The role of angiopoietin-like 4 in skin wound repair.

Abstract

A dynamic cell-matrix interaction is crucial for a rapid cellular response to changes in the environment. Using mice deficient in angiopoietin-like 4 (ANGPTL4) either by gene ablation or immuno-neutralization, we show that ANGPTL4 is important for the wound re-epithelialization. We demonstrate that ANGPTL4 produced by wound keratinocytes coordinates cell-matrix communication. ANGPTL4 interacts with vitronectin and fibronectin in the wound bed, delays their proteolytic degradation by metalloproteinases, and thereby regulates the availability of local extracellular matrix. Importantly, we identify integrins β1 and β5 as novel binding partners of ANGPTL4. These interactions activate the FAK-Src-PAK1 and 14-3-3-mediated signaling pathways to accelerate cell migration. Interestingly, ANGPTL4-bound integrins recruit protein kinase Cα to selectively internalized integrin that culminates in productive lamellipodia formation. The findings presented here reveal an unpredicted role of ANGPTL4. They provide insights into a novel control of keratinocyte behavior, which is mediated by ANGPTL4-mediated cell-matrix communication, and underscores the physiological importance of such modulation of integrin activity in angiogenesis and metastasis.