Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha.
Steroid hormone receptors (SHRs) are ligand-activated transcription factors that regulate gene expression. SHRs also mediate rapid, nongenomic cellular activation by steroids. In vascular endothelial cells, the SHR for estrogen, estrogen receptor (ER) alpha, is targeted by unknown mechanisms to a functional signaling module in membrane caveolae that enables estrogen to rapidly activate the mitogen-activated protein kinase and phosphatidylinositol 3-Akt kinase pathways, and endothelial NO synthase (eNOS). Here we identify the 110-kDa caveolin-binding protein striatin as the molecular anchor that localizes ERalpha to the membrane and organizes the ERalpha-eNOS membrane signaling complex. Striatin directly binds to amino acids 183-253 of ERalpha, targets ERalpha to the cell membrane, and serves as a scaffold for the formation of an ERalpha-Galphai complex. Disruption of complex formation between ERalpha and striatin blocks estrogen-induced rapid activation mitogen-activated protein kinase, Akt kinase, and eNOS, but has no effect on ER-dependent regulation of an estrogen response element-driven reporter plasmid. These findings identify striatin as a molecular scaffold required for rapid, nongenomic estrogen-mediated activation of downstream signaling pathways. Furthermore, by demonstrating independent regulation of nongenomic vs. genomic ER-dependent signaling, these findings provide conceptual support for the potential development of "pathway-specific" selective ER modulators.
Lu
Qing
Q
Molecular Cardiology Research Institute, Department of Medicine, Tufts New England Medical Center, Boston, MA 02111, USA.
Pallas
David C
DC
Surks
Howard K
HK
Baur
Wendy E
WE
Mendelsohn
Michael E
ME
Karas
Richard H
RH
D002148:Calmodulin-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D021941:Caveolae / Q000378:metabolism; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation; D047628:Estrogen Receptor alpha / Q000378:metabolism / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology; D006801:Humans; D046911:Macromolecular Substances / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D011485:Protein Binding; D015398:Signal Transduction
D002148:Calmodulin-Binding Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D046911:Macromolecular Substances; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C491925:STRN protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III