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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adipogenesis
  • Animals
  • Cell Cycle Proteins
  • Cell Differentiation*
  • Cell Lineage*
  • Cytoskeletal Proteins / deficiency
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Focal Adhesions / metabolism
  • HEK293 Cells
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mechanotransduction, Cellular
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mesenchymal Stem Cells / metabolism*
  • Mice, Knockout
  • Mice, Nude
  • Muscle Proteins / deficiency
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Myosin Light Chains / metabolism
  • Myosin-Light-Chain Kinase / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Osteogenesis
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Repressor Proteins / metabolism
  • Stem Cell Niche
  • Stress Fibers / metabolism
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Ubiquitin-Protein Ligases / metabolism
  • YAP-Signaling Proteins
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • FERMT3 protein, human
  • Homeodomain Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Muscle Proteins
  • Myosin Light Chains
  • Neoplasm Proteins
  • Phosphoproteins
  • Prrx1 protein, mouse
  • Repressor Proteins
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • WWTR1 protein, human
  • Wwtr1 protein, mouse
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Yap1 protein, mouse
  • kindlin-2 protein, mouse
  • RHOA protein, human
  • ITCH protein, human
  • Ubiquitin-Protein Ligases
  • Myosin-Light-Chain Kinase
  • rhoA GTP-Binding Protein