Glycogen Synthase Kinase-3 Interacts with and Phosphorylates Estrogen Receptor α and Is Involved in the Regulation of Receptor Activity

Medunjanin, Senad; Hermani, Alexander; Servi, Barbara De; Grisouard, Jean; Rincke, Gabriele; Mayer, Doris

doi:10.1074/jbc.m506758200

Cited by 125 publications

(129 citation statements)

References 47 publications

(31 reference statements)

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“…However, there is increasing evidence that the presence of estrogen is not an absolute requirement for receptor activation, because growth factors, such as IGF-1 or EGF, and intracellular protein kinases can induce an estrogen-independent ERa activation in different model systems (Butt et al, 2005). In breast cancer cells phosphorylation of the Ser-118 residue in the human ERa A/B domain by growth factors stimulated mitogen-activated protein kinase (Kato et al, 1995;Bunone et al, 1996;Chen et al, 2000;Medunjanin et al, 2005;Park et al, 2005;Weitsman et al, 2006) results in the potentiation of the ER ligandindependent transcriptional activation function (AF-1). Interestingly, it has been proposed that phosphorylation in Ser-118 may be associated with an increase in estrogen agonism, progression of breast cancer, resistance to tamoxifen therapy and estrogen-independent growth of MCF-7 cells (Likhite et al, 2006;Murphy et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Activation of the unliganded estrogen receptor by prolactin in breast cancer cells

et al. 2009

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Both prolactin (PRL) and estrogen (E2) are involved in the pathogenesis and progression of mammary neoplasia, but the mechanisms by which these hormones interact to exert their effects in breast cancer cells are not well understood. We show here that PRL is able to activate the unliganded estrogen receptor (ER). In breast cancer cells, PRL activates a reporter plasmid containing estrogen response elements (EREs) and induces the ER target gene pS2. These actions are blocked by the antagonist ICI 182,780, showing that ER is required for the PRLmediated effect. Moreover, PRL leads to phosphorylation of ERa in serine-118 (P-ERa), a modification related to the potentiation of ligand-independent transcriptional activation. In addition, PRL mimics the effect of E2 on target gene expression by inducing cyclical recruitment of ERa and P-ERa to ERE-containing promoters, resulting in recruitment of co-activators and acetylation of histone H3. Finally, PRL induces expression of c-Myc and Cyclin D1 and leads to increased cell proliferation, which is specifically antagonized by ICI 182,780 or ERa depletion. These results show that ligand-independent ERa activation appears to be an important component of the proliferative and transcriptional actions of PRL in breast cancer cells.

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Section: Introductionmentioning

confidence: 99%

Activation of the unliganded estrogen receptor by prolactin in breast cancer cells

et al. 2009

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“…While the identity of the kinase(s) that mediates estrogenic phosphorylation of Ser118 is unknown, cdk7, IKKα, MAPK and GSK3 have been shown to have direct and indirect growth factor-induced phosphorylation. 32,[35][36][37] The phosphorylation of Ser167 is mainly sensitive to growth factor stimuli and is mediated primarily by S6K1, 18,38 while p90Rsk and Akt example, a pre-operative study of letrozole with or without everolimus reported greater tumor shrinkage for the combination. 73 A very recent breast cancer trial of oral everolimus-(BOLERO-2), a phase 3 study in patients with advanced disease, showed that the addition of everolimus to endocrine therapy results in an improved clinical outcome.…”

Section: S6k1 In Er-positivementioning

confidence: 99%

“…The kinases that have been implicated in this event are GSK3, cdk2 and MAPK. [32][33][34] Ser118 phosphorylation is sensitive to both estrogen and growth factor signaling. While the identity of the kinase(s) that mediates estrogenic phosphorylation of Ser118 is unknown, cdk7, IKKα, MAPK and GSK3 have been shown to have direct and indirect growth factor-induced phosphorylation.…”

