期刊
DEVELOPMENT
卷 145, 期 14, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.164004
关键词
MAPK; Smads; Smurfs; Sox9; Proteasomal degradation; Skeletal development; Mouse
资金
- Japan Society for the Promotion of Science [16H05131, 17KT0051, 18H04971]
- Japan Agency for Medical Research and Development [17824969]
- Grants-in-Aid for Scientific Research [18H04971, 17KT0051, 16H05131] Funding Source: KAKEN
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 Thr(249), which promotes the proteasomal degradation of Smad proteins and phosphorylates Smad1 at Ser(206) 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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