Mislocalization of Lck impairs thymocyte differentiation and can promote development of thymomas
| Autor: | Anthony I. Magee, Rose Zamoyska, Niina Pirinen, Andrew Filby, Robert J. Salmond |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Thymoma
T-Lymphocytes Transgene Cellular differentiation Blotting Western Immunology CD2 Antigens Receptors Antigen T-Cell Mice Transgenic chemical and pharmacologic phenomena Thymus Gland Biology Lymphocyte Activation Proto-Oncogene Proteins c-fyn Biochemistry Recombination-activating gene Mice FYN Animals Humans Immunoprecipitation RNA Messenger Reverse Transcriptase Polymerase Chain Reaction Kinase T-cell receptor Cell Differentiation hemic and immune systems Cell Biology Hematology Flow Cytometry Mice Inbred C57BL Thymocyte Lymphocyte Specific Protein Tyrosine Kinase p56(lck) Mice Inbred CBA Cancer research Female biological phenomena cell phenomena and immunity Signal transduction Signal Transduction |
| Zdroj: | Blood. 117:108-117 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | T-cell development is critically dependent on the activities of the Src-family kinases p56lck and p59fyn. While Lck plays a dominant role in the initiation of T-cell receptor (TCR) signaling and in thymocyte differentiation, Fyn plays a more subtle regulatory role. We sought to determine the role of intracellular localization in the differing functions of Lck and Fyn in T cells. By generating transgenic mice that express chimeric Lck-Fyn proteins, we showed that the N-terminal unique domain determines the intracellular localization and function of Lck in pre-TCR and mature αβTCR signaling in vivo. Furthermore, coexpression of a “domain-swap” Lck protein containing the Fyn unique domain with an inducible Lck transgene resulted in the development of thymomas. In contrast to previous reports of Lck-driven thymomas, tumor development was dependent on either pre-TCR or mature TCR signals, and was completely ablated when mice were crossed to a recombination activating gene 1 (Rag1)–deficient background. These data provide a mechanistic basis for the differing roles of Lck and Fyn in T-cell development, and show that intracellular localization as determined by the N-terminal unique domains is critical for Src-family kinase function in vivo. |
| Databáze: | OpenAIRE |
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