Integrin–TGF-β crosstalk mechanisms. (A) In fibrosis and sclerosis, TGF-β signalling induces fibroblast differentiation into contractile myofibroblasts. The myofibroblasts express and deposit collagen (1), express α1β1- and α2β1-integrins that mediate collagen remodelling and contraction (2), and express αv-integrins that activate latent TGF-β from the matrix (3). (B) During TGF-β-mediated EMT of alveolar epithelial cells, integrin α3β1 forms a complex with TGF-βRs and E-cadherin, facilitating β-catenin–Smad2 complex formation and nuclear translocation. (C) During malignant progression, TGF-β frequently represses the expression of laminin and/or laminin-binding integrins α3β1 and α6β4, and induces the expression of fibronectin and integrins α5β1 and αvβ6. αvβ6 mediates migration and invasion and generates new active TGF-β, stimulating other tumour cells as well as myofibroblast differentiation in the tumour stroma. β-cat, β-catenin; Col, collagen; E-cadh, E-cadherin; EMT, epithelial-to-mesenchymal transition; FN, fibronectin; LN332, laminin 332; TGF-β, transforming growth factor-β; TGF-βR, transforming growth factor-β receptor.

Coert Margadant

TGF-β activation by integrins. (A) Protease-dependent activation by integrin αvβ8 and MMP14. (B) Protease-independent activation results from a conformational change of LAP–TGF-β induced by cell traction forces. FXa, coagulation factor X; Gαq, G protein αq; LAP, latency-associated protein; LPA, lysophosphatidic acid; LPAR2, lysophosphatidic acid receptor 2; LTBP, latent TGF-β binding protein; MMP14, matrix metalloproteinase 14; PAR1, protease-activated receptor 1; ROCK; Rho-associated kinase; TGF-β, transforming growth factor-β; TGF-βR, transforming growth factor-β receptor.

Overview of proposed integrin–TGF-β interactions during wound healing. (A) Schematic representation of the main phases in wound healing, which are explained in the figure key. (B) In the granulation tissue, TGF-β induces expression of integrins α1β1 and α2β1, which mediate fibroblast contraction, and of αv-integrins, which activate latent TGF-β. Furthermore, αvβ3 might repress TGF-β signalling by inhibiting TGF-βR expression. (C) During re-epithelialization, TGF-β stimulates the expression of fibronectin and integrins, which mediate keratinocyte migration or activate latent TGF-β. Integrin α3β1 could enhance TGF-β signalling by controlling the expression of Smad7. BM, basement membrane; Col, collagen; FN, fibronectin; LN332, laminin 332.

Arnoud Sonnenberg