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.
© 2018 Guo et al.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Adipogenesis
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Animals
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Cell Cycle Proteins
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Cell Differentiation*
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Cell Lineage*
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Cytoskeletal Proteins / deficiency
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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Focal Adhesions / metabolism
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HEK293 Cells
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Mechanotransduction, Cellular
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mesenchymal Stem Cells / metabolism*
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Mice, Knockout
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Mice, Nude
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Muscle Proteins / deficiency
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Muscle Proteins / genetics
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Muscle Proteins / metabolism*
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Myosin Light Chains / metabolism
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Myosin-Light-Chain Kinase / metabolism
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Osteogenesis
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Phosphorylation
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Repressor Proteins / metabolism
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Stem Cell Niche
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Stress Fibers / metabolism
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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Ubiquitin-Protein Ligases / metabolism
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YAP-Signaling Proteins
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rhoA GTP-Binding Protein / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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Cytoskeletal Proteins
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FERMT3 protein, human
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Homeodomain Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Muscle Proteins
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Myosin Light Chains
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Neoplasm Proteins
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Phosphoproteins
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Prrx1 protein, mouse
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Repressor Proteins
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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WWTR1 protein, human
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Wwtr1 protein, mouse
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YAP-Signaling Proteins
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YAP1 protein, human
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Yap1 protein, mouse
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kindlin-2 protein, mouse
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RHOA protein, human
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ITCH protein, human
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Ubiquitin-Protein Ligases
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Myosin-Light-Chain Kinase
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rhoA GTP-Binding Protein