Inhibition of osteoclasts differentiation by CDC2-induced NFATc1 phosphorylation

Hye min Kim, Long He, Sangku Lee, Chanmi Park, Dong Hyun Kim, Ho Jin Han, Junyeol Han, Joonsung Hwang, Hyunjoo Cha-Molstad, Kyung Ho Lee, Sung Kyun Ko, Jae Hyuk Jang, In Ja Ryoo, John Blenis, Hee Gu Lee, Jong Seog Ahn, Yong Tae Kwon, Nak Kyun Soung, Bo Yeon Kim

Research output: Contribution to journalArticle

Abstract

Bone homeostasis is regulated by a balance of bone formation and bone resorption; dysregulation of bone homeostasis may cause bone-related diseases (e.g., osteoporosis, osteopetrosis, bone fracture). Members of the nuclear factor of activated T cells (NFAT) family of transcription factors play crucial roles in the regulation of immune system, inflammatory responses, cardiac formation, skeletal muscle development, and bone homeostasis. Of these, NFATc1 is a key transcription factor mediating osteoclast differentiation, which is regulated by phosphorylation by distinct NFAT kinases including casein kinase 1 (CK1), glycogen synthase kinase 3 (GSK3), and dual-specificity tyrosine-phosphorylation-regulated kinases (DYRKs). In this study, we report that cell division control protein 2 homolog (cdc2) is a novel NFAT protein kinase that inhibits NFATc1 activation by direct phosphorylation of the NFATc1 S263 residue. Cdc2 inhibitors such as Roscovitine and BMI-1026 induce reduction of phosphorylation of NFATc1, and this process leads to the inhibition of NFATc1 translocation from the nucleus to the cytoplasm, consequently increasing the nuclear pool of NFATc1. Additionally, the inhibition of cdc2-mediated NFATc1 phosphorylation causes an elevation of osteoclast differentiation or TRAP-positive staining in zebrafish scales. Our results suggest that cdc2 is a novel NFAT protein kinase that negatively regulates osteoclast differentiation.

Original languageEnglish
Article number115153
JournalBone
Volume131
DOIs
StatePublished - Feb 2020

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NFATC Transcription Factors
Osteoclasts
Phosphorylation
Cell Division
Bone and Bones
Homeostasis
Protein Kinases
Transcription Factors
Casein Kinase I
Osteopetrosis
Glycogen Synthase Kinase 3
Proteins
Muscle Development
Bone Diseases
Bone Fractures
Zebrafish
Bone Resorption
Osteogenesis
Osteoporosis
Immune System

Keywords

  • Cdc2
  • NFATc1
  • Ostecoclast
  • Zebrafish

Cite this

Kim, H. M., He, L., Lee, S., Park, C., Kim, D. H., Han, H. J., ... Kim, B. Y. (2020). Inhibition of osteoclasts differentiation by CDC2-induced NFATc1 phosphorylation. Bone, 131, [115153]. https://doi.org/10.1016/j.bone.2019.115153
Kim, Hye min ; He, Long ; Lee, Sangku ; Park, Chanmi ; Kim, Dong Hyun ; Han, Ho Jin ; Han, Junyeol ; Hwang, Joonsung ; Cha-Molstad, Hyunjoo ; Lee, Kyung Ho ; Ko, Sung Kyun ; Jang, Jae Hyuk ; Ryoo, In Ja ; Blenis, John ; Lee, Hee Gu ; Ahn, Jong Seog ; Kwon, Yong Tae ; Soung, Nak Kyun ; Kim, Bo Yeon. / Inhibition of osteoclasts differentiation by CDC2-induced NFATc1 phosphorylation. In: Bone. 2020 ; Vol. 131.
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title = "Inhibition of osteoclasts differentiation by CDC2-induced NFATc1 phosphorylation",
abstract = "Bone homeostasis is regulated by a balance of bone formation and bone resorption; dysregulation of bone homeostasis may cause bone-related diseases (e.g., osteoporosis, osteopetrosis, bone fracture). Members of the nuclear factor of activated T cells (NFAT) family of transcription factors play crucial roles in the regulation of immune system, inflammatory responses, cardiac formation, skeletal muscle development, and bone homeostasis. Of these, NFATc1 is a key transcription factor mediating osteoclast differentiation, which is regulated by phosphorylation by distinct NFAT kinases including casein kinase 1 (CK1), glycogen synthase kinase 3 (GSK3), and dual-specificity tyrosine-phosphorylation-regulated kinases (DYRKs). In this study, we report that cell division control protein 2 homolog (cdc2) is a novel NFAT protein kinase that inhibits NFATc1 activation by direct phosphorylation of the NFATc1 S263 residue. Cdc2 inhibitors such as Roscovitine and BMI-1026 induce reduction of phosphorylation of NFATc1, and this process leads to the inhibition of NFATc1 translocation from the nucleus to the cytoplasm, consequently increasing the nuclear pool of NFATc1. Additionally, the inhibition of cdc2-mediated NFATc1 phosphorylation causes an elevation of osteoclast differentiation or TRAP-positive staining in zebrafish scales. Our results suggest that cdc2 is a novel NFAT protein kinase that negatively regulates osteoclast differentiation.",
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author = "Kim, {Hye min} and Long He and Sangku Lee and Chanmi Park and Kim, {Dong Hyun} and Han, {Ho Jin} and Junyeol Han and Joonsung Hwang and Hyunjoo Cha-Molstad and Lee, {Kyung Ho} and Ko, {Sung Kyun} and Jang, {Jae Hyuk} and Ryoo, {In Ja} and John Blenis and Lee, {Hee Gu} and Ahn, {Jong Seog} and Kwon, {Yong Tae} and Soung, {Nak Kyun} and Kim, {Bo Yeon}",
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Kim, HM, He, L, Lee, S, Park, C, Kim, DH, Han, HJ, Han, J, Hwang, J, Cha-Molstad, H, Lee, KH, Ko, SK, Jang, JH, Ryoo, IJ, Blenis, J, Lee, HG, Ahn, JS, Kwon, YT, Soung, NK & Kim, BY 2020, 'Inhibition of osteoclasts differentiation by CDC2-induced NFATc1 phosphorylation', Bone, vol. 131, 115153. https://doi.org/10.1016/j.bone.2019.115153

