title: JAM-A protects from thrombosis by suppressing integrin αIIbβ3-dependent outside-in signaling in platelets.
abstract: 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 α(IIb)β(3). Once platelet activation has occurred, integrin α(IIb)β(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.
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA. unaik@udel.edu.
authors.forename: Meghna U
authors.initials: MU
authors.lastname: Naik
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Stalker
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Brass
authors.forename: Ulhas P
authors.initials: UP
authors.lastname: Naik
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D003018:Clot Retraction / Q000235:genetics; D055786:Gene Knockout Techniques; D056726:Genetic Association Studies; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010973:Platelet Adhesiveness / Q000235:genetics; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D011655:Pulmonary Embolism / Q000235:genetics / Q000401:mortality / Q000473:pathology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013927:Thrombosis / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control
chemical_list: D015815:Cell Adhesion Molecules; C498686:F11r protein, mouse; D016023:Integrins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011956:Receptors, Cell Surface