Annexin A2 Controls Lipid Composition Necessary for Junctional Stability in Response to Sphingosine 1-Phosphate

Abstract

The intersection of protein and lipid biology is of growing importance for understanding how cells respond to changes in structural needs during adhesion and migration. While protein complexes engaged with the cytoskeleton play a vital role, support from the phospholipid membrane is crucial for directing localization and ensuring proper assembly. During angiogenesis, the development of new blood vessels from pre-existing structures, it is well known that dramatic cellular remodeling between proteins and membranes is necessary as endothelial cells shift from a stable monolayer to invasive structures. We better characterized the role of annexin A2, a membrane binding protein that is known to help coordinate the actin cytoskeleton with the plasma membrane. Annexin A2 maintains organization of adherens junctions, focal adhesions, and F-actin in response to sphingosine 1-phosphate, which directly regulates the balance between sprout initiation and sprout maturation during angiogenesis. Further, lipidomic analysis revealed that annexin A2 modulates composition of specific membrane lipids upstream of cytoskeletal coordination with adherens junctions, including accumulation of phosphatidylcholine (16:0_16:0). Incorporation of excess phosphatidylcholine (16:0_16:0) in wild-type cells mimics the annexin A2 knock-down phenotype, indicating that annexin A2 regulates the phospholipid membrane upstream organization of F-actin and adherens junctions. Altogether these data present a novel function for annexin A2, and suggests proper lipid modulation is a critical component of endothelial function.