期刊
JOURNAL OF CELL BIOLOGY
卷 217, 期 4, 页码 1431-1451出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201612177
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类别
资金
- Chinese Ministry of Science and Technology [2016YFC1302100]
- Science and Technology Innovation Committee of Shenzhen Municipality [JCYJ20150831142427959, ZDS YS20140509142721429]
- National Natural Science of Foundation of China [81430068, 31471311, 31401187]
- Natural Science Foundation of Guangdong Province [2015A030313763, 2017B030301018]
- National Institutes of Health [AR068950]
Precise control of mesenchymal stem cell (MSC) differentiation is critical for tissue development and regeneration. We show here that kindlin-2 is a key determinant of MSC fate decision. Depletion of kindlin-2 in MSCs is sufficient to induce adipogenesis and inhibit osteogenesis in vitro and in vivo. Mechanistically, kindlin-2 regulates MSC differentiation through controlling YAP1/TAZ at both the transcript and protein levels. Kindlin-2 physically associates with myosin light-chain kinase in response to mechanical cues of cell microenvironment and intracellular signaling events and promotes myosin light-chain phosphorylation. Loss of kindlin-2 inhibits RhoA activation and reduces myosin light-chain phosphorylation, stress fiber formation, and focal adhesion assembly, resulting in increased Ser127 phosphorylation, nuclear exclusion, and ubiquitin ligase atrophin-1 interacting protein 4-mediated degradation of YAP1/TAZ. Our findings reveal a novel kindlin-2 signaling axis that senses the mechanical cues of cell microenvironment and controls MSC fate decision, and they suggest a new strategy to regulate MSC differentiation, tissue repair, and regeneration.
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