Adhesion formation and Rigidity Sensing are Defined at the Nanometer Level

Session

Imaging Biomechanics

Authors

Michael Sheetz (1), Rishita Changede (2), Kashish Jain (1), Beverly Yang (1), Yunfei Cai (1), Shalom Wind (1), Haguy Wolfenson (1)

Affiliations

1. University of Texas Medical Branch
2. University of Texas Medical Branch,

Abstract text

Our ability to fabricate nanometer level features in cell substrates and to measure protein position and dynamics at the same resolution has enabled us to better understand important aspects of cell adhesions and the process of rigidity sensing.   Matrix adhesions play critical mechanical roles in cell growth and differentiation through sensing of matrix rigidity.  At the heart of fibroblast adhesions to RGD ligands are 100 nm clusters of 40-60 integrins of which only 4 need to bind to ligand (1,2.  Cell forces on integrin clusters will dissociate them rapidly if the RGD ligands are on lines that are <40 nm in width; however, 20 nm lines will support adhesions when they come within 100 nm of another 20 nm line.  We suggest that the cluster size is dependent upon the ability of integrins to sense and create membrane curvature 3(Changede, R., Rupprecht, JF, Prost, J., et al. unpublished results).  Formin-dependent actin filament assembly on closely (1-2 mm) spaced clusters enables forces to be applied that can measure the rigidity of the substrate thereby defining whether adhesions develop or disassemble 4,5.  Rigidity sensing involves a 100 nm contraction of adhesions; and if the force does not exceed 25 pN, then the adhesions will disassemble through PTPN12 dependent hydrolysis of p-tyr in adhesion proteins 4.  Tumor cells lack this early rigidity sensing system because of the depletion of any one of many sensor proteins, such as tropomyosin 2.1, filamin A or myosin IIA 6,7.  Surprisingly, when the rigidity sensor is missing in tumor cells, they are mechanosensitive and apoptose when repeatedly stretched or treated with ultrasound.   Such ultrasound mechanotherapies are becoming important for treating cancers and aging, because they seem to mimic mechanical aspects of exercise that have beneficial effects.  

References

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5            Wolfenson, H. et al. Tropomyosin controls sarcomere-like contractions for rigidity sensing and suppressing growth on soft matrices. Nat Cell Biol 18, 33-42, doi:10.1038/ncb3277 (2016).

6            Simpson, C., Sundararajan, V., Tan, T., Huang, R. & Sheetz, M. Cancer Cells in all EMT States Lack Rigidity Sensing: Depletion of Different Tumor Suppressors Causes Loss of Rigidity Sensing in Cancer Cells. BioRxivs, 2022.2006.2006.495045 (2022).

7            Yang, B. et al. Stopping transformed cancer cell growth by rigidity sensing. Nat Mater 19, 239-250, doi:10.1038/s41563-019-0507-0 (2020).