Regulation of Plasmin-dependent Fibrin Clot Lysis by Annexin II Heterotetramer

In a previous report we showed that plasmin-dependent lysis of a fibrin polymer, produced from purified components, was totally blocked if annexin II heterotetramer (AIIt) was present during fibrin polymer formation. Here, we show that AIIt inhibits fibrin clot lysis by stimulation of plasmin autodegradation, which results in a loss of plasmin activity. Furthermore, the C-terminal lysine residues of its p11 subunit play an essential role in the inhibition of fibrin clot lysis by AIIt. We also found that AIIt binds to fibrin with a K d of 436 nm and a stoichiometry of about 0.28 mol of AIIt/mol of fibrin monomer. The binding of AIIt to fibrin was not dependent on the C-terminal lysines of the p11 subunit. Furthermore, in the presence of plasminogen, the binding of AIIt to fibrin was increased to about 1.3 mol of AIIt/mol of fibrin monomer, suggesting that AIIt and plasminogen do not compete for identical sites on fibrin. Immunohistochemical identification of p36 and p11 subunits of AIIt in a pathological clot provides important evidence for its role as a physiological fibrinolytic regulator. These results suggest that AIIt may play a key role in the regulation of plasmin activity on the fibrin clot surface. In a previous report we showed that plasmin-dependent lysis of a fibrin polymer, produced from purified components, was totally blocked if annexin II heterotetramer (AIIt) was present during fibrin polymer formation. Here, we show that AIIt inhibits fibrin clot lysis by stimulation of plasmin autodegradation, which results in a loss of plasmin activity. Furthermore, the C-terminal lysine residues of its p11 subunit play an essential role in the inhibition of fibrin clot lysis by AIIt. We also found that AIIt binds to fibrin with a K d of 436 nm and a stoichiometry of about 0.28 mol of AIIt/mol of fibrin monomer. The binding of AIIt to fibrin was not dependent on the C-terminal lysines of the p11 subunit. Furthermore, in the presence of plasminogen, the binding of AIIt to fibrin was increased to about 1.3 mol of AIIt/mol of fibrin monomer, suggesting that AIIt and plasminogen do not compete for identical sites on fibrin. Immunohistochemical identification of p36 and p11 subunits of AIIt in a pathological clot provides important evidence for its role as a physiological fibrinolytic regulator. These results suggest that AIIt may play a key role in the regulation of plasmin activity on the fibrin clot surface. tissue-type plasminogen activator annexin II heterotetramer ε-aminocaproic acid polyacrylamide gel electrophoresis polymerase chain reaction p-nitroanilide The formation of a fibrin polymer from its soluble precursor, fibrinogen, results from the hydrolytic catalysis of fibrinogen by thrombin, the terminal proteolytic enzyme in the coagulation cascade (1Collen D. Thromb. 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FASEB J. 1995; 9: 939-945Crossref PubMed Scopus (379) Google Scholar, 6Markus G. Fibrinolysis. 1996; 10: 75-85Crossref Scopus (40) Google Scholar, 7Magnusson S. Sottrup-Jensen L. Petersen T.E. Dudek-Wojciechowska G. Claeys H. Ribbons D.W. Brew K. Proteolysis and Physiological Regulation. Academic Press, New York1996: 38-203Google Scholar, 8Lijnen H.R. Collen D. Thromb. Haemostasis. 1995; 74: 387-390Crossref PubMed Scopus (54) Google Scholar, 9Hajjar K.A. Curr. Opin. Hematol. 1995; 2: 345-350Crossref PubMed Scopus (12) Google Scholar). Dissolution of a fibrin clot is mainly conducted by plasmin, the terminal enzyme of the fibrinolytic cascade. Plasmin, an 85-kDa serine protease, is involved in a variety of physiological and pathological processes, including fibrinolysis, wound healing, tissue remodeling, embryogenesis, and the invasion and spread of transformed tumor cells (5Plow E.F. Herren T. Redlitz A. Miles L.A. Hoover-Plow J.L. 