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, Nakaya Michio, 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

Research output: Contribution to journalArticle

1 Citation (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 languageEnglish
Article numberdev164004
JournalDevelopment (Cambridge)
Volume145
Issue number14
DOIs
Publication statusPublished - Jul 15 2018

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Mitogen-Activated Protein Kinases
Smad Proteins
Ubiquitin-Protein Ligases
Transcription Factors
Cell Count
Alleles
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology

Cite this

The MAPK Erk5 is necessary for proper skeletogenesis involving a smurf-smad-Sox9 molecular axis. / Iezaki, Takashi; Fukasawa, Kazuya; Horie, Tetsuhiro; Park, Gyujin; Robinson, Samuel; Michio, Nakaya; Fujita, Hiroyuki; Onishi, Yuki; Ozaki, Kakeru; Kanayama, Takashi; Hiraiwa, Manami; Kitaguchi, Yuka; Kaneda, Katsuyuki; Yoneda, Yukio; Takarada, Takeshi; Guo, X. Edward; Kurose, Hitoshi; Hinoi, Eiichi.

In: Development (Cambridge), Vol. 145, No. 14, dev164004, 15.07.2018.

Research output: Contribution to journalArticle

Iezaki, T, Fukasawa, K, Horie, T, Park, G, Robinson, S, Michio, N, 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
Iezaki, Takashi ; Fukasawa, Kazuya ; Horie, Tetsuhiro ; Park, Gyujin ; Robinson, Samuel ; Michio, Nakaya ; Fujita, Hiroyuki ; Onishi, Yuki ; Ozaki, Kakeru ; Kanayama, Takashi ; Hiraiwa, Manami ; Kitaguchi, Yuka ; Kaneda, Katsuyuki ; Yoneda, Yukio ; Takarada, Takeshi ; Guo, X. Edward ; Kurose, Hitoshi ; Hinoi, Eiichi. / The MAPK Erk5 is necessary for proper skeletogenesis involving a smurf-smad-Sox9 molecular axis. In: Development (Cambridge). 2018 ; Vol. 145, No. 14.
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