GTPase-Dependent Mechanointegration of Shear-Mediated Cell Contractility Through Dynamic Binding of FLNa and FilGAP
Cellular mechanotransduction is a common mechanism by which cells convert mechanical cues (or stimuli) from their environment into biochemical and cellular responses. In the case of shearing forces, such as when individual cells encounter interstitial shear stress and blood shear stress, mechanotran...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Physics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphy.2022.890865/full |
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| author | L. P. Bergeron-Sandoval Alex Cai Alex Cai Anna Clouvel Cynthia Hitti Allen Ehrlicher Allen Ehrlicher Allen Ehrlicher Allen Ehrlicher Allen Ehrlicher |
| author_facet | L. P. Bergeron-Sandoval Alex Cai Alex Cai Anna Clouvel Cynthia Hitti Allen Ehrlicher Allen Ehrlicher Allen Ehrlicher Allen Ehrlicher Allen Ehrlicher |
| author_sort | L. P. Bergeron-Sandoval |
| collection | DOAJ |
| description | Cellular mechanotransduction is a common mechanism by which cells convert mechanical cues (or stimuli) from their environment into biochemical and cellular responses. In the case of shearing forces, such as when individual cells encounter interstitial shear stress and blood shear stress, mechanotransduction involves mechanical stretching and spatial reconfiguration of Filamin A (FLNa) binding sites and subsequent release of FilGAP molecules normally bound to FLNa. However, the connection and importance of downstream molecular effectors and cellular metrics involved in response to shear stress are not understood. Here we reveal mechano-sensitive GTPase-mediated changes in cell contractility. By varying expression of FilGAP, and expression of FLNa, we show that microfluidic shear stress results in cell contractile changes only when FilGAP and FLNa dynamically bind and dissociate. By using FRET sensors that quantify the Rho or Rac charge state, we demonstrate that only cells with dynamic FLNa and FilGAP convert shear stress into GTPase activity, and the resulting downstream contractile changes. Finally, we show that manipulation of Rho and Rac through pharmacological means rescues the contractile activity, in the absence of intact FLNa-FilGAP mechanosensing. This research clarifies a precise mechanomolecular pathway used for cellular force sensing and may play critical roles in human health challenges from cancer metastasis to cardiovascular disease. |
| first_indexed | 2024-04-12T16:42:54Z |
| format | Article |
| id | doaj.art-0aaf55eb9df14024bcf7f68926ea22f6 |
| institution | Directory Open Access Journal |
| issn | 2296-424X |
| language | English |
| last_indexed | 2024-04-12T16:42:54Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physics |
| spelling | doaj.art-0aaf55eb9df14024bcf7f68926ea22f62022-12-22T03:24:42ZengFrontiers Media S.A.Frontiers in Physics2296-424X2022-05-011010.3389/fphy.2022.890865890865GTPase-Dependent Mechanointegration of Shear-Mediated Cell Contractility Through Dynamic Binding of FLNa and FilGAPL. P. Bergeron-Sandoval0Alex Cai1Alex Cai2Anna Clouvel3Cynthia Hitti4Allen Ehrlicher5Allen Ehrlicher6Allen Ehrlicher7Allen Ehrlicher8Allen Ehrlicher9Department of Bioengineering, McGill University, Montreal, CanadaDepartment of Bioengineering, McGill University, Montreal, CanadaDepartment of Anatomy and Cell Biology, McGill University, Montreal, CanadaDepartment of Bioengineering, McGill University, Montreal, CanadaDepartment of Bioengineering, McGill University, Montreal, CanadaDepartment of Bioengineering, McGill University, Montreal, CanadaDepartment of Anatomy and Cell Biology, McGill University, Montreal, CanadaRosalind and Morris Goodman Cancer Research Institute, McGill University, Montreal, CanadaDepartment of Biomedical Engineering, McGill University, Montreal, CanadaDepartment of Mechanical Engineering, McGill University, Montreal, CanadaCellular mechanotransduction is a common mechanism by which cells convert mechanical cues (or stimuli) from their environment into biochemical and cellular responses. In the case of shearing forces, such as when individual cells encounter interstitial shear stress and blood shear stress, mechanotransduction involves mechanical stretching and spatial reconfiguration of Filamin A (FLNa) binding sites and subsequent release of FilGAP molecules normally bound to FLNa. However, the connection and importance of downstream molecular effectors and cellular metrics involved in response to shear stress are not understood. Here we reveal mechano-sensitive GTPase-mediated changes in cell contractility. By varying expression of FilGAP, and expression of FLNa, we show that microfluidic shear stress results in cell contractile changes only when FilGAP and FLNa dynamically bind and dissociate. By using FRET sensors that quantify the Rho or Rac charge state, we demonstrate that only cells with dynamic FLNa and FilGAP convert shear stress into GTPase activity, and the resulting downstream contractile changes. Finally, we show that manipulation of Rho and Rac through pharmacological means rescues the contractile activity, in the absence of intact FLNa-FilGAP mechanosensing. This research clarifies a precise mechanomolecular pathway used for cellular force sensing and may play critical roles in human health challenges from cancer metastasis to cardiovascular disease.https://www.frontiersin.org/articles/10.3389/fphy.2022.890865/fullmechanointegrationmechanotransductionmechanocomplexesshear stressfilamin AFilGAP |
| spellingShingle | L. P. Bergeron-Sandoval Alex Cai Alex Cai Anna Clouvel Cynthia Hitti Allen Ehrlicher Allen Ehrlicher Allen Ehrlicher Allen Ehrlicher Allen Ehrlicher GTPase-Dependent Mechanointegration of Shear-Mediated Cell Contractility Through Dynamic Binding of FLNa and FilGAP Frontiers in Physics mechanointegration mechanotransduction mechanocomplexes shear stress filamin A FilGAP |
| title | GTPase-Dependent Mechanointegration of Shear-Mediated Cell Contractility Through Dynamic Binding of FLNa and FilGAP |
| title_full | GTPase-Dependent Mechanointegration of Shear-Mediated Cell Contractility Through Dynamic Binding of FLNa and FilGAP |
| title_fullStr | GTPase-Dependent Mechanointegration of Shear-Mediated Cell Contractility Through Dynamic Binding of FLNa and FilGAP |
| title_full_unstemmed | GTPase-Dependent Mechanointegration of Shear-Mediated Cell Contractility Through Dynamic Binding of FLNa and FilGAP |
| title_short | GTPase-Dependent Mechanointegration of Shear-Mediated Cell Contractility Through Dynamic Binding of FLNa and FilGAP |
| title_sort | gtpase dependent mechanointegration of shear mediated cell contractility through dynamic binding of flna and filgap |
| topic | mechanointegration mechanotransduction mechanocomplexes shear stress filamin A FilGAP |
| url | https://www.frontiersin.org/articles/10.3389/fphy.2022.890865/full |
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