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Active plasmin is produced from two serial activation processes. First, [Glu]plasminogen is converted to the more reactive [Lys]plasminogen by plasmin itself through proteolytic removal of the N-terminal 77 amino acids. Second, plasmin also activates the plasminogen activators, tissue-type plasminogen activator (tPA)1 and urokinase-type plasminogen activator, which, in turn, convert [Lys]- or [Glu]plasminogen to plasmin (13Henkin J. Marcotte P. Yang H.C. Prog. Cardiovasc. Dis. 1991; 34: 135-164Crossref PubMed Scopus (66) Google Scholar). It is well established that fibrin stimulates the rate of tPA-dependent plasminogen activation by at least two orders of magnitude due to the localization of plasminogen and tPA to the fibrin surface via their lysine-binding kringle domains (17Suenson E. Lutzen O. Thorsen S. Eur. J. Biochem. 1984; 140: 513-522Crossref PubMed Scopus (195) Google Scholar, 18Fleury V. Angles-Cano E. Biochemistry. 1991; 30: 7630-7638Crossref PubMed Scopus (182) Google Scholar). Other proteins, such as the histidine-proline rich glycoproteins or certain extracellular matrix proteins that interact with the kringle domains of plasminogen, have also been shown to stimulate plasminogen activation (19Borza D.B. Morgan W.T. J. Biol. Chem. 1997; 272: 5718-5726Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 20Moser T.L. Enghild J.J. Pizzo S.V. Stack M.S. J. Biol. Chem. 1993; 268: 18917-18923Abstract Full Text PDF PubMed Google Scholar, 21Stack S. Gonzalez-Gronow M. Pizzo S.V. Biochemistry. 1990; 29: 4966-4970Crossref PubMed Scopus (68) Google Scholar). Typically, these interactions involve the binding of the kringle domains with the C-terminal lysine residues of the plasminogen-binding protein. Hajjar's group recently reported that the Ca2+-binding protein, annexin II, stimulated the tPA-dependent formation of plasmin from [Glu]plasminogen or [Lys]plasminogen 20-fold or 14-fold, respectively, in vitro. They also reported that plasminogen activation was inhibited on human umbilical vein endothelial cell surfaces after transfection of these cells with antisense oligonucleotides directed against annexin II mRNA, suggesting that annexin II may function as a fibrinolytic receptor for plasminogen on the surface of endothelial cells (23Cesarman G.M. Guevara C.A. Hajjar K.A. J. Biol. Chem. 1994; 269: 21198-21203Abstract Full Text PDF PubMed Google Scholar, 24Hajjar K.A. Harpel P.C. Jaffe E.A. Nachman R.L. J. Biol. Chem. 1986; 261: 11656-11662Abstract Full Text PDF PubMed Google Scholar, 25Hajjar K.A. Nachman R.L. J. Clin. Invest. 1988; 82: 1769-1778Crossref PubMed Scopus (73) Google Scholar, 26Hajjar K.A. Menell J.S. Ann. N. Y. Acad. Sci. 1997; 811: 337-349Crossref PubMed Scopus (52) Google Scholar, 27Hajjar K.A. Jacovina A.T. Chacko J. J. Biol. Chem. 1994; 269: 21191-21197Abstract Full Text PDF PubMed Google Scholar). Annexin II was originally described as an intracellular Ca2+- and phospholipid-binding protein, and subsequent studies suggested that this protein could be involved in regulating membrane trafficking events such as exocytosis or endocytosis (28Waisman D.M. Mol. Cell Biochem. 1995; 149/150: 301-322Crossref Scopus (259) Google Scholar). Surprisingly, annexin II not a C-terminal lysine and the by which this protein with plasminogen was Annexin II also in cells as a annexin II heterotetramer which of two annexin II to as the p36 subunit and two of an subunit to as the p11 p11 two lysine residues at its to of the annexin II is present in the in cells such as and endothelial cells V. K. J. 1984; 227-233Crossref PubMed Scopus Google Scholar, V. J. G. S. K. G. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus (68) Google Scholar). was established that AIIt binds plasminogen, and plasmin and stimulates tPA-dependent plasminogen activation about in G. J. T. S. M. A. D.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). activation was by binding of plasminogen kringle domains to the C-terminal lysine of the p11 suggesting that the p11 subunit the of the stimulation of tPA-dependent plasminogen Furthermore, and established the of p11 and annexin II on the surface of human umbilical vein endothelial cells G. J. T. S. M. A. D.