Cutaneous wound healing is a complex and highly coordinated process of proliferation and migration of keratinocytes at the wound edge through interactions of different signaling molecules. Growth factors, transmembrane protein integrins and extracellular matrix play an important role in epidermal wound healing process, although the interplay among these proteins is poorly understood. Angiopoietin-like 4 (ANGPTL4), which is a secreted protein, exemplifies the first known non-inflammatory factor that is produced by the keratinocytes and adipocytes, and thus represents a novel connection threading wound repair, diabetes and obesity. We show here that the interacting partners of ANGPTL4 are vitronectin and fibronectin present in wound site. We also identify integrins β1 and β5 as binding partners of ANGPTL4, which form a functional ternary complex when present with its cognate matrix protein. This ternary complex modulates cell-matrix communication and enhances the keratinocyte migration through the formation of extended lamellipodia in human keratinocytes during wound healing process.