Integrin Binding Dynamics Modulate Ligand-Specific Mechanosensing in Mammary Gland Fibroblasts

• Published in: iScience Vol. 23; no. 3; p. 100907
• Main Authors: Lerche, Martina, Elosegui-Artola, Alberto, Kechagia, Jenny Z., Guzmán, Camilo, Georgiadou, Maria, Andreu, Ion, Gullberg, Donald, Roca-Cusachs, Pere, Peuhu, Emilia, Ivaska, Johanna
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.03.2020; Elsevier
• Subjects: Biological Sciences; Cell Biology; Functional Aspects of Cell Biology; Biological Sciences; Functional Aspects of Cell Biology; Cell Biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2020.100907

The link between integrin activity regulation 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, generate high forces, and display nuclear YAP on soft collagen-coated substrates, resembling the soft mammary gland tissue. We describe that loss of the integrin inhibitor, SHARPIN, impedes MSF spreading specifically on soft type I collagen but not on fibronectin. Through quantitative experiments and computational modeling, 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. Mechanistically, we link the impaired mechanotransduction of SHARPIN-deficient cells on collagen to reduced levels of collagen-binding integrin α11β1. Thus integrin activity regulation and α11β1 play a role in collagen-specific mechanosensing in MSFs. [Display omitted] •Mammary gland stromal fibroblasts are mechanically adapted to a soft environment•Loss of SHARPIN reduces cell spreading and force generation on soft collagen•Low integrin α11β1 level in SHARPIN-null cells causes faster unbinding from collagen•Molecular clutch model predicts the lower forces based on faster integrin unbinding Biological Sciences; Cell Biology; Functional Aspects of Cell Biology