期刊
BLOOD
卷 119, 期 14, 页码 3352-3360出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-12-397398
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资金
- National Heart, Lung, and Blood Institute (NHLBI) [HL57630, HL63960, HL40387]
- National Center for Research Resources [5P20 RR015588-10, 2P20 RR016472-11]
Mounting evidence suggests that agonist-initiated signaling in platelets is closely regulated to avoid excessive responses to injury. A variety of physiologic agonists induce a cascade of signaling events termed as inside-out signaling that culminate in exposure of high-affinity binding sites on integrin alpha(IIb)beta(3). Once platelet activation has occurred, integrin alpha(IIb)beta(3) stabilizes thrombus formation by providing agonist-independent outside-in signals mediated in part by contractile signaling. Junctional adhesion molecule A (JAM-A), a member of the cortical thymocyte marker of the Xenopus (CTX) family, was initially identified as a receptor for a platelet stimulatory mAb. Here we show that JAM-A in resting platelets functions as an endogenous inhibitor of platelet function. Genetic ablation of Jam-A in mice enhances thrombotic function of platelets in vivo. The absence of Jam-A results in increase in platelet aggregation ex vivo. This gain of function is not because of enhanced inside-out signaling because granular secretion, Thromboxane A2 (TxA2) generation, as well as fibrinogen receptor activation, are normal in the absence of Jam-A. Interestingly, integrin outside-in signaling such as platelet spreading and clot retraction is augmented in Jam-A-deficient platelets. We conclude that JAM-A normally limits platelet accumulation by inhibiting integrin outside-in signaling thus preventing premature platelet activation. (Blood. 2012;119(14):3352-3360)
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