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google human human cells J. D.M. PubMed Scopus Google Scholar, J. R.L. D.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and in in these evidence that AIIt a key role in plasminogen activation on the cell surface. We recently reported that AIIt inhibited the fibrinolytic activity of plasmin J. G. D.M. Biochemistry. PubMed Scopus Google Scholar). These conducted fibrin from purified in a J. G. D.M. Biochemistry. PubMed Scopus Google Scholar). We also that AIIt with the fibrin clot in J. G. D.M. Biochemistry. PubMed Scopus Google Scholar). In a of we showed that of AIIt and plasmin in the stimulation of the of the plasmin and in a in plasmin activity G. J. T. S. M. A. D.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). It was from results if the activity of AIIt was due to its stimulation of plasmin or due to its to with fibrin the of plasmin with fibrin. In the present we that the activity of AIIt is due to its stimulation of plasmin by a that the C-terminal lysine residues of the p11 subunit. ε-aminocaproic acid and from tPA was from was purified by on Biochem. 1991; PubMed Scopus Google and was an chain as by plasmin, the plasmin and the tPA from was from and purified by on to Annexin II (AIIt) was from as described S. R. D.M. Biochemistry. 1990; 29: PubMed Scopus (66) Google Scholar). annexin II monomer and p11 subunits in as described G. D.M. Biochemistry. 1997; PubMed Scopus Google G. S. P. D.M. Biochemistry. PubMed Scopus Google Scholar). of annexin II from involved on on and gel on of p11 involved on and and gel on AIIt was by annexin II and p11 by gel on proteins at in and and annexin II from The the of human annexin II was by Ca2+-binding sites of annexin II and the in the annexin II to an for M. K. V. Biochem. J. 1994; PubMed Scopus Google Scholar). was to the D.M. J. Biol. Chem. Full Text Full Text PDF Scopus Google Scholar). The annexin II was from the D.M. J. Biol. Chem. Full Text Full Text PDF Scopus Google Scholar). The reaction in a the amino acid of annexin II and not for the amino as was to the with the was These transformed E. and as described G. D.M. Biochemistry. 1997; PubMed Scopus Google Scholar). The of the p11 subunit the two C-terminal lysine was produced by as described G. S. P. D.M. Biochemistry. PubMed Scopus Google Scholar). The was by to and The of the in E. and the subsequent as described G. D.M. Biochemistry. 1997; PubMed Scopus Google Scholar). polymer lysis in a of at a to in at nm J. G. D.M. Biochemistry. PubMed Scopus Google Scholar). fibrin by of with in and at a of nm plasmin and such as or proteins on of the fibrin polymer reaction and was as described J. G. D.M. Biochemistry. PubMed Scopus Google Scholar). AIIt and [Glu]plasminogen as described E. Thorsen S. Biochemistry. 1988; PubMed Scopus Google Scholar). AIIt or plasminogen was for at with of and in and protein a and with A. The activity of the protein from to of protein. as described for the fibrin polymer lysis a fibrin clot lysis was by nm plasminogen and nm tPA with or AIIt. of at of reaction was to and the of plasminogen or plasmin degradation was by The by a and polymerization was by of to a of to fibrinogen, and of AIIt in A. the binding of AIIt to fibrin in the presence of plasminogen, fibrin was by of fibrinogen, and of plasminogen in the or presence of E. P. A. M. J. Petersen J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar). for at and by at for at The with and AIIt to the fibrin clot was from of the fibrin of the in the was from that of the in the binding was of in by of fibrinogen with in as described The of plasminogen activation in the or presence of AIIt on fibrin was by activity of the plasmin during activation of The reaction was with the at a of and in nm tPA in the or presence of AIIt. plasmin formation on the fibrin clot was in the presence of of AIIt. The reaction was by the