The interaction between uPAR and vitronectin triggers ligand‐independent adhesion signalling by integrins

Abstract

The urokinase-type plasminogen activator receptor (uPAR) is a non-integrin vitronectin (VN) cell adhesion receptor linked to the plasma membrane by a glycolipid anchor. Through structurefunction analyses of uPAR, VN and integrins, we document that uPARmediated cell adhesion to VN triggers a novel type of integrin signalling that is independent of integrin-matrix engagement. The signalling is fully active on VN mutants deficient in integrin binding site and is also efficiently transduced by integrins deficient in ligand binding. Although integrin ligation is dispensable, signalling is crucially dependent upon an active conformation of the integrin and its association with intracellular adaptors such as talin. This non-canonical integrin signalling is not restricted to uPAR as it poses no structural constraints to the receptor mediating cell attachment. In contrast to canonical integrin signalling, where integrins form direct mechanical links between the ECM and the cytoskeleton, the molecular mechanism enabling the crosstalk between non-integrin adhesion receptors and integrins is dependent upon membrane tension. This suggests that for this type of signalling, the membrane represents a critical component of the molecular clutch.

Talin determines the nanoscale architecture of focal adhesions

“…In other words, talin may exert a pulling force on both the integrin and the surrounding plasma membrane. Consistent with this, a number of studies have documented how membrane tension may influence integrin-ECM interaction (51,52). An interesting possibility is that such in-plane tensions may influence other FAs in the vicinity, thus providing a degree of local mechanical coordination.…”

Emerging properties of adhesion complexes: what are they and what do they do?

“…It is also apparent that regulation of these processes via the cytoskeleton can occur in both directions with the cytoskeleton feeding back to regulate plasma membrane organisation and signalling [62]. In this respect, it is intriguing that membrane tension can drive ligand-independent integrin signalling via urokinase receptor (uPAR) [63] and that mechanotransduction can be augmented by the glycosaminoglycan matrix component hyaluronic acid, which is frequently upregulated in cancer [64]. Furthermore, the cancer glycocalyx, a layer of glycans and glyoproteins surrounding cells, can bypass the actomyosin machinery, applying tension to matrix-bound integrins and facilitating signalling to support cancer growth and survival [65].…”

Nanomechanical and topographical imaging of living cells by atomic force microscopy with colloidal probes

“…We have tested our protocol for topographic/mechanical imaging by CPs on living cells from the lines PC12 (pheochromocytoma of the rat adrenal medulla) and MDA-MB-231 (human breast adenocarcinoma), which have been cultured in vitro and then transferred into the thermostatic AFM fluid cell and kept for a few hours at 37 • C (recently, we have also applied our protocol to characterise lamellipodial membrane tension in the newly discovered phenomenon of ligandindependent adhesion signalling by integrins 77 ). We have first investigated the effect of the finite-thickness correction on the determination of the elastic modulus, then we have studied the action of Cytochalasin-D, a cytoskeleton-targeting drug, on cellular elasticity.…”