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

Research output: Contribution to journalArticlepeer-review

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

Keywords

  • MAPK
  • Mouse
  • Proteasomal degradation
  • Skeletal development
  • Smads
  • Smurfs
  • Sox9

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Fingerprint Dive into the research topics of 'The MAPK Erk5 is necessary for proper skeletogenesis involving a smurf-smad-Sox9 molecular axis'. Together they form a unique fingerprint.

Cite this