of [Glu]plasminogen and was at nm in a of plasmin of as G. PubMed Scopus Google Scholar). was with the the to the nm K is the rate for the of is the the rate of p-nitroanilide from a of plasminogen, and K was to the rate of plasmin formation from Typically, the of plasmin reported in tissue was from an of a a The tissue was in and in from the and on The and was a with a was at an in the was with to a of the II was to a of with for The with and the which a with a was are of a of fibrinogen, and [Glu]plasminogen the and We reported that the plasmin-dependent lysis of a fibrin polymer, produced from purified components, was totally blocked if AIIt was present during fibrin polymer formation J. G. D.M. Biochemistry. PubMed Scopus Google Scholar). It was from these studies in the presence of AIIt inhibited plasmin activity or inhibited plasmin activity by plasmin We an in fibrin polymer lysis to this In this fibrin was from fibrinogen by and fibrin polymer was by of plasmin in the presence or of AIIt. clot polymerization and subsequent lysis with a shown in the two of fibrin polymerization and fibrinolysis are by an in to a after of plasmin to the fibrin polymer, a subsequent to the of of the fibrin clot was in the presence of AIIt. the inhibition of plasmin fibrinolytic activity was blocked by in a been shown to plasmin not plasmin-dependent clot lysis J. J. T. Thromb. 1986; Full Text PDF PubMed Scopus Google Scholar). suggested that AIIt blocked fibrin clot lysis by plasmin autodegradation, the of plasmin for fibrin clot It been that plasmin results in a loss in plasmin activity and degradation of the plasmin and if AIIt blocked fibrin clot lysis via stimulation of plasmin autodegradation, we the plasmin reaction during was with thrombin, after a fibrin clot was plasminogen was to the and fibrinolysis was by of the reaction by shown in in the presence of tPA converted plasminogen plasmin as by the of the chain and chain of In AIIt was to the degradation of the plasmin and chain was of the showed that of the chain and of the chain of plasmin after with AIIt. Furthermore, in the presence of of the chain and of the chain of plasmin These results that the inhibition of fibrin clot lysis by AIIt is due to its of plasmin AIIt is a Ca2+-binding protein, and binding of to the p36 subunit of its (28Waisman D.M. Mol. Cell Biochem. 1995; 149/150: 301-322Crossref Scopus (259) Google Scholar, G. M. D.M. Cardiovasc. Med. 1999; 9: PubMed Scopus (52) Google Scholar). The p36 subunit of AIIt established Ca2+-binding We a AIIt to if the Ca2+-binding sites of AIIt a role in the inhibition of fibrin clot which Ca2+-binding sites of the p36 subunit blocked plasmin-dependent fibrin clot lysis in a to AIIt suggested that the Ca2+-binding sites in the p36 subunit of AIIt do not play a role in the of AIIt on fibrin clot AIIt binds plasminogen via the C-terminal lysine residues of its p11 subunit G. S. P. D.M. Biochemistry. PubMed Scopus Google Scholar). of the C-terminal lysines the of AIIt to tPA-dependent plasminogen to plasmin G. S. P. D.M. Biochemistry. PubMed Scopus Google Scholar). if the C-terminal lysines of the p11 subunit of AIIt in the activity of we plasmin-dependent fibrin clot lysis in the presence of AIIt two p11 C-terminal lysine residues The results show the and not plasmin-dependent fibrin clot these suggested that the C-terminal lysine residues of AIIt play an important role in the of AIIt on fibrin clot We that AIIt with a fibrin clot J. G. D.M. Biochemistry. PubMed Scopus Google Scholar). to the binding of AIIt to the fibrin fibrin polymer was by of fibrinogen and with AIIt. The fibrin clot was and the AIIt binding to the fibrin clot was the binding for the binding of AIIt to fibrin. AIIt fibrin polymer in a and with a K d of nm The binding a at about which to about 0.28 mol of AIIt/mol of fibrin monomer. established that the binding of AIIt to fibrin was by a The binding of AIIt to fibrin could be due to is that the binding sites in the of the clot may not be to AIIt. It