The MAPK Erk5 is necessary for proper skeletogenesis through a molecular axis that involves Smurfs-Smads-Sox9

2017 Fiscal Year Final Research Report

• Project/Area Number: 16H06825
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: Kanazawa University
• Principal Investigator: IEZAKI Takashi 金沢大学, 先端科学・イノベーション推進機構, 博士研究員 (30784285)
• Project Period (FY): 2016-08-26 – 2018-03-31
• Keywords: キナーゼ / 軟骨細胞 / 骨関節疾患 / 骨格形成

Outline of Final Research Achievements

Erk5 belongs to the MAPK family. Following its phosphorylation by Mek5, Erk5 modulates several signaling pathways in a number of cell types. Here, we show that Erk5 inactivation in mesenchymal cells caused abnormalities in skeletal development by inducing the protein level of Sox9, which is 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 from Erk5-deficient mice rescued some abnormalities of skeletogenesis. These findings highlight the critical requirement of the Mek5-Erk5-Smurfs-Smads-Sox9 axis in mammalian skeletogenesis.

Free Research Field

骨格形成