ER ER ER ER - Endocrine Reviews

laboratory data further suggests that the ER protein within isolated caveolar vesicles
typically spreads throughout the cell membrane in a similar fashion to growth factor
receptors (60, 68-70) and assembles as part of a large signalsome complex that includes
both receptor tyrosine kinases (EGFR, IGF1R, HER2 receptor), non-receptor tyrosine
kinases such as Src (71), and G proteins (68, 72, 73). Additional evidence from
endothelial (56, 74) and breast cancer (75) cell culture models suggests that estrogen-
bound ER co-immunoprecipitates with and/or activates distinct G protein subunits. These
interactions trigger secondary downstream signaling pathways including effectors of
p21Ras, leading to activation of Raf/Mek/MAPK and of the AKT/PI3K modules.
More detailed recent work has identified and defined motifs in a specific domain of ER
that are critical to membrane localization and function of the receptor (61, 76, 77). This
domain, also known as the E domain, resides in the carboxyl (C) part of ER and harbors
the ligand-binding domain and AF-2 function. Mutations in these motifs prevent ER
dimerization, association with caveolin-1, and non-genomic ER signaling to activate
p42/44 MAPK, PI3K, and cAMP (76, 78). Similarly, specific deletions at the caveolin-1
scaffolding domain largely prevent the localization of ER at the plasma membrane (60,
76). Interestingly however, ER interaction with the signaling molecule MNAR involves
both the amino (N)-terminus and portions of the E domain of ER (79). In contrast,
interaction of ER with shc and striatin has been reported to involve the N-terminus of the
receptor (64). ER with deleted portions of its N-terminus still localizes to the membrane
and signals to p42/44 MAPK equivalently to wild type ER (76) consistent with the idea
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