Crk adaptor proteins mediate actin-dependent T cell migration and mechanosensing induced by the integrin LFA-1
| Autor: | Joanna L. MacKay, Daniel A. Hammer, Janis K. Burkhardt, Tanner F. Robertson, Nathan H. Roy |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
rho GTP-Binding Proteins T cell T-Lymphocytes Integrin macromolecular substances Biochemistry Mechanotransduction Cellular Article 03 medical and health sciences Adapter molecule crk Mice 0302 clinical medicine Cell Movement medicine Cell Adhesion Animals Cytoskeleton Molecular Biology Cells Cultured Mice Knockout biology Chemistry Signal transducing adaptor protein Actin remodeling Cell migration Cell Biology Proto-Oncogene Proteins c-crk Intercellular Adhesion Molecule-1 Actins Lymphocyte Function-Associated Antigen-1 Ubiquitin ligase Cell biology 030104 developmental biology medicine.anatomical_structure biology.protein 030215 immunology |
| Popis: | T cell entry into inflamed tissue involves firm adhesion, spreading, and migration of the T cells across endothelial barriers. These events depend on “outside-in” signals through which engaged integrins direct cytoskeletal reorganization. We investigated the molecular events that mediate this process and found that T cells from mice lacking expression of the adaptor protein Crk exhibited defects in phenotypes induced by the integrin lymphocyte function–associated antigen 1 (LFA-1), namely, actin polymerization, leading edge formation, and two-dimensional cell migration. Crk protein was an essential mediator of LFA-1 signaling–induced phosphorylation of the E3 ubiquitin ligase c-Cbl and its subsequent interaction with the phosphatidylinositol 3-kinase (PI3K) subunit p85, thus promoting PI3K activity and cytoskeletal remodeling. In addition, we found that Crk proteins were required for T cells to respond to changes in substrate stiffness, as measured by alterations in cell spreading and differential phosphorylation of the force-sensitive protein CasL. These findings identify Crk proteins as key intermediates coupling LFA-1 signals to actin remodeling and provide mechanistic insights into how T cells sense and respond to substrate stiffness. |
| Databáze: | OpenAIRE |
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