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J Cell Biol. 2018 Apr 2;217(4):1431-1451. doi: 10.1083/jcb.201612177. Epub 2018 Mar 1.

Kindlin-2 regulates mesenchymal stem cell differentiation through control of YAP1/TAZ.

Author information

1
Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, and Department of Biology, Southern University of Science and Technology, Shenzhen, China.
2
Department of Biochemistry, Rush University Medical Center, Chicago, IL.
3
Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, and Department of Biology, Southern University of Science and Technology, Shenzhen, China wucy@sustc.edu.cn.
4
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Abstract

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.

PMID:
29496737
PMCID:
PMC5881491
DOI:
10.1083/jcb.201612177
[Indexed for MEDLINE]
Free PMC Article

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