Stages of fibronectin (FN)-matrix assembly: initiation, unfolding and fibrillar assembly. (A) FN initiation involves interactions with cell-surface receptors: (i) FNI1-5 within the 70-kDa domain binds to cell-surface receptors possibly including integrins, (ii) FNIII9-10 binds to integrin α5β1, (iii) integrin activation by outside-in or inside-out signaling induces integrins to adopt a high-affinity state and allow FN binding and (iv) FNIII12-14 binds to heparan sulfate proteoglycans (HSPGs). (B) FN unfolding: (i) FN binding to cell-surface receptors induces cyctoskeletal reorganization of the actin cytoskeleton and myosin II-dependent contractility that results in (ii) receptor clustering and translation. This causes the tethered FN molecules to become unfolded. (C) Unfolding of FN results in the exposure of FN binding sites that allow FN-FN intermolecular interactions to occur. The domains important for each step are circled and denoted.