RT Journal Article
SR Electronic
T1 Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 570721
DO 10.1101/570721
A1 Martina Lerche
A1 Alberto Elosegui-Artola
A1 Camilo Guzmán
A1 Maria Georgiadou
A1 Jenny Z. Kechagia
A1 Donald Gullberg
A1 Pere Roca-Cusachs
A1 Emilia Peuhu
A1 Johanna Ivaska
YR 2019
UL http://biorxiv.org/content/early/2019/03/15/570721.abstract
AB 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 mechanically distinct from previously studied cell types. In particular, MSFs generate high forces at a low matrix stiffness, equivalent to the soft mammary gland tissue, supported by maximal focal adhesion maturation, strong actin stress fiber formation, and myosin phosphorylation. We describe that loss of the cytosolic integrin inhibitor, SHARPIN, triggers impeded spreading of MSFs specifically on soft type I collagen but not on fibronectin. Through quantitative experiments and computational modelling, we find that reduced expression of the collagen-binding integrin α11β1 in SHARPIN-deficient MSFs leads to faster force-induced unbinding of adhesions from collagen. 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. Our results unveil a collagen-specific mechanosensing mechanism and suggest a key function for integrin activity regulation and integrin α11β1 in MSF mechanotransduction.