Do annexins participate in lipid messenger mediated intracellular signaling? A question revisited

Abstract

Annexins are physiologically important proteins that play a role in calcium buffering but also influence membrane structure, participate in Ca²⁺-dependent membrane repair events and in remodelling of the cytoskeleton. Thirty years ago several peptides isolated from lung perfusates, peritoneal leukocytes, neutrophiles and renal cells were proven inhibitory to the activity of phospholipase A₂. Those peptides were found to derive from structurally related proteins: annexins AnxA1 and AnxA2. These findings raised the question whether annexins may participate in regulation of the production of lipid second messengers and, therefore, modulate numerous lipid mediated signaling pathways in the cell. Recent advances in the field of annexins made also with the use of knock-out animal models revealed that these proteins are indeed important constituents of specific signaling pathways. In this review we provide evidence supporting the hypothesis that annexins, as membrane-binding proteins and organizers of the membrane lateral heterogeneity, may participate in lipid mediated signaling pathways by affecting the distribution and activity of lipid metabolizing enzymes (most of the reports point to phospholipase A₂) and of protein kinases regulating activity of these enzymes. Moreover, some experimental data suggest that annexins may directly interact with lipid metabolizing enzymes and, in a calcium-dependent or independent manner, with some of their substrates and products. On the basis of these observations, many investigators suggest that annexins are capable of linking Ca²⁺, redox and lipid signaling to coordinate vital cellular responses to the environmental stimuli.

Annexin-Phospholipid Interactions. Functional Implications

“…Annexins interact with membranes at specific microdomains that are characterized by their lipid composition and structure [106,107]. As previously discussed, annexins preferentially associate with PS, but they also interact with other phospholipids, such as PA, PI, PIP 2 , PE, fatty acids ( i.e ., arachidonic acid), ceramides and lipid-derived metabolites [108]. Most of these molecules participate in lipid-mediated signaling pathways that regulate key cellular processes [109].…”

Annexin A3 plays a role in cytoplasmic calcium oscillation by extracellular calcium in the human promyelocytic leukemia HL-60 cells differentiated by phorbol-12-myristate-13-acetate

“…Annexins (ANXs) function not only as an inhibitor for calcium-dependent cytosolic phospholipase A2 (cPLA2) but also as an organizer between calcium signaling and lipid signaling during remodeling of phospholipid bilayer in cell migration (Bandorowicz-Pikula et al, 2012). ANXA2 expressed in osteoblasts of bone marrow interacts with stromal cell-derived factor for localization and homing of hematopoietic stem cells via CXCR4, belongs to Gi protein-coupled receptor (GiPCR) (Jung et al, 2011).…”

Annexin A2 is a discriminative serological candidate in early hepatocellular carcinoma

“…It is located on the surface of endothelial cells and most epithelial cells (11,12). Annexin A2 has been implicated in many functions, for example, exocytosis, endocytosis, vesicle transport, regulating ion channels, immune response, cell–cell adhesions, mitogenic- and lipid-messenger-mediated signalling and fibrinolysis(11–15). The aberrated expression of annexin A2 was observed in several malignant tumors, such as colon, lung, gastric, esophageal, and breast (16–20).…”