Dynamic reciprocity: the role of annexin A2 in tissue integrity

Interactions between cells and the extracellular matrix are integral to tissue development, remodelling and pathogenesis. This is underlined by bi-directional flow of information signalling, referred to as dynamic reciprocity. Annexin A2 is a complex and multifunctional protein that belongs to a large family of Ca(2+)-dependent anionic phospholipid and membrane-binding proteins. It has been implicated in diverse cellular processes at the nuclear, cytoplasmic and extracellular compartments including Ca(2+)-dependent regulation of endocytosis and exocytosis, focal adhesion dynamics, transcription and translation, cell proliferation, oxidative stress and apoptosis. Most of these functions are mediated by the annexin A2-S100A10 heterotetramer (AIIt) via its ability to simultaneously interact with cytoskeletal, membrane and extracellular matrix components, thereby mediating regulatory effects of extracellular matrix adhesion on cell behaviour and vice versa. While Src kinase-mediated phosphorylation of filamentous actin-bound AIIt results in membrane-cytoskeletal remodelling events which control cell polarity, cell morphology and cell migration, AIIt at the cell surface can bind to a number of extracellular matrix proteins and catalyse the activation of serine and cysteine proteases which are important in facilitating tissue remodelling during tissue repair, neoangiogenesis and pathological situations. This review will focus on the role of annexin A2 in regulating tissue integrity through intercellular and cell-extracellular matrix interaction. Annexin A2 is differentially expressed in various tissue types as well as in many pathologies, particularly in several types of cancer. These together suggest that annexin A2 acts as a central player during dynamic reciprocity in tissue homeostasis.