Aberrant TCR-mediated signaling in CD45-null thymocytes involves dysfunctional regulation of Lck, Fyn, TCR-zeta, and ZAP-70
| Autor: | J D, Stone, L A, Conroy, K F, Byth, R A, Hederer, S, Howlett, Y, Takemoto, N, Holmes, D R, Alexander |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
ZAP-70 Protein-Tyrosine Kinase
T-Lymphocytes Receptors Antigen T-Cell Membrane Proteins Protein-Tyrosine Kinases Lymphocyte Activation Proto-Oncogene Proteins c-fyn Mice src-Family Kinases Lymphocyte Specific Protein Tyrosine Kinase p56(lck) Proto-Oncogene Proteins Animals Leukocyte Common Antigens Tyrosine Phosphorylation Signal Transduction |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 158(12) |
| ISSN: | 0022-1767 |
| Popis: | CD45 is a transmembrane phosphotyrosine phosphatase expressed on all nucleated hemopoietic cells. Targeting of CD45 exon 9 has generated a mouse line completely lacking CD45 expression (CD45-null) in which there are severe abnormalities in T cell development. Defects in TCR-mediated signals underlying these abnormalities have now been investigated using CD45-null T cells. No T cell proliferation was detected in response to a CD3 mAb. In thymocytes the p56(lck) and p59(fyn) tyrosine kinases were hyperphosphorylated, and p56(lck) was in its inactive conformation. Both basal and TCR-stimulated tyrosine phosphorylation of TCR-zeta and CD3-epsilon were much reduced, and TCR stimulation induced an abnormal p18 phosphoisomer of TCR-zeta previously noted in T cells stimulated by altered peptide ligands. These defects were associated with the failure of ZAP-70 kinase recruitment to the TCR-zeta chain. TCR coupling to the tyrosine phosphorylation of several proteins, including HS1 and p120(cbl), was also much reduced. However, TCR-induced signaling was not ablated, and significant inositol phosphate and calcium signals were observed in CD45-null thymocytes. Our molecular analysis suggests that the threshold for TCR signal transduction is greatly increased in CD45-null T cells, thus explaining the profound defects in thymic development. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|