The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor α to the plasma membrane

Song, Robert X.-D.; Barnes, Christopher J.; Zhang, Zhenguo; Bao, Yongde; Kumar, Rakesh; Santen, Richard J.

doi:10.1073/pnas.0308334100

Cited by 318 publications

(291 citation statements)

References 37 publications

(31 reference statements)

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“…The mER has no intrinsic transmembrane domain, raising the question of how it binds to the plasma membrane. The mER from a cytoplasmic pool may translocate to the inner face of the plasma membrane and tether to it through proteins, such as caveolin-1 or growth factor receptors, possibly via palmitoylation (Acconcia et al, 2005a;Razandi et al, 2002;Song et al, 2004). Caveolin- Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Using antibodies directed against different epitopes of nuclear ER, many laboratories have demonstrated that some forms of ER can locate in the region of the cell membrane (Razandi et al, 2003;Simoncini et al, 2003;Song et al, 2004). Toran-Allerand et al (2002) described a novel mER, designated ER-X, which is enriched in the brain, uterus, and lung of the postnatal rodent and prefers 17a-estradiol to 17b-estradiol as the ligand.…”

Section: Introductionmentioning

confidence: 99%

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The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

Hirahara

Matsuda

Gao

et al. 2008

Glia

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There is general acceptance that the estrogen receptor can act as a transcription factor. However, estrogens can also bind to receptors that are located at the plasma membrane and stimulate rapid intracellular signaling processes. We recently showed that a membrane-associated estrogen receptor (mER) is present within myelin and at the oligodendrocyte (OL) plasma membrane. To understand the physiological function of mER in OLs, we investigated its cellular localization and involvement in rapid signaling in CG4 cells and OL primary cultures. An ERa was expressed along the lacy network of veins in the membrane sheets and in the perikaryon and nucleus in OLs. ERb was located in the nucleus, and to a lesser extent along the veins. The expression of ERa and ERb in OL membranes was confirmed by Western analysis of isolated membranes. OL membranes mainly had truncated forms of ERa, 53 and 50 kDa, in addition to some 65 kDa form, whereas ERb was a 54 kDa form. CG4 cells and OLs were pulsed with 17a-and 17b-estradiol for various times and the total lysates were analyzed for phosphorylated kinases. Both 17a-and 17b-estradiol elicited rapid phosphorylation of p42/44MAPK, Akt, and GSK-3b within 8 min. This rapid signaling is consistent with estradiol ligation of a membrane form of ER. Since 17a-estradiol is produced at higher concentrations than 17b-estradiol in the brain of both sexes, signaling via 17a-estradiol-liganded mER may have an important function in OLs. V V C

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

Hirahara

Matsuda

Gao

et al. 2008

Glia

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“…Effector molecules such as SHC-transforming protein 1, Akt, and MAPK are activated by adaptor protein Src and PI3K [62,63]. The crosstalk between E2 and other growth factor signals suggests that adaptor proteins are essential for extranuclear actions of ERα.…”

Section: E2 Signaling In Breast Carcinogenesismentioning

confidence: 99%

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

Zhou

Qiao

Shetty

et al. 2013

Cell. Mol. Life Sci.

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Estrogen and estrogen receptors (ERs) are critical regulators of breast epithelial cell proliferation, differentiation, and apoptosis. Compromised signaling vis-à-vis the estrogen receptor is believed © Springer Basel 2013 yow4@pitt.edu. ), which predicts for response to endocrine-based therapy; however, innate or acquired resistance to endocrinebased drugs remains a serious challenge. The complexity of regulation for estrogen signaling coupled with the crosstalk of other oncogenic signaling pathways is a reason for endocrine therapy resistance. Alternative strategies that target novel molecular mechanisms are necessary to overcome this current and urgent gap in therapy. A thorough analysis of estrogen-signaling regulation is critical. In this review article, we will summarize current insights into the regulation of estrogen signaling as related to breast carcinogenesis and breast cancer therapy. NIH Public Access

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“…28 A series of studies by other investigators suggested that ERα and the IGF-1 receptor might interact. 28 We tested the model that estradiol caused binding of SHC to ERα but also caused phosphorylation of the IGF-1 receptor. In this way, SHCwould serve as the "glue" which would tether ER alpha to the plasma membrane where it would bind to the SHC acceptor site.…”

Section: Phenomenon Of Hypersensitivity: Mechanisms and Pathwaysmentioning

confidence: 99%

Adaptation to Estradiol Deprivation Causes Up-Regulation of Growth Factor Pathways and Hypersensitivity to Estradiol in Breast Cancer Cells

Santen

Song

Masamura

et al. 2008

Advances in Experimental Medicine and Biology

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Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby Long Term Estradiol Deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response including upregulation of ERα and the MAP kinase, PI-3-kinase and mTOR growth factor pathways. ERα is 4-10 fold up-regulated as a result of demethylation of its C promoter, is nuclear receptor then co-opts a classical growth factor pathway using SHC, Grb-2 and Sos. is induces rapid nongenomic effects which are enhanced in LTED cells.The molecules involved in the nongenomic signaling process have been identified. Estradiol binds to cell membrane-associated ERα which physically associates with the adaptor protein SHC and induces its phosphorylation. In turn, SHC binds Grb-2 and Sos which results in the rapid activation of MAP kinase. These nongenomic effects of estradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the PI-3-kinase and mTOR pathways through estradiol-induced binding of ERα to the IGF-1 and EGF receptors.A major question is how ERα locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-1 receptor serves as an anchor for ERα in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, SHC and the IGF-1 receptor itself. SHC, after binding to ERα, serves as the "glue" which tethers ERα to SHC binding sites on the activated IFG-1 receptors. Use of siRNA methodology to knock down SHC allows the conclusion that SHC is needed for ERα to localize in the plasma membrane.In order to abrogate growth factor induced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1 and reduces the activation of MAP kinase. We have shown that this drug is a potent inhibitor of mTOR and this provides the major means for inhibition of cell proliferation. The concept of "adaptive hypersensitivity" and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy of aromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.

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The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor α to the plasma membrane

Cited by 318 publications

References 37 publications

The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

Adaptation to Estradiol Deprivation Causes Up-Regulation of Growth Factor Pathways and Hypersensitivity to Estradiol in Breast Cancer Cells

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