TY - JOUR
T1 - NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis
AU - Fukushima, Hidefumi
AU - Shimizu, Kouhei
AU - Watahiki, Asami
AU - Hoshikawa, Seira
AU - Kosho, Tomoki
AU - Oba, Daiju
AU - Sakano, Seiji
AU - Arakaki, Makiko
AU - Yamada, Aya
AU - Nagashima, Katsuyuki
AU - Okabe, Koji
AU - Fukumoto, Satoshi
AU - Jimi, Eijiro
AU - Bigas, Anna
AU - Nakayama, Keiichi I.
AU - Nakayama, Keiko
AU - Aoki, Yoko
AU - Wei, Wenyi
AU - Inuzuka, Hiroyuki
N1 - Funding Information:
We thank the patients, their families, and physicians for their cooperation; Dr. Osamu Suzuki (Tohoku University) for an instruction of a three-point bending test; Dr. Kiyoko Sameshima (Minami Kyushu National Hospital) for an arrangement of blood sampling from a patient; Dr. Yueyong Liu for critical technical assistance; and Dr. Brian J. North for careful proofreading of the manuscript. This work was supported by JSPS Kakenhi grants ( 17H04396 and 26462829 to H.F., 26253092 to S.F., 16H05548 to A.Y., and 16H05529 and 16K15811 to H.I.), NIH R01 grants ( GM094777 and CA177910 to W.W.), and American Cancer Society Research Scholar grants to W.W. and H.I.
PY - 2017/11/16
Y1 - 2017/11/16
N2 - 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.
AB - 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.
KW - FBW7
KW - Hajdu-Cheney syndrome
KW - NOTCH inhibitor
KW - NOTCH2
KW - SCF E3 ubiquitin ligase
KW - osteoclast
KW - osteoclastogenesis
KW - osteolysis
KW - osteoporosis
KW - ubiquitination
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U2 - 10.1016/j.molcel.2017.10.018
DO - 10.1016/j.molcel.2017.10.018
M3 - Article
C2 - 29149593
AN - SCOPUS:85034790791
VL - 68
SP - 645-658.e5
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 4
ER -