Intracellular matrix metalloproteinase-2 (MMP-2) regulates human platelet activation via hydrolysis of talin

Gerald Soslau; Christopher Mason; Stephen Lynch; James Benjamin; Dani Ashak; Jamunabai M. Prakash; Andrew Moore; Pamela Bagsiyao; Trevine Albert; Lynn M. Mathew; Monika Jost

doi:10.1160/TH13-03-0248

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 111(01): 140-153
DOI: 10.1160/TH13-03-0248

Platelets and Blood Cells

Schattauer GmbH

Intracellular matrix metalloproteinase-2 (MMP-2) regulates human platelet activation via hydrolysis of talin

Gerald Soslau

¹Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

²Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

,

Christopher Mason

¹Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

,

Stephen Lynch

¹Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

,

James Benjamin

¹Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

,

Dani Ashak

¹Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

,

Jamunabai M. Prakash

¹Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

,

Andrew Moore

¹Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

,

Pamela Bagsiyao

¹Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

,

Trevine Albert

¹Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

,

Lynn M. Mathew

¹Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

,

Monika Jost

¹Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

³Department of Radiation Oncology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

› Author Affiliations

Abstract

Summary

Matrix metalloproteinase (MMP) activity is generally associated with normal or pathological extracellular processes such as tissue remodeling 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 agonistinduced 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.

Keywords

Matrix metalloproteinase - platelet physiology - thrombin - talin

Full Text

References

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