Journal article
Intracellular matrix metalloproteinase-2 (MMP-2) regulates human platelet activation via hydrolysis of talin
Thrombosis and haemostasis, v 111(1)
01 Jan 2014
PMID: 24136115
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Matrix metalloproteinase (MMP) activity is generally associated with 1 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.
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Details
- Title
- Intracellular matrix metalloproteinase-2 (MMP-2) regulates human platelet activation via hydrolysis of talin
- Creators
- Gerald Soslau - Drexel UniversityChristopher Mason - Drexel Univ, Coll Med, Off Profess Studies Hlth Sci, Philadelphia, PA 19102 USAStephen Lynch - Drexel Univ, Coll Med, Off Profess Studies Hlth Sci, Philadelphia, PA 19102 USAJames Benjamin - Drexel Univ, Coll Med, Off Profess Studies Hlth Sci, Philadelphia, PA 19102 USADani Ashak - Drexel Univ, Coll Med, Off Profess Studies Hlth Sci, Philadelphia, PA 19102 USAJamunabai M. Prakash - Drexel Univ, Coll Med, Off Profess Studies Hlth Sci, Philadelphia, PA 19102 USAAndrew Moore - Drexel Univ, Coll Med, Off Profess Studies Hlth Sci, Philadelphia, PA 19102 USAPamela Bagsiyao - Drexel Univ, Coll Med, Off Profess Studies Hlth Sci, Philadelphia, PA 19102 USATrevine Albert - Drexel Univ, Coll Med, Off Profess Studies Hlth Sci, Philadelphia, PA 19102 USALynn M. Mathew - Drexel Univ, Coll Med, Off Profess Studies Hlth Sci, Philadelphia, PA 19102 USAMonika Jost - Drexel Univ, Coll Med, Off Profess Studies Hlth Sci, Philadelphia, PA 19102 USA
- Publication Details
- Thrombosis and haemostasis, v 111(1)
- Publisher
- Thieme Medical Publishers
- Number of pages
- 14
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- [Retired Faculty]; Intensive Medical Sciences (IMS)
- Web of Science ID
- WOS:000330014300019
- Scopus ID
- 2-s2.0-84891887337
- Other Identifier
- 991019169535604721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Hematology
- Peripheral Vascular Disease