PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation
| Autor: | Edward Y. Skolnik, Shekhar Srivastava, Inbar Azoulay-Alfaguter, Marianne Strazza, Alan V. Smrcka, Adam Mor, Michael Peled |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
T-Lymphocytes Telomere-Binding Proteins Intercellular Adhesion Molecule-1 Integrin Biology Shelterin Complex Mice 03 medical and health sciences Phosphoinositide Phospholipase C Cell Movement Cell Adhesion Animals Humans Lymphocytes Cell adhesion Inflammation Multidisciplinary ras-GRF1 Cell adhesion molecule Biological Sciences Intercellular adhesion molecule Chemokine CXCL12 Cell biology Receptors Antigen 030104 developmental biology Cancer research biology.protein Rap1 Neural cell adhesion molecule Cytokine secretion Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 114:2693-2698 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1612900114 |
| Popis: | 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 Cε 1 (PLCε1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1α)-induced Rap1 activation. We have shown that SDF-1α-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor. We identified that PLCε1 was necessary for SDF-1α-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 PLCε1 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 PLCε1 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-1α induces T-cell adhesion through activation of PLCε1, suggesting that PLCε1 is a specific potential target in treating conditions involving migration of T cells to inflamed organs. |
| Databáze: | OpenAIRE |
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