Mechanism of angiostatin generation from plasminogen

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The protein plasminogen circulates in the blood as an inactive zymogen whereas proteolytic cleavage of the molecule produces the major extracellular protease, plasmin, which plays a crucial role in mediating cancer cell invasion and metastasis. The further cleavage of plasmin produces an antiangiogenic fragment called angiostatin. Since the first identification of angiostatin, many laboratories have suggested different mechanisms of angiostatin generation. Our laboratory has shown that annexin II tetramer (AIIt) functions as a plasminogen receptor and that AIIt enhances the destruction of plasmin via stimulation of the plasmin autoproteolysis, which results in the generation of a 61 kDa fragment. The hypothesis of this thesis was that AIIt participates in angiostatin formation. In this thesis, the following new findings are presented. First, the plasminogen fragment generated by plasmin autoproteolysis was identified as a novel antiangiogenic plasminogen fragment which we named A₆₁. In contrast to previous reports which claimed that antiangiogenic plasminogen fragments were produced exclusively by cancer cells, A₆₁ was shown to be produced by normal cells, and was also present in normal mouse and human sera. Second, a novel small antiangiogenic plasminogen fragment produced by cells was discovered and named p22. We demonstrated that p22 was a potent antiangiogenic protein that was produced by normal cells as well as cancer cells. However, unlike A₆₁, p22 was not detected in the sera from both human and mouse or in human urine. The mechanism by which cells generate p22 is not known at the present time, but it appears to be different from that of A₆₁. Third, AIIt was shown to act as a plasmin reductase, and A₆₁ generation was regulated by the extracellular expression of Allt in HT1080 fibrosarcoma cells. These findings allowed us to develop a model to define the mechanism by which HTl 080 cells generate A₆₁ from plasminogen. Although the intrinsic plasmin reductase activity of AIIt is distinct from that of the traditional protein reductases, it is suspected that AIIt functions as a catalyst. Thioredoxin reduced the oxidized AIIt both in vitro and in vivo, suggesting that thioredoxin might be one of the candidate Allt-recharging factor(s). These findings suggest that AIIt may play a role in angiogenesis by regulating the cellular release of an antiangiogenic protein.
Bibliography: p. 189-214
Kwon, M. (2004). Mechanism of angiostatin generation from plasminogen (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from doi:10.11575/PRISM/19679