Estradiol stimulates tyrosine phosphorylation of the insulin-like growth factor-1 receptor and insulin receptor substrate-1 in the uterus.

Richards, Randall G.; DiAugustine, Richard P.; Petrusz, Peter; Clark, G C; Sebastian, Joseph

doi:10.1073/pnas.93.21.12002

Cited by 115 publications

(91 citation statements)

References 47 publications

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“…In adult mice, E 2 treatment has been reported to induce IGF1 receptor activation in the uterine epithelium as determined by immunohistochemistry (21,22), and this activation required ER (15). Furthermore, exogenously administered IGF1 stimulated the IGF1 receptor and induced the cell proliferation marker proliferating cell nuclear antigen, although only a small increase, if any, in DNA synthesis was reported (15).…”

Section: Discussionmentioning

confidence: 99%

Estradiol-17β regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling

Zhu¹,

Pollard

2007

Proc. Natl. Acad. Sci. U.S.A.

118

108

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Estradiol-17␤ (E2) causes cell proliferation in the uterine epithelium of mice and humans by signaling through its transcription factor receptor ␣ (ER␣). In this work we show that this signaling is mediated by the insulin-like growth factor 1 receptor (IGF1R) expressed in the epithelium, whose activation leads to the stimulation of the phosphoinositide 3-kinase/protein kinase B pathway leading to cyclin D1 nuclear accumulation and engagement with the canonical cell cycle machinery. This cyclin D1 nuclear accumulation results from the inhibition of glycogen synthase kinase 3␤ (GSK3␤) activity caused by an inhibitory phosphorylation by protein kinase B. Once the IGF1 pathway is activated, inhibition of ER signaling demonstrates that it is independent of ER. Inhibition of GSK3␤ in the absence of E2 is sufficient to induce uterine epithelial cell proliferation, and GSK3␤ is epistatic to IGF1 signaling, indicating a linear pathway from E 2 to cyclin D1. Exposure to E2 is the major risk factor for endometrial cancer, suggesting that downstream activation of this IGF1-mediated pathway by mutation could be causal in the progression to ER-independent tumors.cell cycle ͉ cyclin D ͉ estrogen ͉ glycogen synthase kinase 3␤(GSK3␤) ͉ estrogen receptor T he adult mouse and human uterus undergoes waves of cell proliferation that are regulated by estradiol-17␤ (E 2 ) and progesterone (P 4 ). In both species, E 2 induces cell proliferation in the luminal and glandular epithelium, but in contrast to mice the human stroma also undergoes proliferation during this so-called proliferative phase (1). P 4 synthesized cyclically in the human or in response to copulation in the mouse inhibits this epithelial cell proliferation but primes the stromal cells to respond to E 2 by cell division (1). Because Ͼ50% of women seek medical advice due to uterine bleeding disorders, many of which are associated with proliferation at least once in their lives, and because E 2 is the major risk factor for endometrial and breast adenocarcinomas thought to be the result of the continuous stimulation of cell proliferation (1, 2), it is essential to understand the mechanism of action of these hormones in inducing cell division.In most cell types the entry into DNA synthesis is regulated by the sequential activity of cyclins and their attendant cyclindependent kinases (CDK) in phosphorylating and inactivating the members of the Rb family of proteins (3). These cyclin/CDKs are, in turn, regulated by the expression of a variety of cyclindependent inhibitors that fall into two classes the CIP/KIP family and the pl6 ink4 family, by phosphorylation of activating and inhibitory sites, as well as by their subcellular localization. In most cases, the initial sensing of external mitogenic stimuli is through altering the activity of D-type cyclins and their cognate CDK4 and CDK6 kinases (4, 5), which is also true in the uterine epithelium of mice in response to E 2 . But in contrast to the mitogenic responses of cells to E 2 in culture, the level of cyclin D1 does not ...

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Section: Discussionmentioning

confidence: 99%

Estradiol-17β regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling

Zhu¹,

Pollard

2007

Proc. Natl. Acad. Sci. U.S.A.

118

108

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“…The tyrosine phosphorylation and activation of IGF-1R induced by E2 were reported in uterine epithelial cells and ER-transfected COS-7 cells (24)(25)(26). Previously, we demonstrated strong interaction between ER␣ and Shc through N-terminal ER␣ and PTB͞SH2 domains of Shc in MCF-7 cells (9).…”

