A Molecular Framework for Two-Step T Cell Signaling: Lck Src Homology 3 Mutations Discriminate Distinctly Regulated Lipid Raft Reorganization Events
| Autor: | Miriana Moran, Teresa A. Low, M. Carrie Miceli, Viresh P. Patel |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
T-Lymphocytes
T cell Immunology Receptors Antigen T-Cell Apoptosis chemical and pharmacologic phenomena CD48 Antigen Biology Ligands Lymphocyte Activation src Homology Domains Mice chemistry.chemical_compound Membrane Microdomains CD28 Antigens Antigens CD medicine Animals Immunology and Allergy Phosphorylation Lipid raft Hybridomas T-cell receptor CD28 hemic and immune systems Tyrosine phosphorylation Raft Phosphoproteins Cell biology Enzyme Activation medicine.anatomical_structure chemistry Lymphocyte Specific Protein Tyrosine Kinase p56(lck) Mutagenesis Site-Directed Interleukin-2 Signal transduction Protein Binding Signal Transduction Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | The Journal of Immunology. 166:754-764 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.166.2.754 |
| Popis: | Costimulation by CD28 or lipid-raft-associated CD48 potentiate TCR-induced signals, cytoskeletal reorganization, and IL-2 production. We and others have proposed that costimulators function to construct a raft-based platform(s) especially suited for TCR engagement and sustained and processive signal transduction. Here, we characterize TCR/CD48 and TCR/CD28 costimulation in T cells expressing Lck Src homology 3 (SH3) mutants. We demonstrate that Lck SH3 functions after initiation of TCR-induced tyrosine phosphorylation and concentration of transducers within rafts, to regulate the costimulation-dependent migration of rafts to the TCR contact site. Expression of kinase-active/SH3-impaired Lck mutants disrupts costimulation-dependent raft recruitment, sustained TCR protein tyrosine phosphorylation, and IL-2 production. However, TCR-induced apoptosis, shown only to require “partial” TCR signals, is unaffected by expression of kinase-active/SH3-impaired Lck mutants. Therefore, two distinctly regulated raft reorganization events are required for processive and sustained “complete” TCR signal transduction and T cell activation. Together with recent characterization of CD28 and CD48 costimulatory activities, these findings provide a molecular framework for two signal models of T cell activation. |
| Databáze: | OpenAIRE |
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