title: Mechanism of plasmin generation by S100A10.
abstract: Plasminogen (Pg) is cleaved to form plasmin by the action of specific plasminogen activators such as the tissue plasminogen activator (tPA). Although the interaction of tPA and Pg with the surface of the fibrin clot has been well characterised, their interaction with cell surface Pg receptors is poorly understood. S100A10 is a cell surface Pg receptor that plays a key role in cellular plasmin generation. In the present report, we have utilised domain-switched/deleted variants of tPA, truncated plasminogen variants and S100A10 site-directed mutant proteins to define the regions responsible for S100A10-dependent plasmin generation. In contrast to the established role of the finger domain of tPA in fibrin-stimulated plasmin generation, we show that the kringle-2 domain of tPA plays a key role in S100A10-dependent plasmin generation. The kringle-1 domain of plasminogen, indispensable for fibrin-binding, is also critical for S100A10-dependent plasmin generation. S100A10 retains activity after substitution or deletion of the carboxyl-terminal lysine suggesting that internal lysine residues contribute to its plasmin generating activity. These studies define a new paradigm for plasminogen activation by the plasminogen receptor, S100A10.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Miller
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Madureira
authors.forename: Ain Adilliah
authors.initials: AA
authors.lastname: Kamaludin
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Komar
authors.forename: Vandna
authors.initials: V
authors.lastname: Sharma
authors.forename: Girish
authors.initials: G
authors.lastname: Sahni
authors.forename: Craig
authors.initials: C
authors.lastname: Thelwell
authors.forename: Colin
authors.initials: C
authors.lastname: Longstaff
authors.affiliation: David M. Waisman*, Departments of Biochemistry & Molecular Biology and Pathology, Sir Charles Tupper Medical Building, 5850 College Street, room 11-N2, PO Box 15000, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada, Tel.: +1 902 494 1803, Fax: +1 902 494 1355, E-mail: david.waisman@dal.ca.
authors.forename: David M
authors.initials: DM
authors.lastname: Waisman
mesh_terms: D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism*; D005337:Fibrin / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism*; D006801:Humans; D018082:Kringles / Q000235:genetics; D008239:Lysine / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D010958:Plasminogen / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D015202:Protein Engineering; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D005337:Fibrin; D005341:Fibrinolysin; D008239:Lysine; D010958:Plasminogen; D011956:Receptors, Cell Surface; D009418:S100 Proteins; D010959:Tissue Plasminogen Activator; D000099248:S100 Calcium Binding Protein A10
keywords: S100A10; annexin A2; plasmin; plasminogen; plasminogen regulation; tissue plasminogen activator