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

Abstract:

: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.

journal_name

EMBO Rep

journal_title

EMBO reports

authors

Löwenberg M,Verhaar AP,Bilderbeek J,Marle Jv,Buttgereit F,Peppelenbosch MP,van Deventer SJ,Hommes DW

doi

10.1038/sj.embor.7400775

subject

Has Abstract

pub_date

2006-10-01 00:00:00

pages

1023-9

issue

10

eissn

1469-221X

issn

1469-3178

pii

7400775

journal_volume

7

pub_type

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