Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts

Lerche, M.; Elosegui-Artola, A.; Guzman, C.; Georgiadou, M.; Kechagia, J. Z.; Gulberg, D.; Roca-Cusachs, P.; Peuhu, E.; Ivaska, J.

doi:10.1101/570721

bioRxiv · 10.1101/570721

Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts

Lerche, M.·Elosegui-Artola, A.·Guzman, C.·Georgiadou, M.·Kechagia, J. Z.·Gulberg, D.·Roca-Cusachs, P.·Peuhu, E.·Ivaska, J.

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Abstract

The link between the modulation of integrin activity and cellular mechanosensing of tissue rigidity, especially on different extracellular matrix ligands, remains poorly understood. Here, we find that primary mouse mammary gland stromal fibroblasts (MSFs) are able to spread efficiently on soft collagen-coated substrates, resembling the soft mammary gland tissue. In addition, MSFs generate high forces and display nuclear YAP at a low matrix stiffness, supported by mature focal adhesions, prominent actin stress fibers, and myosin phosphorylation. We describe that loss of the cytosolic integrin inhibitor, SHARPIN, impedes MSF spreading specifically on soft type I collagen but not on fibronectin. Through quantitative experiments and computational modelling, we find that SHARPIN-deficient MSFs display faster force-induced unbinding of adhesions from collagen-coated beads. Faster unbinding, in turn, impairs force transmission in these cells, particularly, at the stiffness optimum observed for wild-type cells, and increases actin retrograde flow. Mechanistically, we link the impaired mechanotransduction of SHARPIN-deficient cells on collagen to reduced levels of the collagen-binding integrin 11{beta}1. Our results unveil a collagen-specific mechanosensing mechanism and suggest a key function for integrin activity regulation and integrin 11{beta}1 in MSF mechanotransduction.

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Lerche, M., Elosegui-Artola, A., Guzman, C., Georgiadou, M., Kechagia, J. Z., Gulberg, D., Roca-Cusachs, P., Peuhu, E., Ivaska, J.. 2019-03-07. Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts. https://doi.org/10.1101/570721

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