Negative Feedback Control of Osteoclast Formation through Ubiquitin-mediated Down-regulation of NFATc1

被引：44

作者：

Kim, Jung Ha

Kim, Kabsun

Jin, Hye Mi

Song, Insun

Youn, Bang Ung

Lee, Seoung-Hoon ^{[2
,3
]}

Choi, Yongwon ^{[3
]}

Kim, Nacksung ^{[1
]}

机构：

[1] Chonnam Natl Univ, Sch Med, Natl Res Lab Regulat Bone Metab & Dis, Med Res Ctr Gene Regulat,Res Inst Med Sci,Dept Ph, Kwangju 501746, South Korea

[2] Wonkwang Univ, Sch Dent, Dept Oral Microbiol & Immunol, Iksan 570749, South Korea

[3] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2010年 / 285卷 / 08期

基金：

美国国家卫生研究院;

关键词：

T-CELLS C1; NUCLEAR-FACTOR; CBL-B; TYROSINE PHOSPHORYLATION; GENE-EXPRESSION; RECEPTOR; DIFFERENTIATION; BONE; ACTIVATION; PROTEINS;

D O I：

10.1074/jbc.M109.042812

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The regulation of NFATc1 expression is important for osteoclast differentiation and function. Herein, we demonstrate that macrophage-colony-stimulating factor induces NFATc1 degradation via Cbl proteins in a Src kinase-dependent manner. NFATc1 proteins are ubiquitinated and rapidly degraded during late stage osteoclastogenesis, and this degradation is mediated by Cbl-b and c-Cbl ubiquitin ligases in a Src-dependent manner. In addition, NFATc1 interacts endogenously with c-Src, c-Cbl, and Cbl-b in osteoclasts. Overexpression of c-Src induces down-regulation of NFATc1, and depletion of Cbl proteins blocks NFATc1 degradation during late stage osteoclastogenesis. Taken together, our data provide a negative regulatory mechanism by which macrophage-colony-stimulating factor activates Src family kinases and Cbl proteins, and subsequently, induces NFATc1 degradation during osteoclast differentiation.

引用

页码：5224 / 5231

页数：8

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