was reported that binds AIIt G. A. C. P. S. D.M. J. Biol. Chem. 1997; 272: PubMed Scopus Google and that inhibits the of AIIt with the fibrin polymer J. G. D.M. Biochemistry. PubMed Scopus Google Scholar). shown in the binding of AIIt to fibrin of AIIt binding to fibrin by was and inhibition at if the Ca2+-binding sites of the p36 subunit or the C-terminal lysines of the p11 subunit of AIIt a role in fibrin we the of the AIIt and to AIIt from the fibrin It was that the AIIt compete with the the the protein to to fibrin. and that AIIt and inhibited AIIt binding to fibrin polymer with an of about or the Ca2+-binding sites of AIIt the C-terminal lysine residues of the p11 subunit of AIIt the binding of AIIt to the fibrin at in plasminogen binds to fibrin and we the binding of AIIt to the fibrin clot in the presence of plasminogen The binding of AIIt to fibrin polymer was increased by of plasminogen in a and a at about binding was at nm plasminogen binding was also in the presence of a lysine which inhibits the AIIt and The of blocked the increased AIIt binding to fibrin polymer by plasminogen that the p11 C-terminal lysine residues of AIIt are involved in binding of AIIt to fibrin. also that binding of plasminogen to fibrin may the of AIIt with fibrin The of AIIt with the fibrin polymer may physiologically in at least of two its binding of the C-terminal lysine as shown in or through binding which is by its p11 C-terminal lysine AIIt been reported to stimulate the tPA-dependent of plasminogen to plasmin as well as plasmin in vitro. in the presence of fibrin stimulation of plasmin is the we could not the that AIIt also stimulate tPA-dependent plasmin formation. that fibrin tPA-dependent plasmin formation tPA-dependent plasmin formation was increased by AIIt of the of the stimulation of tPA-dependent plasmin formation by AIIt showed that about AIIt was for stimulation of plasmin formation of AIIt was to that for inhibition of plasmin-dependent fibrin polymer suggest that AIIt may the of plasmin at the fibrin clot surface by plasmin formation and the reaction AIIt or annexin II been shown by to to the extracellular surface of variety of cells G. J. T. S. M. A. D.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. D.M. PubMed Scopus Google Scholar, J. R.L. D.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). or not AIIt with fibrin physiological not been tissue from a with a was for annexin II and p11 The results show that annexin II and p11 at of the fibrin clot and cell the of AIIt with fibrin in to be of physiological The formation of a fibrin polymer subsequent to not also provides temporary for the of a fibrin clot due to may to a variety of pathological including or the formation of a fibrinolysis is by the of endothelial cells on the fibrin during the wound healing on the and regulation of plasmin activity the fibrin annexin II, the subunit of was shown to function as a receptor for plasminogen and tPA on the surface of endothelial cells M.S. R. T. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, recently been shown that not annexin II, inhibits plasmin-dependent fibrinolysis J. G. D.M. Biochemistry. PubMed Scopus Google as well as tPA-dependent plasminogen activation G. J. T. S. M. A. D.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and subsequent plasmin G. D.M. Biochemistry. PubMed Scopus Google Scholar). In this we that AIIt to the fibrin clot in and with the fibrin clot in Furthermore, we show that AIIt inhibits plasmin-dependent fibrin clot lysis by stimulation of plasmin in vitro. The of AIIt to the fibrinolytic activity of plasmin the of plasmin that is for fibrin clot is by the that an of the plasmin autodegradation, inhibits the activity of AIIt The inhibition of plasmin-dependent fibrinolysis by AIIt also with plasmin and chain degradation suggesting a the activity of AIIt and plasmin the stimulation of plasmin is the reaction we have also shown in the presence of the fibrin AIIt stimulates tPA-dependent plasmin formation. that