The Src kinase p56(lck) up-regulates VLA-4 integrin affinity. Implications for rapid spontaneous and chemokine-triggered T cell adhesion to VCAM-1 and fibronectin
| Autor: | S W, Feigelson, V, Grabovsky, E, Winter, L L, Chen, R B, Pepinsky, T, Yednock, D, Yablonski, R, Lobb, R, Alon |
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| Rok vydání: | 2000 |
| Předmět: |
Integrins
Dose-Response Relationship Drug T-Lymphocytes Blotting Western Receptors Lymphocyte Homing Vascular Cell Adhesion Molecule-1 Integrin alpha4beta1 Flow Cytometry Ligands Fibronectins Up-Regulation Jurkat Cells Kinetics Lymphocyte Specific Protein Tyrosine Kinase p56(lck) Cell Adhesion Humans Interleukin-2 Endothelium Lymphocytes Enzyme Inhibitors Vanadates Phosphotyrosine Protein Binding Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 276(17) |
| ISSN: | 0021-9258 |
| Popis: | In circulating lymphocytes, the VLA-4 integrin preexists in multiple affinity states that mediate spontaneous tethering, rolling, and arrest on its endothelial ligand, vascular cell adhesion molecule-1 (VCAM-1). The regulation and function of VLA-4 affinity in lymphocytes has never been elucidated. We show here that p56(lck), the major Src kinase in T cells, is a key regulator of high affinity VLA-4. This high affinity is essential for the rapid development of firm adhesion of resting T cells to VCAM-1 and to their extracellular matrix ligand, fibronectin. Lck-regulated VLA-4 function does not require intact TCR nor several key components of the TCR signaling pathway, including ZAP-70 and SLP-76. Furthermore, stimulation of p56(lck) by the phosphatase inhibitor, pervanadate, triggers firm VLA-4-dependent adhesion to VCAM-1. Although Lck is not required for chemokine receptor signaling to mitogen-activated protein kinase, the presence of Lck-regulated high affinity VLA-4 also facilitates firm adhesion triggered by the chemokine, SDF-1, at short-lived contacts. Surprisingly, bond formation rates, ability to tether cells to VLA-4 ligand, and VLA-4 tether bond stability under shear flow are not affected by VLA-4 affinity or Lck activity. Thus, the ability of high affinity VLA-4 to arrest cells on VCAM-1 under flow arises from instantaneous post-ligand strengthening rather than from increased kinetic stability of individual VLA-4 bonds. These results suggest that p56(lck) maintains high affinity VLA-4 on circulating lymphocytes, which determines their ability to strengthen VLA-4 adhesion and rapidly respond to proadhesive chemokine signals at endothelial sites. |
| Databáze: | OpenAIRE |
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