Requirements for estrogen receptor at membrane localization and function

The estrogen receptor a (ER(x) exists as a functional receptor at the plasma membrane. The structural requirements for localization and function are not well understood. Several laboratories have recently elucidated certain requirements. We recently found the translocation of ER alpha to the membrane in the absence of estrogen is dependent on caveolin-1 and serine 522 of the ERa protein. Mutation of serine 522 to alanine results in a 62% decrease in membrane localization and association with caveolin-1. Similarly, deletion of the caveolin-1 scaffolding domain (amino acids 60-100) largely prevents the localization of ER alpha at the plasma membrane. In the presence of estradiol (EA ERU, Src-homology and collagen homology (Shc), and insulin-like growth factor receptor-1 proteins associate with and increase the localization of ERa at the membrane. Membrane-localized ER(x functions as an atypical G-protein coupled receptor. There is no good evidence that ERa spans the membrane or contains an extracellular domain. E-2/ER alpha activates different G-proteins in cell context-related fashion. These G-proteins lead to the activation of Src through PLC, PKC, IP3 and calcium influx. In breast cancer, Src activates matrix metalloprotemase-2 and -9, which cleaves heparin binding epidermal growth factor, and thus activates EGFR. This leads to downstream signaling through ERK and P13 kinase, imparting cell growth and survival. Crown Copyright (c) 2005 Published by Elsevier Inc. All rights reserved.