| First Author | Molteni R | Year | 2009 |
| Journal | Blood | Volume | 114 |
| Issue | 5 | Pages | 1073-82 |
| PubMed ID | 19429870 | Mgi Jnum | J:151172 |
| Mgi Id | MGI:4352962 | Doi | 10.1182/blood-2008-10-183699 |
| Citation | Molteni R, et al. (2009) Beta-arrestin 2 is required for the induction and strengthening of integrin-mediated leukocyte adhesion during CXCR2-driven extravasation. Blood 114(5):1073-82 |
| abstractText | Leukocyte extravasation involves interdependent signaling pathways underlying the complex dynamics of firm adhesion, crawling, and diapedesis. While signal transduction by agonist-bound chemokine receptors plays a central role in the above responses, it is unclear how it contributes to the sustained and concurrent nature of such responses, given the rapid kinetics of chemokine-induced trimeric G protein coupling and homologous desensitization. Our findings unveil a novel role of beta-arrestins in regulating the activation of signaling pathways underlying discrete integrin-mediated steps in CXCR2-driven leukocyte extravasation. By combining in vivo approaches in beta-arrestin knockout mice with in vitro studies in engineered cellular models, we show that membrane-recruited beta-arrestin 2 is required for the onset and maintenance of shear stress-resistant leukocyte adhesion mediated by both beta(1) and beta(2) integrins. While both beta-arrestin isoforms are required for rapid keratinocyte-derived chemokine (KC)-induced arrest onto limiting amounts of vascular cell adhesion molecule-1 (VCAM-1), adhesion strengthening under shear is selectively dependent on beta-arrestin 2. The latter synergizes with phospholipase C in promoting activation of Rap1A and B, both of which co-operatively control subsecond adhesion as well as postarrest adhesion stabilization. Thus, receptor-induced Galpha(i) and beta-arrestins act sequentially and in spatially distinct compartments to promote optimal KC-induced integrin-dependent adhesion during leukocyte extravasation. |
