PT  - JOURNAL ARTICLE
AU  - Lerche, Martina
AU  - Elosegui-Artola, Alberto
AU  - Guzmán, Camilo
AU  - Georgiadou, Maria
AU  - Kechagia, Jenny Z.
AU  - Gullberg, Donald
AU  - Roca-Cusachs, Pere
AU  - Peuhu, Emilia
AU  - Ivaska, Johanna
TI  - Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts
AID  - 10.1101/570721
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 570721
4099  - http://biorxiv.org/content/early/2019/03/15/570721.short
4100  - http://biorxiv.org/content/early/2019/03/15/570721.full
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.