Details

Autor(en) / Beteiligte

• Belcher, Scott M
• Le, Hoa H
• Spurling, Lynda
• Wong, Jeremy K

Titel

Rapid Estrogenic Regulation of Extracellular Signal- Regulated Kinase 1/2 Signaling in Cerebellar Granule Cells Involves a G Protein- and Protein Kinase A-Dependent Mechanism and Intracellular Activation of Protein Phosphatase 2A

Ist Teil von

• Endocrinology (Philadelphia), 2005-12, Vol.146 (12), p.5397-5406

Ort / Verlag

Bethesda, MD: Endocrine Society

Erscheinungsjahr

2005

Link zum Volltext

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• In neonatal rat cerebellar neurons, 17β-estradiol (E2) rapidly stimulates ERK1/2 phosphorylation through a membrane-associated receptor. Here the mechanism of rapid E2-induced ERK1/2 signaling in primary cultured granule cells was investigated in more detail. The results of these studies show that E2 and ICI182,780, a steroidal antagonist of estrogen receptor transactivation, rapidly increased ERK signaling with a time course similar to the transient activation induced by epidermal growth factor (EGF). However, EGF receptor (EGFR) autophosphorylation was not increased by E2, and blockade of EGFR tyrosine kinase activity did not abrogate the rapid actions of E2. The involvement of Src-tyrosine kinase activity was demonstrated by detection of increased c-Src phosphorylation in response to E2 and by blockade of E2-induced ERK1/2 activation by inhibition of Src-family tyrosine kinase activity. Inhibition of Gαi signaling or protein kinase A (PKA) activity blocked the ability of ICI182,780 to rapidly stimulate ERK signaling. Under those conditions, E2 treatment induced a rapid and transient suppression of basal ERK1/2 phosphorylation. Protein phosphatase 2A (PP2A) activity was rapidly increased by E2 but not by E2 covalently linked to BSA. Rapid E2-induced increases in PP2A activity were insensitive to pertussis toxin. The presented evidence indicates that the rapid effects of estrogens on ERK signaling in cerebellar granule cells are induced through a novel G protein-coupled receptor mechanism that requires PKA and Src-kinase activity to link E2 to the ERK/MAPK signaling module. Along with stimulating ERK signaling, E2 rapidly activates PP2A via an independent signaling mechanism that may serve as a cell-specific regulator of signal duration.