Protease-activated receptor signalling initiates α5β1-integrin-mediated adhesion in non-haematopoietic cells.

Abstract

Haematopoietic cells and platelets employ G-protein-coupled receptors (GPCRs) to sense extracellular information and respond by initiating integrin-mediated adhesion. So far, such processes have not been demonstrated in non-haematopoietic cells. Here, we report that the activation of protease-activated receptors PAR1 and PAR2 induce multiple signalling pathways to establish α5β1-integrin-mediated adhesion. First, PARs signal via Gβγ and PI3K to α5β1-integrins to adopt a talin- and kindlin-dependent high-affinity conformation, which triggers fibronectin binding and initiates cell adhesion. Then, within 60 s, PARs signal via Gα13, Gαi, ROCK and Src to strengthen the α5β1-integrin-mediated adhesion. Furthermore, PAR signalling changes the abundance of numerous proteins in the adhesome assembled by α5β1-integrins, including Gα13, vacuolar protein-sorting-associated protein 36, and band 4.1-like protein 4B or 5, and accelerates cell adhesion maturation, spreading and migration. The mechanistic insights describe how agonist binding to PAR employs GPCR and integrin-signalling pathways to initiate and regulate adhesion and to guide physiological responses of non-haematopoietic cells.