Section: Discussionmentioning

confidence: 99%

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

Song

Barnes

Zhang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

318

269

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Our previous studies demonstrated that 17␤-estradiol (E2) rapidly induces the interaction of estrogen receptor ␣ (ER␣) with the adapter protein Shc, the translocation of ER␣ to the cell membrane, and the formation of dynamic membrane structures in MCF-7 breast cancer cells. The present study examined how E2 causes ER␣ to translocate to the region of the plasma membrane and focused on mechanisms whereby Shc and the insulin-like growth factor-1 receptor (IGF-1R) mediate this process. Shc physically interacts with IGF-1R in the plasma membrane, and E2 activates IGF-1R. We reasoned that ER␣, when bound to Shc, would be directed to the region of the plasma membrane by the same processes, causing membrane translocation of Shc. We confirmed that E2 rapidly induced IGF-1R phosphorylation and demonstrated that E2 induced formation of a ternary protein complex among Shc, ER␣, and IGF-1R. Knock down of Shc with a specific small inhibitory RNA decreased the association of ER␣ with IGF-1R by 87%, suggesting that Shc is a crucial molecule in the formation of this ternary complex. Confocal microscopy studies provided further confirmation of the functional roles of Shc and the IGF-1R in the translocation of ER␣ to the region of the membrane. Down-regulation of Shc, ER␣, or IGF-1R with specific small inhibitory RNAs all blocked E2-induced mitogen-activated protein kinase phosphorylation. Together, our results demonstrate that Shc and IGF-1R serve as key elements in the translocation of ER␣ to the cell membrane and in the facilitation of ER␣-mediated rapid E2 action.

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“…The interaction of ER␣ and ER␤ with membrane-associated signaling pathways is currently under investigation but is still poorly understood (3,4,6,26,27). In our understanding of the role and function of estrogen receptors on the cell membrane level two major points deserve further attention: the interaction between estrogen receptors and tyrosine kinase receptor signaling pathways as well as the differences of ER␣ and ER␤ in coupling to the cell membrane.…”

Section: Discussionmentioning

confidence: 99%

“…Both mitogens act through receptor-mediated signaling pathways. The cross-talk between these two signaling pathways is currently under investigation (3)(4)(5)(6). Estrogen is a steroid hormone that binds to members of the nuclear receptor superfamily (7), whereas IGF-1 as a peptide-growth factor binds to a transmembrane tyrosine kinase receptor, which signals via a series of phosphorylation events (2).…”

mentioning

confidence: 99%

Estrogen Receptor α Rapidly Activates the IGF-1 Receptor Pathway

Kahlert¹,

Nuedling²,

Eickels³

et al. 2000

Journal of Biological Chemistry

427

297

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Estrogen and insulin-like-growth factor 1 (IGF-1) are potent mitogenic stimuli that share important properties in the control of cellular proliferation. However, the coupling between the signaling cascades of estrogen receptors ␣ and ␤ and the IGF-1 receptor (IGF-1R) is poorly understood. Therefore, we selectively transfected estrogen receptor ␣ or ␤ in COS7 and HEK293 cells, which contain IGF-1R. In presence of estrogen receptor ␣ but not ␤, 17␤-estradiol (E2) rapidly induces phosphorylation of the IGF-1R and the extracellular signal-regulated kinases 1/2. Furthermore, upon stimulation with E2, estrogen receptor ␣ but not ␤ bound rapidly to the IGF-1R in COS7 as well as L6 cells, which express all investigated receptors endogenously. Control experiments in the IGF-1R-deficient fibroblast cell line R ؊ showed that after stimulation with E2 only estrogen receptor ␣ bound to the transfected IGF-1R. Overexpression of dominant negative mitogen-activated protein kinases kinase inhibited this effect. Finally, estrogen receptor ␣ but not ␤ is required to induce the activation of the estrogen receptor-responsive reporter ERE-LUC in IGF-1-stimulated cells. Taken together, these data demonstrate that ligand bound estrogen receptor ␣ is required for rapid activation of the IGF-1R signaling cascade.Estrogen as well as insulin-like growth factor 1 (IGF-1) 1 are potent mitogens that are involved in a large array of processes that control proliferation and differentiation in mammalian cells (1, 2). Both mitogens act through receptor-mediated signaling pathways. The cross-talk between these two signaling pathways is currently under investigation (3-6). Estrogen is a steroid hormone that binds to members of the nuclear receptor superfamily (7), whereas IGF-1 as a peptide-growth factor binds to a transmembrane tyrosine kinase receptor, which signals via a series of phosphorylation events (2).Two different estrogen receptors, ER␣ and ER␤, which are encoded by genes located on different chromosomes, have been identified so far (8,9). Sequence analysis demonstrates a high degree of homology between ER␣ and ER␤ in the DNA-binding domain and the ligand-binding domain. However, there are significant differences in regions that would be expected to influence transcriptional activity. The ability of estrogen receptors to activate target gene transcription has been attributed to two regions: the N-terminal activation function 1 (AF-1) and the ligand-dependent AF-2, which is localized in the C-terminal hormone-binding domain (10, 11). AF-1 and AF-2 can activate transcription independently and synergistically, and they act in a promoter-and cell-specific manner (12, 13). Phosphorylation of a serine residue at position 118 is required for full action of the AF-1 (14). Both AF-1 and AF-2 are required to enhance transcription of target genes through AP-1 sites (15). Interestingly, ER␣ and ER␤ act differently at AP-1 sites (16), which may be due to differences in their AF domains (17). ER␣ and ER␤ can form homo-and heterodimers (18), and thus t...

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Estradiol stimulates tyrosine phosphorylation of the insulin-like growth factor-1 receptor and insulin receptor substrate-1 in the uterus.

Cited by 115 publications

References 47 publications

Estradiol-17β regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling

Estradiol-17β regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling

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

Estrogen Receptor α Rapidly Activates the IGF-1 Receptor Pathway

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