title: Intracellular matrix metalloproteinase-2 (MMP-2) regulates human platelet activation via hydrolysis of talin.
abstract: Matrix metalloproteinase (MMP) activity is generally associated with normal or pathological extracellular processes such as tissue remodelling in growth and development or in tumor metastasis and angiogenesis. Platelets contain at least three MMPs, 1, 2 and 9 that have been reported to stimulate or inhibit agonist-induced platelet aggregation via extracellular signals. The non-selective Zn+2 chelating MMP inhibitor, 1,10-phenanthroline, and the serine protease inhibitor, AEBSF, were found to inhibit all tested agonist-induced platelet aggregation reactions. In vitro analysis demonstrated that 1,10-phenanthroline completely inhibited MMP-1,2,and 9 but had little to no effect on calpain activity while the converse was true with AEBSF. We now demonstrate that MMP-2 functions intracellularly to regulate agonist-induced platelet aggregations via the hydrolytic activation of talin, the presumed final activating factor of glycoprotein (GP)IIb/IIIa integrin (the inside-out signal). Once activated GPIIb/IIIa binds the dimeric fibrinogen molecule required for platelet aggregation. The active intracellular MMP-2 molecule is complexed with JAK 2/STAT 3, as demonstrated by the fact that all three proteins are co-immunoprecipitated with either anti-JAK 2, or anti-STAT 3 antibodies and by immunofluorescence studies. The MMP-2 platelet activation pathway can be synergistically inhibited with the non-selective MMP inhibitor, 1,10-phenanthroline, plus a JAK 2 inhibitor. This activation pathway is distinct from the previously reported calpain-talin activating pathway. The identification of a new central pathway for platelet aggregation presents new potential targets for drug regulation and furthers our understanding of the complexity of platelet activation mechanisms.
authors.affiliation: Gerald Soslau, PhD, Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, 245 N 15th Street, Philadelphia, PA 19102, USA, Tel.: +1 215 762 7831, Fax: +1 215 762 7434, E-mail: gsoslau@drexelmed.edu.
authors.forename: Gerald
authors.initials: G
authors.lastname: Soslau
authors.forename: Christopher
authors.initials: C
authors.lastname: Mason
authors.forename: Stephen
authors.initials: S
authors.lastname: Lynch
authors.forename: James
authors.initials: J
authors.lastname: Benjamin
authors.forename: Dani
authors.initials: D
authors.lastname: Ashak
authors.forename: Jamunabai M
authors.initials: JM
authors.lastname: Prakash
authors.forename: Andrew
authors.initials: A
authors.lastname: Moore
authors.forename: Pamela
authors.initials: P
authors.lastname: Bagsiyao
authors.forename: Trevine
authors.initials: T
authors.lastname: Albert
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Mathew
authors.forename: Monika
authors.initials: M
authors.lastname: Jost
mesh_terms: D000328:Adult; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry; D019281:Dimerization; D005786:Gene Expression Regulation; D006801:Humans; D006868:Hydrolysis; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010618:Phenanthrolines / Q000737:chemistry; D015539:Platelet Activation; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D016608:Talin / Q000378:metabolism*; D013997:Time Factors; D015032:Zinc / Q000737:chemistry
chemical_list: D002614:Chelating Agents; D010618:Phenanthrolines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016608:Talin; D002154:Calpain; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D015032:Zinc; C025205:1,10-phenanthroline
keywords: Matrix metalloproteinase; platelet physiology; talin; thrombin