| First Author | Lefort CT | Year | 2012 |
| Journal | Blood | Volume | 119 |
| Issue | 18 | Pages | 4275-82 |
| PubMed ID | 22431571 | Mgi Jnum | J:185175 |
| Mgi Id | MGI:5427560 | Doi | 10.1182/blood-2011-08-373118 |
| Citation | Lefort CT, et al. (2012) Distinct roles for talin-1 and kindlin-3 in LFA-1 extension and affinity regulation. Blood 119(18):4275-82 |
| abstractText | In inflammation, neutrophils and other leukocytes roll along the microvascular endothelium before arresting and transmigrating into inflamed tissues. Arrest requires conformational activation of the integrin lymphocyte function-associated antigen-1 (LFA-1). Mutations of the FERMT3 gene encoding kindlin-3 underlie the human immune deficiency known as leukocyte adhesion deficiency-III. Both kindlin-3 and talin-1, another FERM domain-containing cytoskeletal protein, are required for integrin activation, but their individual roles in the induction of specific integrin conformers are unclear. Here, we induce differential LFA-1 activation in neutrophils through engagement of the selectin ligand P-selectin glycoprotein ligand-1 or the chemokine receptor CXCR2. We find that talin-1 is required for inducing LFA-1 extension, which corresponds to intermediate affinity and induces neutrophil slow rolling, whereas both talin-1 and kindlin-3 are required for induction of the high-affinity conformation of LFA-1 with an open headpiece, which results in neutrophil arrest. In vivo, both slow rolling and arrest are defective in talin-1-deficient neutrophils, whereas only arrest is defective in kindlin-3-deficient neutrophils. We conclude that talin-1 and kindlin-3 serve distinct functions in LFA-1 activation. |
