Glucocorticoids cause rapid dissociation of a T-cell-receptor-associated protein complex containing LCK and FYN.

Although glucocorticoid (GC)-induced nongenomic effects have been reported, the underlying mechanisms remain unexplained. We previously described that lymphocyte-specific protein tyrosine kinase (LCK) and FYN oncogene related to SRC, FGR, YES (FYN) mediate GC-induced inhibition of T-cell-receptor (TCR) signalling. Here we characterize the underlying molecular mechanism. The present study shows that ...
the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation. Experiments with cells transfected with GC-receptor short interfering RNA (siRNA) showed that the GC receptor is an essential component of the TCR signalling complex. Short-term GC treatment induces dissociation of this protein complex, resulting in impaired TCR signalling as a consequence of abrogated LCK/FYN activation. HSP90siRNA-transfected cells are not able to assemble this TCR-associated multiprotein complex, and accordingly HSP90siRNA treatment mimics GC effects on LCK/FYN activities. These observations support a model for nongenomic GC-induced immunosuppression on the basis of dissolution of membrane-bound GC-receptor multiprotein complexes after GC-receptor ligation.
Mesh Terms:
Antigens, CD4, Cells, Cultured, Dexamethasone, Glucocorticoids, HSP90 Heat-Shock Proteins, Humans, Leukocytes, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Models, Biological, Multiprotein Complexes, Protein Binding, Proto-Oncogene Proteins c-fyn, RNA Interference, RNA, Small Interfering, Receptors, Antigen, T-Cell, Receptors, Glucocorticoid, T-Lymphocytes, Tissue Distribution, Transfection
EMBO Rep.
Date: Oct. 01, 2006
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