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

• 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
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• 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.

Research Products

• [Journal Article] Bone Resorption Is Regulated by Circadian Clock in Osteoblasts. (2017)
  • Author(s): Takarada T, Xu C, Ochi H, Nakazato R, Yamada D, Nakamura S, Kodama A, Shimba S, Mieda M, Fukasawa K, Ozaki K, Iezaki T, Fujikawa K, Yoneda Y, Numano R, Hida A, Tei H, Takeda S, Hinoi E.
  • Journal Title: J Bone Miner Res. Volume: 32 Issue: 4 Pages: 872-881
  • DOI: 10.1002/jbmr.3053
  • Peer Reviewed
• [Journal Article] The transcriptional modulator Ifrd1 controls PGC-1α expression under short-term adrenergic stimulation in brown adipocytes (2017)
  • Author(s): Park Gyujin、Horie Tetsuhiro、Kanayama Takashi、Fukasawa Kazuya、Iezaki Takashi、Onishi Yuki、Ozaki Kakeru、Nakamura Yukari、Yoneda Yukio、Takarada Takeshi、Hinoi Eiichi
  • Journal Title: The FEBS Journal Volume: 284 Issue: 5 Pages: 784-795
  • DOI: 10.1111/febs.14019
  • Peer Reviewed
• [Journal Article] Daily oral intake of β-cryptoxanthin ameliorates neuropathic pain (2017)
  • Author(s): Park Gyujin、Horie Tetsuhiro、Iezaki Takashi、Okamoto Maika、Fukasawa Kazuya、Kanayama Takashi、Ozaki Kakeru、Onishi Yuki、Sugiura Minoru、Hinoi Eiichi
  • Journal Title: Biosci Biotechnol Biochem Volume: 81 Issue: 5 Pages: 1014-1017
  • DOI: 10.1080/09168451.2017.1280661
  • Peer Reviewed
• [Journal Article] Amelioration of the Development of Osteoarthritis by Daily Intake of β-Cryptoxanthin (2017)
  • Author(s): Park G, Horie T, Fukasawa K, Ozaki K, Onishi Y, Kanayama T, Iezaki T, Kaneda K, Sugiura M, Hinoi E.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 40 Issue: 7 Pages: 1116-1120
  • DOI: 10.1248/bpb.b17-00161
  • NAID: 130006846429
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed
• [Journal Article] Hypoxic Stress Upregulates the Expression of <b><i>Slc38a1</i></b> in Brown Adipocytes via Hypoxia-Inducible Factor-1α (2017)
  • Author(s): Horie Tetsuhiro、Fukasawa Kazuya、Iezaki Takashi、Park Gyujin、Onishi Yuki、Ozaki Kakeru、Kanayama Takashi、Hiraiwa Manami、Kitaguchi Yuka、Kaneda Katsuyuki、Hinoi Eiichi
  • Journal Title: Pharmacology Volume: 101 Issue: 1-2 Pages: 64-71
  • DOI: 10.1159/000480405
  • Peer Reviewed
• [Journal Article] The transcriptional modulator Ifrd1 is a negative regulator of BMP-2-dependent osteoblastogenesis. (2017)
  • Author(s): Onishi Y, Park G, Iezaki T, Horie T, Kanayama T, Fukasawa K, Ozaki K, Hinoi E.
  • Journal Title: Biochem Biophys Res Commun. Volume: 482(2) Issue: 2 Pages: 329-334
  • DOI: 10.1016/j.bbrc.2016.11.063
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ATF3 deficiency in chondrocytes alleviates osteoarthritis development. (2016)
  • Author(s): Iezaki T, Ozaki K, Fukasawa K, Inoue M, Kitajima S, Muneta T, Takeda S, Fujita H, Onishi Y, Horie T, Yoneda Y, Takarada T, Hinoi E.
  • Journal Title: J Pathol. Volume: 239(4) Issue: 4 Pages: 426-437
  • DOI: 10.1002/path.4739
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway. (2016)
  • Author(s): Iezaki T, Fukasawa K, Park G, Horie T, Kanayama T, Ozaki K, Onishi Y, Takahata Y, Nakamura Y, Takarada T, Yoneda Y, Nakamura T, Vacher J, Hinoi E.
  • Journal Title: Mol Cell Biol. Volume: 36(19) Issue: 19 Pages: 2451-2463
  • DOI: 10.1128/mcb.01075-15
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ATF3 controls proliferation of osteoclast precursor and bone remodeling. (2016)
  • Author(s): Fukasawa K, Park G, Iezaki T, Horie T, Kanayama T, Ozaki K, Onishi Y, Takahata Y, Yoneda Y, Takarada T, Kitajima S, Vacher J, Hinoi E.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 30918-30918
  • DOI: 10.1038/srep30918
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Remarks] 金沢大学 医薬保健研究域 薬学系 薬理学研究室
  • URL: http://www.p.kanazawa-u.ac.jp/~yakuri/