Negative feedback control of osteoclast formation through ubiquitin-mediated down-regulation of NFATc1.
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.
Kim
Jung Ha
JH
National Research Laboratory for Regulation of Bone Metabolism and Disease, Medical Research Center for Gene Regulation, Research Institute of Medical Sciences, Brain Korea 21, Chonnam National University Medical School, Gwangju 501-746, Korea.
Kim
Kabsun
K
Jin
Hye Mi
HM
Song
Insun
I
Youn
Bang Ung
BU
Lee
Seoung-Hoon
SH
Choi
Yongwon
Y
Kim
Nacksung
N
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D025801:Ubiquitin; D016173:Macrophage Colony-Stimulating Factor; D050721:Proto-Oncogene Proteins c-cbl; D016392:Proto-Oncogene Proteins pp60(c-src); C493849:Cbl protein, mouse