Novel non-transcriptional mechanisms for estrogen receptor signaling in the cardiovascular system. Interaction of estrogen receptor alpha with phosphatidylinositol 3-OH kinase.
Estrogen receptor (ER) signaling has been, for a long time, associated with transcriptional processes involving nuclear translocation and binding on specific response elements, leading to regulation of target gene expression. However, rapid, non-transcriptional mechanisms of signal transduction through steroid hormone receptors have been identified. These so-called 'non-genomic' effects are independent from gene transcription or protein synthesis and involve steroid-induced modulation of cytoplasmic or cell membrane-bound regulatory proteins. Several biological actions of estrogen have been associated with this type of signaling, and intracellular regulatory cascades such as extracellular signal-regulated kinase/mitogen-activated protein kinases (ERK/MAPK) and tyrosine kinases or the modulation of G-protein-coupled receptors have been shown to be non-transcriptionally recruited by estrogen in diverse tissues. The vascular wall is one of these sites, where estrogen triggers rapid vasodilatation mainly due to increased nitric oxide (NO) release. We have recently described a novel, non-transcriptional mechanism for ER signaling in human as well as in animal endothelial cells, showing that ER alpha can physically and functionally couple to the lipid kinase phosphatidylinositol 3-OH kinase (PI3K). This interaction leads to activation of PI3K signaling cascade to Ser/Thr kinase Akt, which mediates several PI3K-dependent intracellular effects, including endothelial isoform of NO synthase (eNOS) phosphorylation and activation. This original non-transcriptional mechanism for ER signaling may play an important role in the generation of some of the rapid 'non-genomic' effects of estrogen.
Simoncini
Tommaso
T
Division of Obstetrics and Gynecology, University of Pisa, Via Roma, 67, 56100, Pisa, Italy. t.simoncini@obgyn.med.unipi.it
Fornari
Letizia
L
Mannella
Paolo
P
Varone
Gaetano
G
Caruso
Antonella
A
Liao
James K
JK
Genazzani
Andrea R
AR
D002319:Cardiovascular System / Q000378:metabolism; D047628:Estrogen Receptor alpha; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000502:physiology*; D015398:Signal Transduction
D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D019869:Phosphatidylinositol 3-Kinases