Angiopoietin-Like 4 Interacts with Integrins β1 and β5 to Modulate Keratinocyte Migration

Adipose tissue secretes adipocytokines for energy homeostasis but recent evidence indicates that some adipocytokines also have a profound local impact on wound healing Upon skin injury keratinocytes use various signaling molecules to promote reepithelialization for efficient wound closure In this study we identify a novel function of adipocytokine angiopoietin like 4 (ANGPTL4) in keratinocytes during wound healing through the control of both integrin mediated signaling and internalization Using two different in vivo models based on topical immuno neutralization of ANGPTL4 as well as ablation of the ANGPTL4 gene we show that ANGPTL4 deficient mice exhibit delayed wound reepithelialization with impaired keratinocyte migration Human keratinocytes in which endogenous ANGPTL4 expression was suppressed by either siRNA or a neutralizing antibody show impaired migration associated with diminished integrin mediated signaling Importantly we identify integrins beta 1 and beta 5 but not beta 3 as novel binding partners of AN GPTL4 ANGPTL4-bound integrin beta 1 activated the FAK Src PAK1 signaling pathway which is important for cell migration The findings presented herein reveal an unpredicted role of ANGPTL4 during wound healing and demonstrate how ANGPTL4 stimulates intracellular signaling mechanisms to coordinate cellular behavior Our findings provide insight into a novel cell migration con trol mechanism and underscore the physiological importance of the modulation of integrin activity in cancer metastasis (Am J Pathol 2010 177 2791-2803, DOI 10 2353/ajpath 2010 100129)