU - Ozaki, Kakeru

AU - Kanayama, Takashi

AU - Hiraiwa, Manami

AU - Kitaguchi, Yuka

AU - Kaneda, Katsuyuki

AU - Yoneda, Yukio

AU - Takarada, Takeshi

AU - Guo, X. Edward

AU - Kurose, Hitoshi

AU - Hinoi, Eiichi

N1 - Funding Information: This work was supported in part by the Japan Society for the Promotion of Science (16H05131, 17KT0051 and 18H04971 to E.H.); and the Japan Agency for Medical Research and Development (17824969 to E.H.). Publisher Copyright: © 2018. Published by The Company of Biologists Ltd.

PY - 2018/7/15

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N2 - Erk5 belongs to the mitogen-activated protein kinase (MAPK) family. Following its phosphorylation by Mek5, Erk5 modulates several signaling pathways in a number of cell types. In this study, we demonstrated that Erk5 inactivation in mesenchymal cells causes abnormalities in skeletal development by inducing Sox9, an important transcription factor of skeletogenesis. We further demonstrate that Erk5 directly phosphorylates and activates Smurf2 (a ubiquitin E3 ligase) at Thr249, which promotes the proteasomal degradation of Smad proteins and phosphorylates Smad1 at Ser206 in the linker region known to trigger its proteasomal degradation by Smurf1. Smads transcriptionally activated the expression of Sox9 in mesenchymal cells. Accordingly, removal of one Sox9 allele in mesenchymal cells fromErk5-deficient mice rescued some abnormalities of skeletogenesis. These findings highlight the importance of the Mek5-Erk5-Smurf-Smad-Sox9 axis in mammalian skeletogenesis.

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The MAPK Erk5 is necessary for proper skeletogenesis involving a smurf-smad-Sox9 molecular axis

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