| Full text | |
| Author(s): Show less - |
Ottaiano, Tatiana F.
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Andrade, Sheila S.
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de Oliveira, Cleide
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Silva, Mariana C. C.
;
Buri, Marcus V.
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Juliano, Maria A.
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Girao, Manoel J. B. C.
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Sampaio, Misako U.
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Schmaier, Alvin H.
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Wlodawer, Alexander
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Maffei, Francisco H. A.
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Oliva, Maria Luiza V.
Total Authors: 12
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| Document type: | Journal article |
| Source: | Biochimie; v. 135, p. 72-81, APR 2017. |
| Web of Science Citations: | 8 |
| Abstract | |
Human plasma kallikrein (huPK) potentiates platelet responses to subthreshold doses of ADP, although huPK itself, does not induce platelet aggregation. In the present investigation, we observe that huPK pretreatment of platelets potentiates ADP-induced platelet activation by prior proteolysis of the G-protein -coupled receptor PAR-1. The potentiation of ADP-induced platelet activation by huPK is mediated by the integrin alpha(IIb)beta(3) through interactions with the KGD/KGE sequence motif in huPK. Integrin alpha(IIb)beta(3) is a cofactor for huPK binding to platelets to support PAR-1 hydrolysis that contributes to activation of the ADP signaling pathway. This activation pathway leads to phosphorylation of Src, AktS(473), ERK1/2, and p38 MAPK, and to Cat(2+) release. The effect of huPK is blocked by specific antagonists of PAR-1 (SCH 19197) and alpha(IIb)beta(3) (abciximab) and by synthetic peptides comprising the KGD and KGE sequence motifs of huPK. Further, recombinant plasma kallikrein inhibitor, rBbKI, also blocks this entire mechanism. These results suggest a new function for huPK. Formation of plasma kallikrein lowers the threshold for ADP-induced platelet activation. The present observations are consistent with the notion that plasma kallikrein promotes vascular disease and thrombosis in the intravascular compartment and its inhibition may ameliorate cardiovascular disease and thrombosis. (C) 2017 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. (AU) | |
| FAPESP's process: | 12/19780-3 - Heterotypic culture: the cross-talking between epithelial tumor cells, mammary stroma, macrophages and platelets in breast cancer: the release of proteolytic enzymes and signaling of toll-like receptors |
| Grantee: | Manoel João Batista Castello Girão |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 09/53766-5 - Proteins from plant source with selectivity for inhibition of mammalian enzymes and their role as an anti-inflammatory, antithrombotic, anti-diabetic and anti-tumor agent |
| Grantee: | Maria Luiza Vilela Oliva |
| Support Opportunities: | Research Projects - Thematic Grants |