Glucocorticoids act within minutes to inhibit recruitment of signalling factors to activated EGF receptors through a receptor‐dependent, transcription‐independent …
JD Croxtall, Q Choudhury… - British journal of …, 2000 - Wiley Online Library
JD Croxtall, Q Choudhury, RJ Flower
British journal of pharmacology, 2000•Wiley Online LibraryRecruitment to activated tyrosine kinase growth factor receptors of Grb2 and p21ras leads to
downstream activation of the kinases Raf, MAPK/Erk kinase (Mek) and, subsequently,
extracellular signal‐regulated kinase (Erk). Activated Erk phosphorylates specific serine
residues within cytosolic phospholipase A2 (PLA2), promoting enzyme translocation to
membranes and facilitating liberation of arachidonic acid (AA). In the A549 human
adenocarcinoma cell line dexamethasone inhibited epidermal growth factor (EGF) …
downstream activation of the kinases Raf, MAPK/Erk kinase (Mek) and, subsequently,
extracellular signal‐regulated kinase (Erk). Activated Erk phosphorylates specific serine
residues within cytosolic phospholipase A2 (PLA2), promoting enzyme translocation to
membranes and facilitating liberation of arachidonic acid (AA). In the A549 human
adenocarcinoma cell line dexamethasone inhibited epidermal growth factor (EGF) …
- Recruitment to activated tyrosine kinase growth factor receptors of Grb2 and p21ras leads to downstream activation of the kinases Raf, MAPK/Erk kinase (Mek) and, subsequently, extracellular signal‐regulated kinase (Erk). Activated Erk phosphorylates specific serine residues within cytosolic phospholipase A2 (PLA2), promoting enzyme translocation to membranes and facilitating liberation of arachidonic acid (AA).
- In the A549 human adenocarcinoma cell line dexamethasone inhibited epidermal growth factor (EGF)‐stimulated cytosolic PLA2 (cPLA2) 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.
- 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.
- Like dexamethasone, peptides containing E‐Q‐E‐Y‐V from the N‐terminal domain of LC1 also blocked ligand‐induced association of Grb2, p21ras and Raf.
- Our results point to an unsuspected rapid effect 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 off signalling factors to EGF‐R
British Journal of Pharmacology (2000) 130, 289–298; doi:10.1038/sj.bjp.0703272
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