| First Author | Alenghat FJ | Year | 2012 |
| Journal | J Cell Sci | Volume | 125 |
| Issue | Pt 22 | Pages | 5535-45 |
| PubMed ID | 22976304 | Mgi Jnum | J:200271 |
| Mgi Id | MGI:5507951 | Doi | 10.1242/jcs.111260 |
| Citation | Alenghat FJ, et al. (2012) Macrophages require Skap2 and Sirpalpha for integrin-stimulated cytoskeletal rearrangement. J Cell Sci 125(Pt 22):5535-45 |
| abstractText | Macrophages migrate to sites of insult during normal inflammatory responses. Integrins guide such migration, but the transmission of signals from integrins into the requisite cytoskeletal changes is poorly understood. We have discovered that the hematopoietic adaptor protein Skap2 is necessary for macrophage migration, chemotaxis, global actin reorganization and local actin reorganization upon integrin engagement. Binding of phosphatidylinositol [3,4,5]-triphosphate to the Skap2 pleckstrin-homology (PH) domain, which relieves its conformational auto-inhibition, is critical for this integrin-driven cytoskeletal response. Skap2 enables integrin-induced tyrosyl phosphorylation of Src-family kinases (SFKs), Adap, and Sirpalpha, establishing their roles as signaling partners in this process. Furthermore, macrophages lacking functional Sirpalpha unexpectedly have impaired local integrin-induced responses identical to those of Skap2(-/-) macrophages, and Skap2 requires Sirpalpha for its recruitment to engaged integrins and for coordinating downstream actin rearrangement. By revealing the positive-regulatory role of Sirpalpha in a Skap2-mediated mechanism connecting integrin engagement with cytoskeletal rearrangement, these data demonstrate that Sirpalpha is not exclusively immunoinhibitory, and illuminate previously unexplained observations implicating Skap2 and Sirpalpha in mouse models of inflammatory disease. |
