Role of Angiopoietin-like 4 (ANGPTL4), a Member of Matricellular Proteins: from Homeostasis to Inflammation and Cancer Metastasis

ANGPTL4 is a member of the angiopoietin/angiopoietin-like gene family and encodes a glycosylated, secreted protein consisting of a signal sequence, N-terminal coiled-coil and a fibrinogen like C-terminal domain. The encoded protein has emerged as a member of dynamically expressed, extracellular matrix-associated proteins that play critical roles in regulating glucose homeostasis, lipid metabolism, and insulin sensitivity and also acts as an apoptosis survival factor for vascular endothelial cells. Recent studies have uncovered novel ANGPTL4 activities unexpected for matricellular proteins, including the ability to modulate integrin-mediated signaling and added a new facet to the cell-matrix interactions and signaling during wound repair and cancer metastasis. ANGPTL4 function primarily through direct binding to specific integrin receptors, thereby triggering signal transduction events that by modulating gene expression culminate in the regulation of cell adhesion, migration, proliferation, differentiation and survival. This review surveys the published data on molecular functions and mechanism by which ANGPTL4 exerts its effects. We also discuss use of ANGPTL4 as diagnostic or prognostic marker for wound healing process and cancer; and highlight the therapeutic potential of this ligand, as well as possible limitations to its use. We also consider the data on ANGPTL4 receptors and speculate on how to maximize therapeutic benefit.