NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis

Hidefumi Fukushima, Kouhei Shimizu, Asami Watahiki, Seira Hoshikawa, Tomoki Kosho, Daiju Oba, Seiji Sakano, Makiko Arakaki, Aya Yamada, Katsuyuki Nagashima, Koji Okabe, Satoshi Fukumoto, Eijiro Jimi, Anna Bigas, Keiichi Nakayama, Keiko Nakayama, Yoko Aoki, Wenyi Wei, Hiroyuki Inuzuka

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Abstract

Hajdu-Cheney syndrome (HCS), a rare autosomal disorder caused by heterozygous mutations in NOTCH2, is clinically characterized by acro-osteolysis, severe osteoporosis, short stature, neurological symptoms, cardiovascular defects, and polycystic kidneys. Recent studies identified that aberrant NOTCH2 signaling and consequent osteoclast hyperactivity are closely associated with the bone-related disorder pathogenesis, but the exact molecular mechanisms remain unclear. Here, we demonstrate that sustained osteoclast activity is largely due to accumulation of NOTCH2 carrying a truncated C terminus that escapes FBW7-mediated ubiquitination and degradation. Mice with osteoclast-specific Fbw7 ablation revealed osteoporotic phenotypes reminiscent of HCS, due to elevated Notch2 signaling. Importantly, administration of Notch inhibitors in Fbw7 conditional knockout mice alleviated progressive bone resorption. These findings highlight the molecular basis of HCS pathogenesis and provide clinical insights into potential targeted therapeutic strategies for skeletal disorders associated with the aberrant FBW7/NOTCH2 pathway as observed in patients with HCS. Fukushima et al. demonstrated that the sustained osteoclast activity in Hajdu-Cheney syndrome (HCS) is largely due to elevated protein abundance of the C terminus truncating NOTCH2 mutant that escapes FBW7-mediated ubiquitination and proteolysis, suggesting that the FBW7/NOTCH2 signaling pathway is a potential therapeutic target for osteolytic bone disorders, including HCS.

Original languageEnglish
Pages (from-to)645-658.e5
JournalMolecular Cell
Volume68
Issue number4
DOIs
Publication statusPublished - Nov 16 2017

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Hajdu-Cheney Syndrome
Proteolysis
Osteoporosis
Osteoclasts
Mutation
Ubiquitination
Acro-Osteolysis
Bone and Bones
Polycystic Kidney Diseases
Bone Resorption
Protein C
Knockout Mice
Phenotype

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Fukushima, H., Shimizu, K., Watahiki, A., Hoshikawa, S., Kosho, T., Oba, D., ... Inuzuka, H. (2017). NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis. Molecular Cell, 68(4), 645-658.e5. https://doi.org/10.1016/j.molcel.2017.10.018

NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis. / Fukushima, Hidefumi; Shimizu, Kouhei; Watahiki, Asami; Hoshikawa, Seira; Kosho, Tomoki; Oba, Daiju; Sakano, Seiji; Arakaki, Makiko; Yamada, Aya; Nagashima, Katsuyuki; Okabe, Koji; Fukumoto, Satoshi; Jimi, Eijiro; Bigas, Anna; Nakayama, Keiichi; Nakayama, Keiko; Aoki, Yoko; Wei, Wenyi; Inuzuka, Hiroyuki.

In: Molecular Cell, Vol. 68, No. 4, 16.11.2017, p. 645-658.e5.

Research output: Contribution to journalArticle

Fukushima, H, Shimizu, K, Watahiki, A, Hoshikawa, S, Kosho, T, Oba, D, Sakano, S, Arakaki, M, Yamada, A, Nagashima, K, Okabe, K, Fukumoto, S, Jimi, E, Bigas, A, Nakayama, K, Nakayama, K, Aoki, Y, Wei, W & Inuzuka, H 2017, 'NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis', Molecular Cell, vol. 68, no. 4, pp. 645-658.e5. https://doi.org/10.1016/j.molcel.2017.10.018
Fukushima H, Shimizu K, Watahiki A, Hoshikawa S, Kosho T, Oba D et al. NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis. Molecular Cell. 2017 Nov 16;68(4):645-658.e5. https://doi.org/10.1016/j.molcel.2017.10.018
Fukushima, Hidefumi ; Shimizu, Kouhei ; Watahiki, Asami ; Hoshikawa, Seira ; Kosho, Tomoki ; Oba, Daiju ; Sakano, Seiji ; Arakaki, Makiko ; Yamada, Aya ; Nagashima, Katsuyuki ; Okabe, Koji ; Fukumoto, Satoshi ; Jimi, Eijiro ; Bigas, Anna ; Nakayama, Keiichi ; Nakayama, Keiko ; Aoki, Yoko ; Wei, Wenyi ; Inuzuka, Hiroyuki. / NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis. In: Molecular Cell. 2017 ; Vol. 68, No. 4. pp. 645-658.e5.
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AU - Wei, Wenyi

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