| First Author | Naik MU | Year | 2014 |
| Journal | Blood | Volume | 123 |
| Issue | 9 | Pages | 1393-402 |
| PubMed ID | 24300854 | Mgi Jnum | J:208709 |
| Mgi Id | MGI:5564853 | Doi | 10.1182/blood-2013-04-496232 |
| Citation | Naik MU, et al. (2014) Junctional adhesion molecule-A suppresses platelet integrin alphaIIbbeta3 signaling by recruiting Csk to the integrin-c-Src complex. Blood 123(9):1393-402 |
| abstractText | Fibrinogen binding to activated integrin induces outside-in signaling that results in stable platelet aggregates and clot retraction. How integrin alphaIIbbeta3 is discouraged from spontaneous activation is not known. We have recently shown that junctional adhesion molecule-A (JAM-A) renders protection from thrombosis by suppressing integrin outside-in signaling. In this study, we show that JAM-A associates with integrin alphaIIbbeta3 in resting platelets and dissociates upon platelet activation by agonists. We also show that integrin-associated JAM-A is tyrosine phosphorylated and is rapidly dephosphorylated upon platelet activation. C-terminal Src kinase (Csk) binds to tyrosine phosphorylated JAM-A through its Src homology 2 domain. Thus, JAM-A recruits Csk to the integrin-c-Src complex in resting platelets. Csk, in turn, keeps integrin-associated c-Src in an inactive state by phosphorylating Y(529) in its regulatory domain. Absence of JAM-A results in impaired c-SrcY(529) phosphorylation and augmentation of outside-in signaling-dependent c-Src activation. Our results strongly suggest that tyrosine-phosphorylated JAM-A is a Csk-binding protein and functions as an endogenous inhibitor of integrin signaling. JAM-A recruits Csk to the integrin-c-Src complex, where Csk negatively regulates c-Src activation, thereby suppressing the initiation of outside-in signaling. Upon agonist stimulation, JAM-A is dephosphorylated on the tyrosine, allowing the dissociation of Csk from the integrin complex, and thus facilitating outside-in signaling. |