the physiological role of AIIt may be to a of plasmin activity on the fibrin surface. We also two AIIt to the role of the Ca2+-binding sites of the p36 subunit of AIIt or of the C-terminal lysine residues of p11 subunit of AIIt in its activity We a AIIt in which Ca2+-binding sites of the p36 subunit was an essential in the coagulation and to that the Ca2+-binding sites of AIIt play a role in its inhibition of fibrin clot as in the AIIt also inhibited plasmin-dependent the Ca2+-binding sites of AIIt do not play a role in its activity. The of AIIt involved the removal of the C-terminal lysine residues of the p11 subunit We have shown that removal of these key residues the of AIIt to stimulate tPA-dependent plasminogen activation G. S. P. D.M. Biochemistry. PubMed Scopus Google Scholar). These residues are to be involved in the binding of kringle domains of plasminogen, plasmin, and shown in this AIIt not plasmin-dependent fibrin clot that the C-terminal lysine residues of the p11 subunit of AIIt in the stimulation of plasmin formation and by AIIt. In the of fibrin the reaction is in the presence of the reaction is The of fibrin on the of AIIt to in the of AIIt with fibrin. we found that AIIt fibrin with a K d of nm that a binding is involved in this The stoichiometry mol of AIIt/mol of fibrin that of the AIIt binding sites in the fibrin polymer in are not to AIIt. Second, we found that the of AIIt with fibrin was inhibited by with an of The binding is at residues of the p36 subunit and be involved in the of AIIt with fibrin the AIIt and the we found that the binding of AIIt to fibrin not involve the Ca2+-binding sites of the p36 subunit the C-terminal lysine of the p11 subunit and we found that in the presence of plasminogen the binding of AIIt to fibrin was increased The for this was that AIIt to fibrin and to was an important the that AIIt and plasminogen for sites on the fibrin we the localization of AIIt to a in established that physiological AIIt with fibrin The binding of these to the p11 subunit of AIIt plasminogen, plasmin, and AIIt to the fibrin surface. It is to that the by which the C-terminal lysines of the p11 subunit of AIIt stimulates plasmin is due to the localization of plasmin to the C-terminal lysine binding sites of AIIt in a of plasmin at these It is also that the of plasmin with the C-terminal lysines of the p11 subunit of AIIt may a in plasmin in stimulation of plasmin results suggest that the inhibition of plasmin-dependent fibrinolytic activity by AIIt the of AIIt with the plasminogen activation and with the fibrin polymer These binding events to plasminogen, plasmin, and AIIt to the fibrin surface. The of tPA-dependent plasminogen activation on the fibrin surface that AIIt may plasmin activity on the fibrin surface It is in the presence of AIIt stimulates plasmin formation and the of plasmin We the that of AIIt may be present at or in the of the fibrin These could or not plasmin formation or is the reaction stimulated by AIIt. The with previous the for a of the of plasmin regulation by AIIt AIIt to fibrin is of the tPA-dependent formation of plasmin from plasminogen to fibrin or AIIt The of AIIt to plasminogen, and tPA of plasminogen and tPA to the fibrin surface and plasmin AIIt also the of plasmin subsequent to its The is a regulation of plasmin activity on the fibrin surface. It is that the role of AIIt in plasmin formation and provides the fibrin surface with a of proteolytic activity. for of the fibrin clot and activation of plasminogen, which is also to hemostatic In the present report that the of AIIt to plasmin-dependent fibrin clot lysis is due to its of plasmin activity and the of AIIt tPA-dependent plasmin plasmin is the reaction stimulated by AIIt. Furthermore, AIIt and plasminogen a on the fibrin polymer, in vitro. The also for the that AIIt is present on the surface of a fibrin These suggest that AIIt may play a role in regulation of plasmin activity on the fibrin surface.

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