| First Author | Rudolph JM | Year | 2019 |
| Journal | Mol Cell Biol | Volume | 39 |
| Issue | 9 | PubMed ID | 30833485 |
| Mgi Jnum | J:280246 | Mgi Id | MGI:6359119 |
| Doi | 10.1128/MCB.00365-18 | Citation | Rudolph JM, et al. (2019) Characterization of Mice with a Platelet-Specific Deletion of the Adapter Molecule ADAP. Mol Cell Biol 39(9) |
| abstractText | The adhesion and degranulation-promoting adapter protein (ADAP) is expressed in T cells, NK cells, myeloid cells, and platelets. The involvement of ADAP in the regulation of receptor-mediated inside-out signaling leading to integrin activation is well characterized, especially in T cells and in platelets. Due to the fact that animal studies using conventional knockout mice are limited by the overlapping effects of the different ADAP-expressing cells, we generated conditional ADAP knockout mice (ADAP(fl/fl) PF4-Cre(tg)) (PF4, platelet factor 4). We observed that loss of ADAP restricted to the megakaryocytic lineage has no impact on other hematopoietic cells even under stimulation conditions. ADAP(fl/fl) PF4-Cre(tg) mice showed thrombocytopenia in combination with reduced plasma levels of PF4 and transforming growth factor beta1 (TGF-beta1). In vitro, platelets from these mice revealed reduced P-selectin expression, lower levels of TGF-beta1 release, diminished integrin alphaIIbbeta3 activation, and decreased fibrinogen binding after stimulation with podoplanin, the ligand of C-type lectin-like receptor 2 (CLEC-2). Furthermore, loss of ADAP was associated with impaired CLEC-2-mediated activation of phospholipase Cgamma2 (PLCgamma2) and extracellular signal-regulated kinase 1/2 (ERK1/2). Induction of experimental autoimmune encephalomyelitis (EAE) in mice lacking ADAP expression in platelets caused a more severe disease. In vivo administration of TGF-beta1 early after T cell transfer reduced EAE severity in mice with loss of ADAP restricted to platelets. Our results reveal a regulatory function of ADAP in platelets in vitro and during autoimmune disease EAE in vivo. |
