Effects of Cell Contractility on Dynamic Movement of YAP in Living Cells

Newsha Koushki 

 

Dynamic YAP localization in contractile 3T3 cells. a) example images of EBFP-nuclei with EGFP-YAP and immunofluorescently labeled endogenous YAP demonstrate that exogenous and endogenous YAP are both found principally in the cytoplasm (YR = YAP nuclear to cytoplasmic ratio, YR < 1 YAP in cytoplasm, YR  > 1.5 YAP in nucleus. b) YAP nuclear localization (YR) is dynamic in time, and uncorrelated with substrate stiffness (color depicts substrate modulus). c) YR is correlated with cell contractile work across all investigated substrate stiffness(color depicts substrate modulus). d) YR is inversely correlated with nuclear volume, with intact or inhibited cytoskeleton.

The detailed mechanobiology of how cells biochemically transduce mechanical signals is reshaping our basic understanding of life and pathology. In particular, Yes Associated Protein (YAP) has emerged as a key mechanosensitive transcriptional factor in diverse organisms, and quite broadly in human development and pathology. In our research, we employ a variety of biophysical approaches to present a comprehensive analysis of the relationship between cell contractility, nuclear deformation, Lamin A localization, and YAP nuclear translocation.  We have found that nuclear deformation from LINC-mediated cytoskeletal contractility or extracellular osmotic forces triggers YAP nuclear localization. By modulating the expression of lamin A and nuclear stiffness, we find that nuclear rigidity modulates deformation-mediated YAP nuclear localization.

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Dr. Allen Ehrlicher

Department of Bioengineering

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