Dual Mechanism of Integrin αIIbβ3 Closure in Procoagulant Platelets

被引:96
作者
Mattheij, Nadine J. A. [1 ]
Gilio, Karen [1 ]
van Kruchten, Roger [1 ]
Jobe, Shawn M. [2 ]
Wieschhaus, Adam J. [3 ,4 ]
Chishti, Athar H. [4 ]
Collins, Peter [5 ]
Heemskerk, Johan W. M. [1 ]
Cosemans, Judith M. E. M. [1 ]
机构
[1] Maastricht Univ, Dept Biochem, Cardiovasc Res Inst Maastricht, NL-6200 MD Maastricht, Netherlands
[2] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA
[3] Univ Illinois, Dept Pharmacol, Chicago, IL 60607 USA
[4] Tufts Univ, Sch Med, Dept Mol Physiol & Pharmacol, Boston, MA 02111 USA
[5] Cardiff Univ, Sch Med, Dept Haematol, Arthur Bloom Haemophilia Ctr, Cardiff CF14 4YU, S Glam, Wales
关键词
PHOSPHATIDYLSERINE EXPOSURE; THROMBUS FORMATION; CALPAIN CLEAVAGE; ACTIVATION; APOPTOSIS;
D O I
10.1074/jbc.M112.428359
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Aggregation of platelets via activated integrin alpha(IIb)beta(3) is a prerequisite for thrombus formation. Phosphatidylserine-exposing platelets with a key role in the coagulation process disconnect from a thrombus by integrin inactivation via an unknown mechanism. Here we show that alpha(IIb)beta(3) inactivation in procoagulant platelets relies on a sustained high intracellular Ca2+, stimulating intracellular cleavage of the beta(3) chain, talin, and Src kinase. Inhibition of calpain activity abolished protein cleavage, but only partly suppressed alpha(IIb)beta(3) inactivation. Integrin alpha(IIb)beta(3) inactivation was unchanged in platelets from Capn1(-/-) mice, suggesting a role of the calpain-2 isoform. Scott syndrome platelets, lacking the transmembrane protein TMEM16F and having low phosphatidylserine exposure, displayed reduced alpha(IIb)beta(3) inactivation with the remaining activity fully dependent on calpain. In platelets from Ppif(-/-) mice, lacking mitochondrial permeability transition pore (mPTP) formation, agonist-induced phosphatidylserine exposure and alpha(IIb)beta(3) inactivation were reduced. Treatment of human platelets with cyclosporin A gave a similar phenotype. Together, these data point to a dual mechanism of alpha(IIb)beta(3) inactivation via calpain(-2) cleavage of integrin-associated proteins and via TMEM16F-dependent phospholipid scrambling with an assistant role of mPTP formation.
引用
收藏
页码:13325 / 13336
页数:12
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