Annexin A2 heterotetramer in monocyte invasiveness
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AbstractGeneration of plasmin is central to cell movement during wound healing, tumor metastasis, and inflammation, and is accelerated when plasminogen binds to cell surface receptors bearing lysine at their carboxy-terminus. The identity of the plasminogen receptor(s) responsible for regulating plasmin generation at the cell surface is currently unclear. In this study we found that the candidate plasminogen receptor, annexin A2 heterotetramer, accelerates the generation of plasmin by tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA), and that this acceleration is dependent upon lysine residues at the carboxy-terminus of the S100AI0 subunit of the heterotetramer. Physiological concentrations of plasma carboxypeptidases were capable of abrogating the effect on plasmin generation, by removal of both the ultimate and penultimate lysine residues from SIOOAI0, suggesting a possible mechanism of regulating plasmin formation in vivo. It was found that SIOOAI0 expression was induced in the monocytoid cell lines, THP-I and U937, by high cell culture density, which was dependent upon de novo proteinsynthesis. Increased cell surface expression of SIOOAI0 was induced upon differentiation of THP-I cells by exposure to phorbol 12-myristate 13acetate, interferon y, fibronectin, and la, 25-dihydroxyvitamin D3 and correlated with an increase in cellular plasminogen binding. Annexin A2 heterotetramer localized to discrete regions of the surface of a subpopulation of cells after polarization. This distribution overlapped to a great degree with that of the uPA receptor, which is known to redistribute to the leading edge of polarized cells. Importantly, plasminogen was also found to localize to these discrete membrane regions and also largely colocalized with SIOOAlO. Specific downregulation of SIOOAIO expression by small interfering RNA led to a decrease in extracellular levels of both S1OOAI0 and annexin A2, as well as a decrease in the rate of plasminogen activation on the surface of THP-I cells. In addition, invasion of both THP-l cells and K562 cells through physiological extracellular matrix was inhibited by siRNA-mediated reduction of SlOOAIO expression. Thus the current work establishes that S1OOAlOis a regulated cell surface protein that is directly involved in cellular plasmin production and contributes to the invasiveness of monocytoid cells.
Bibliography: p. 175-195