| First Author | Strazza M | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 10 | Pages | 2693-2698 |
| PubMed ID | 28213494 | Mgi Jnum | J:241589 |
| Mgi Id | MGI:5903158 | Doi | 10.1073/pnas.1612900114 |
| Citation | Strazza M, et al. (2017) PLCepsilon1 regulates SDF-1alpha-induced lymphocyte adhesion and migration to sites of inflammation. Proc Natl Acad Sci U S A 114(10):2693-2698 |
| abstractText | Regulation of integrins is critical for lymphocyte adhesion to endothelium and migration throughout the body. Inside-out signaling to integrins is mediated by the small GTPase Ras-proximate-1 (Rap1). Using an RNA-mediated interference screen, we identified phospholipase Cepsilon 1 (PLCepsilon1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1alpha)-induced Rap1 activation. We have shown that SDF-1alpha-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor. We identified that PLCepsilon1 was necessary for SDF-1alpha-induced adhesion using shear stress, cell morphology alterations, and crawling on intercellular adhesion molecule 1 (ICAM-1)-expressing cells. Structure-function experiments to separate the dual-enzymatic function of PLCepsilon1 uncover necessary contributions of the CDC25, Pleckstrin homology, and Ras-associating domains, but not phospholipase activity, to this pathway. In the mouse model of delayed type hypersensitivity, we have shown an essential role for PLCepsilon1 in T-cell migration to inflamed skin, but not for cytokine secretion and proliferation in regional lymph nodes. Our results reveal a signaling pathway where SDF-1alpha induces T-cell adhesion through activation of PLCepsilon1, suggesting that PLCepsilon1 is a specific potential target in treating conditions involving migration of T cells to inflamed organs. |