Inhibition of osteoclasts differentiation by CDC2-induced NFATc1 phosphorylation. / Kim, Hye min; He, Long; Lee, Sangku; Park, Chanmi; Kim, Dong Hyun; Han, Ho Jin; Han, Junyeol; Hwang, Joonsung; Cha-Molstad, Hyunjoo; Lee, Kyung Ho; Ko, Sung Kyun; Jang, Jae Hyuk; Ryoo, In Ja; Blenis, John; Lee, Hee Gu; Ahn, Jong Seog; Kwon, Yong Tae; Soung, Nak Kyun; Kim, Bo Yeon.

In: Bone, Vol. 131, 115153, 02.2020.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibition of osteoclasts differentiation by CDC2-induced NFATc1 phosphorylation

AU - Kim, Hye min

AU - He, Long

AU - Lee, Sangku

AU - Park, Chanmi

AU - Kim, Dong Hyun

AU - Han, Ho Jin

AU - Han, Junyeol

AU - Hwang, Joonsung

AU - Cha-Molstad, Hyunjoo

AU - Lee, Kyung Ho

AU - Ko, Sung Kyun

AU - Jang, Jae Hyuk

AU - Ryoo, In Ja

AU - Blenis, John

AU - Lee, Hee Gu

AU - Ahn, Jong Seog

AU - Kwon, Yong Tae

AU - Soung, Nak Kyun

AU - Kim, Bo Yeon

PY - 2020/2

Y1 - 2020/2

N2 - Bone homeostasis is regulated by a balance of bone formation and bone resorption; dysregulation of bone homeostasis may cause bone-related diseases (e.g., osteoporosis, osteopetrosis, bone fracture). Members of the nuclear factor of activated T cells (NFAT) family of transcription factors play crucial roles in the regulation of immune system, inflammatory responses, cardiac formation, skeletal muscle development, and bone homeostasis. Of these, NFATc1 is a key transcription factor mediating osteoclast differentiation, which is regulated by phosphorylation by distinct NFAT kinases including casein kinase 1 (CK1), glycogen synthase kinase 3 (GSK3), and dual-specificity tyrosine-phosphorylation-regulated kinases (DYRKs). In this study, we report that cell division control protein 2 homolog (cdc2) is a novel NFAT protein kinase that inhibits NFATc1 activation by direct phosphorylation of the NFATc1 S263 residue. Cdc2 inhibitors such as Roscovitine and BMI-1026 induce reduction of phosphorylation of NFATc1, and this process leads to the inhibition of NFATc1 translocation from the nucleus to the cytoplasm, consequently increasing the nuclear pool of NFATc1. Additionally, the inhibition of cdc2-mediated NFATc1 phosphorylation causes an elevation of osteoclast differentiation or TRAP-positive staining in zebrafish scales. Our results suggest that cdc2 is a novel NFAT protein kinase that negatively regulates osteoclast differentiation.

AB - Bone homeostasis is regulated by a balance of bone formation and bone resorption; dysregulation of bone homeostasis may cause bone-related diseases (e.g., osteoporosis, osteopetrosis, bone fracture). Members of the nuclear factor of activated T cells (NFAT) family of transcription factors play crucial roles in the regulation of immune system, inflammatory responses, cardiac formation, skeletal muscle development, and bone homeostasis. Of these, NFATc1 is a key transcription factor mediating osteoclast differentiation, which is regulated by phosphorylation by distinct NFAT kinases including casein kinase 1 (CK1), glycogen synthase kinase 3 (GSK3), and dual-specificity tyrosine-phosphorylation-regulated kinases (DYRKs). In this study, we report that cell division control protein 2 homolog (cdc2) is a novel NFAT protein kinase that inhibits NFATc1 activation by direct phosphorylation of the NFATc1 S263 residue. Cdc2 inhibitors such as Roscovitine and BMI-1026 induce reduction of phosphorylation of NFATc1, and this process leads to the inhibition of NFATc1 translocation from the nucleus to the cytoplasm, consequently increasing the nuclear pool of NFATc1. Additionally, the inhibition of cdc2-mediated NFATc1 phosphorylation causes an elevation of osteoclast differentiation or TRAP-positive staining in zebrafish scales. Our results suggest that cdc2 is a novel NFAT protein kinase that negatively regulates osteoclast differentiation.

KW - Cdc2

KW - NFATc1

KW - Ostecoclast

KW - Zebrafish

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