| First Author | Kasirer-Friede A | Year | 2014 |
| Journal | Blood | Volume | 123 |
| Issue | 20 | Pages | 3156-65 |
| PubMed ID | 24523237 | Mgi Jnum | J:210761 |
| Mgi Id | MGI:5571802 | Doi | 10.1182/blood-2013-08-520627 |
| Citation | Kasirer-Friede A, et al. (2014) ADAP interactions with talin and kindlin promote platelet integrin alphaIIbbeta3 activation and stable fibrinogen binding. Blood 123(20):3156-65 |
| abstractText | ADAP is a hematopoietic-restricted adapter protein that promotes integrin activation and is a carrier for other adapter proteins, Src kinase-associated phosphoprotein 1 (SKAP1) and SKAP2. In T lymphocytes, SKAP1 is the ADAP-associated molecule that activates integrins through direct linkages with Rap1 effectors (regulator of cell adhesion and polarization enriched in lymphoid tissues; Rap1-interacting adapter molecule). ADAP also promotes integrin alphaIIbbeta3 activation in platelets, which lack SKAP1, suggesting an ADAP integrin-regulatory pathway different from those in lymphocytes. Here we characterized a novel association between ADAP and 2 essential integrin-beta cytoplasmic tail-binding proteins involved in alphaIIbbeta3 activation, talin and kindlin-3. Glutathione S-transferase pull-downs identified distinct regions in ADAP necessary for association with kindlin or talin. ADAP was physically proximal to talin and kindlin-3 in human platelets, as assessed biochemically, and by immunofluorescence microscopy and proximity ligation. Relative to wild-type mouse platelets, ADAP-deficient platelets exhibited reduced co-localization of talin with alphaIIbbeta3, and reduced irreversible fibrinogen binding in response to a protease activated receptor 4 (PAR4) thrombin receptor agonist. When ADAP was heterologously expressed in Chinese hamster ovary cells co-expressing alphaIIbbeta3, talin, PAR1, and kindlin-3, it associated with an alphaIIbbeta3/talin complex and enabled kindlin-3 to promote agonist-dependent ligand binding to alphaIIbbeta3. Thus, ADAP uniquely promotes activation of and irreversible fibrinogen binding to platelet alphaIIbbeta3 through interactions with talin and kindlin-3. |
