Glucocorticoids act within minutes to inhibit recruitment of signalling factors to activated EGF receptors through a receptor‐dependent, transcription‐independent mechanism

Abstract

1 Recruitment to activated tyrosine kinase growth factor receptors of Grb2 and p21 ras leads to downstream activation of the kinases Raf, MAPK/Erk kinase (Mek) and, subsequently, extracellular signal-regulated kinase (Erk). Activated Erk phosphorylates speci®c serine residues within cytosolic phospholipase A 2 (PLA 2 ), promoting enzyme translocation to membranes and facilitating liberation of arachidonic acid (AA). 2 In the A549 human adenocarcinoma cell line dexamethasone inhibited epidermal growth factor (EGF)-stimulated cytosolic PLA 2 (cPLA 2 ) activation and AA release by blocking the recruitment of Grb2 to the activated EGF receptor (EGF-R) through a glucocorticoid receptor (GR)-dependent (RU486-sensitive), transcription-independent (actinomycin-insensitive), mechanism. 3 The dexamethasone-induced block of Grb2 recruitment was parallelled by changes in phosphorylation status and subcellular localization of lipocortin 1 (LC1) and an increase in the amount of the tyrosine phosphoprotein co-localized with EGF-R. 4 Like dexamethasone, peptides containing E-Q-E-Y-V from the N-terminal domain of LC1 also blocked ligand-induced association of Grb2, p21 ras and Raf. 5 Our results point to an unsuspected rapid eect of glucocorticoids, mediated by occupation of GR but not by changes in gene transcription, which is brought about by competition between LC1 and Grb2 leading to a failure of recruitment o signalling factors to EGF-R

Nontranscriptional actions of the glucocorticoid receptor

“…The synthetic corticosteroid dexamethasone (Dex) rapidly inhibits cytosolic phospholipase A 2 activity and release of arachidonic acid, which are important mediators of inflammation. Inhibition was reversed by the GR antagonist RU486 (mifepristone), and by pharmacological inhibition of Src, suggesting that rapid inhibition of cytosolic phospholipase A 2 by GR is mediated by Src [60]. Interestingly, a nonclassical effect of GR on rapid kinase signaling is also involved in the inhibition of AP-1 by steroids.…”

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

“…This mechanism may account for the change in bronchial blood flow induced by inhaled corticosteroids. In addition, the classical receptor is associated with a number of kinases and phosphatases within the inactive GR-hsp90 complex [14,15]. These enzymes are released on hormone binding and might also account for the rapid induction of tyrosine kinases seen in some cell types by glucocorticoids.…”

Specific association of annexin 1 with plasma membrane‐resident and internalized EGF receptors mediated through the protein core domain

“…Annexin 1 is highly expressed and phosphorylated during hepatocarcinoma development and has been implicated in liver regeneration and tumorigenesis, probably by modulating EGF receptor (EGFR) activity [17]. A link between annexin 1 and EGFR signaling has also been observed in lung cells [18]. In particular, phosphorylation of annexin 1 by activated EGFR has been proposed to play a role in mediating inward vesiculation in multivesicular endosomes and thereby the sorting of internalized EGFR to the degradative lysosomal pathway [2].…”