JAM-A protects from thrombosis by suppressing integrin αIIbβ3-dependent outside-in signaling in platelets

• Published in: Blood 2012-04, Vol.119 (14), p.3352-3360
• Main Authors: Naik, Meghna U., Stalker, Timothy J., Brass, Lawrence F., Naik, Ulhas P.
• Format: Article
• Language: English
• Subjects: Animals; Bleeding Time; Blood Platelets - metabolism; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Clot Retraction - genetics; Gene Knockout Techniques; Genetic Association Studies; Humans; Integrins - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Platelet Adhesiveness - genetics; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism; Platelets and Thrombopoiesis; Pulmonary Embolism - genetics; Pulmonary Embolism - mortality; Pulmonary Embolism - pathology; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Signal Transduction; Thrombosis - etiology; Thrombosis - genetics; Thrombosis - prevention & control; Thrombosis and Hemostasis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-12-397398

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 αIIbβ3. Once platelet activation has occurred, integrin αIIbβ3 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.