Abstract
The plasminogen receptors mediate the production and localization to the cell surface of the broad spectrum proteinase, plasmin. S100A10 is a key regulator of cellular plasmin production and may account for as much as 50% of cellular plasmin generation. In parallel to plasminogen, the plasminogen-binding site on S100A10 is highly conserved from mammals to fish. S100A10 is constitutively expressed in many cells and is also induced by many diverse factors and physiological stimuli including dexamethasone, epidermal growth factor, transforming growth factor-α, interferon-γ, nerve growth factor, keratinocyte growth factor, retinoic acid, and thrombin. Therefore, S100A10 is utilized by cells to regulate plasmin proteolytic activity in response to a wide diversity of physiological stimuli. The expression of the oncogenes, PML-RARα and KRas, also stimulates the levels of S100A10, suggesting a role for S100A10 in pathophysiological processes such as in the oncogenic-mediated increases in plasmin production. The S100A10-null mouse model system has established the critical role that S100A10 plays as a regulator of fibrinolysis and oncogenesis. S100A10 plays two major roles in oncogenesis, first as a regulator of cancer cell invasion and metastasis and secondly as a regulator of the recruitment of tumor-associated cells, such as macrophages, to the tumor site.
Highlights
Several fundamental studies have shown that cellular receptors for plasminogen play a major role in the regulation of important physiological processes such as fibrinolysis and in the development of disease, such as cancer [1,2,3,4]
In vitro studies have demonstrated that when HT1080 fibrosarcoma cells were transfected with antisense S100A10, resulting in depletion of S100A10 but not annexin A2, plasmin production was reduced by 95% and extracellular matrix hydrolysis was decreased by almost 70% in comparison to the vector controls
Taking into consideration that the annexin A2-depleted telomerase immortalized microvascular endothelial (TIME) cells were depleted of S100A10, we concluded that the loss of cell surface annexin A2 did not affect plasminogen binding or plasmin generation in these endothelial cells. In view of these results we have proposed that annexin A2 functions to stabilize S100A10 protein levels and to localize S100A10 to the cell surface of endothelial cells, while S100A10 is directly responsible for plasminogen binding and plasmin generation by endothelial cells [12]
Summary
Several fundamental studies have shown that cellular receptors for plasminogen play a major role in the regulation of important physiological processes such as fibrinolysis and in the development of disease, such as cancer [1,2,3,4]. S100A10 possesses two carboxyl-terminal lysine residues that have been shown to bind both tPA and plasminogen and to play a critical role in the conversion of plasminogen to plasmin by the plasminogen activators [19, 20]. We will summarize our observations that document that S100A10 is responsible for a significant amount of total cellular plasmin generation and develop the second theme that S100A10 plays a key role in physiological processes, such as fibrinolysis and inflammation.
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