Molecular basis of cell membrane estrogen receptor interaction with phosphatidylinositol 3-kinase in endothelial cells.
OBJECTIVE
Nontranscriptional signaling mechanisms mediate some of the biological effects of estrogen, such as the rapid actions on the blood vessels. By interacting with phosphatidylinositol 3-kinase (PI3K), estrogen receptor (ER) alpha leads to activation of protein kinase Akt and to subsequent increase in endothelial nitric oxide synthase activity. Because PI3K is mainly a cytoplasmic complex, we studied the cellular site of interaction between this enzyme and ERalpha, and we dissected the molecular mechanisms that mediate this interaction.


RESULTS
By using cultured human saphenous vain endothelial cells, we found that cell membrane-bound ERalpha colocalizes with PI3K and may be responsible for PI3K activation. Furthermore, we characterized the subsequent steps in the activation of the PI3K/Akt signaling cascade, comparing the molecular events that follow insulin or estradiol activation of PI3K.


CONCLUSIONS
We provide novel evidence for an important role of nonnuclear estrogen receptor in rapid, nontranscriptional responses of human endothelial cells to estrogen.
Simoncini
Tommaso
T
Cardiovascular Division, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Cambridge, Mass, USA. t.simoncini@obgyn.med.unipi.it
Rabkin
Elena
E
Liao
James K
JK
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D047628:Estrogen Receptor alpha; D005347:Fibroblasts / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011960:Receptors, Estrogen / Q000378:metabolism*; D012501:Saphenous Vein / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
D047628:Estrogen Receptor alpha; D008565:Membrane Proteins; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011960:Receptors, Estrogen; C496314:NOS3 protein, human; C496315:Nos3 protein, mouse; C494918:AKT1 protein, human