Section: S6k1 In Er-positivementioning

confidence: 99%

The role of S6K1 in ER-positive breast cancer

Holz

2012

Cell Cycle

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T he 40S ribosomal S6 kinase 1 (S6K1) is a conserved serine/threonine protein kinase that belongs to the AGC family of protein kinases, which also includes Akt and many others. S6K1 is the principal kinase effector downstream of the mammalian target of rapamycin complex 1 (mTORC1). S6K1 is sensitive to a wide range of signaling inputs, including growth factors, amino acids, energy levels and hypoxia. S6K1 relays these signals to regulate a growing list of substrates and interacting proteins in control of oncogenic processes, such as cell growth and proliferation, cell survival and apoptosis and cell migration and invasion. Several lines of evidence suggest an important role for S6K1 in estrogen receptor (ER)-positive breast cancer. S6K1 directly phosphorylates and activates ERα. Furthermore, S6K1 expression is estrogenically regulated. Therefore, hyperactivation of mTORC1/ S6K1 signaling may be closely related to ER-positive status in breast cancer and may be utilized as a marker for prognosis and a therapeutic target. IntroductionThe mTORC1 signaling pathway. Since its cloning and biochemical purification almost 20 y ago, mTOR, a conserved protein kinase, emerged as a central node in the plexus coordinating cellular growth and proliferation in response to numerous extracellular cues, including nutrient availability and growth stimuli. In eukaryotic cells, mTOR exists in two complexes. mTORC1 and mTORC2 consist of distinct sets of proteins and perform non-redundant functions. 1 a naturally derived inhibitor of mTORC1 and an inhibitor of cell proliferation, as manifested by its potent immunosuppressive properties and activity against solid tumors. 2 Growth factor signaling to mTORC1 is primarily mediated by the phosphatidylinositol-3 kinase (PI3K) pathway and inactivation of the tuberous sclerosis complex protein TSC2 (tuberin). As illustrated in Figure 1, in response to extracellular activating stimuli, PI3K mediates cell membrane recruitment and activation of the serine/threonine protein kinases phosphatidylinositol-dependent kinase-1 (PDK1) and Akt. 3,4 The lipid phosphatase PTEN opposes the action of PI3K. TSC2 functions as a heterodimer with TSC1 (hamartin) to negatively regulate mTORC1 signaling by acting as a GTPase-activating protein (GAP) for the small GTPase Rheb. 5 Rheb directly binds to mTORC1 and regulates its activity in a GTP-dependent manner. 6 Thus, TSC2 inhibits Rheb-dependent activation of mTORC1. Phosphorylation and inactivation of TSC2 has first been shown to occur via PI3K/Akt. 7 Subsequently, several groups have shown that the Ras/ERK pathway also converges on the TSC1/2 complex. Ras-activated ERK1/2 directly phosphorylates TSC2 at sites different than Akt, resulting in TSC2 inactivation. 8 The downstream effector of ERK, RSK, also phosphorylates TSC2 at a unique site, thus inactivating it. 9 Therefore, TSC2 serves as a convergence point for multiple signaling inputs to mTORC1.Activation of S6K1. S6K1 is one of the best-characterized downstream targets of mTORC1, and rapamycin treatment re...

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“…3β. The non-bound residues in green (ER-α) and wheat (GSK-3β) are the binding sites described by Medunjanin et al [69] and Ilouz et al [48], respectively. The GSK-3β amino acid residue responsible for phosphorylating ER-α depicted in this figure is the same residue that phosphorylates CREB at serine 129 (figure 3).…”

Section: Gln54mentioning

confidence: 99%

“…Medunjanin et al [69] suggested that when GSK-3β is phosphorylated at serine 9 it will disassociate itself from ER-α, allowing ER-α to migrate to the nucleus for a subsequent phosphorylation by GSK-3β -consequently activating ER-α transcriptional properties (figure 6). Palindromic DNA sequences are recognized by ER-α, and expressed in promoter regions for NMDA receptor subunits [103]; thus, estrogen has a direct genomic role in NMDA receptor subunit expression.…”

Section: Lys205mentioning

confidence: 99%

Estrogen and Lithium: Facilitating Factors Involved in Brain Cell Signaling Pathways

Valdés¹

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Glycogen Synthase Kinase-3 Interacts with and Phosphorylates Estrogen Receptor α and Is Involved in the Regulation of Receptor Activity

Cited by 125 publications

References 47 publications

Activation of the unliganded estrogen receptor by prolactin in breast cancer cells

Activation of the unliganded estrogen receptor by prolactin in breast cancer cells

The role of S6K1 in ER-positive breast cancer

Estrogen and Lithium: Facilitating Factors Involved in Brain Cell Signaling Pathways

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