AIB1 Is a Conduit for Kinase-Mediated Growth Factor Signaling to the Estrogen Receptor

Abstract

Growth factor modulation of estrogen receptor (ER) activity plays an important role in both normal estrogen physiology and the pathogenesis of breast cancer. Growth factors are known to stimulate the ligand-independent activity of ER through the activation of mitogen-activated protein kinase (MAPK) and the direct phosphorylation of ER. We found that the transcriptional activity of AIB1, a ligand-dependent ER coactivator and a gene amplified preferentially in ER-positive breast cancers, is enhanced by MAPK phosphorylation. We demonstrate that AIB1 is a phosphoprotein in vivo and can be phosphorylated in vitro by MAPK. Finally, we observed that MAPK activation of AIB1 stimulates the recruitment of p300 and associated histone acetyltransferase activity. These results suggest that the ability of growth factors to modulate estrogen action may be mediated through MAPK activation of the nuclear receptor coactivator AIB1.The estrogen receptor (ER) is a member of the class I family of nuclear receptors (NRs) (for a review, see reference 24). It contains three major functional domains: an N-terminal activation domain (AF-1), a DNA-binding domain (DBD) highly conserved among other NRs, and a C-terminal hormone-binding domain which contains a second activation domain (AF-2) (19, 38). Although AF-1 and AF-2 contribute synergistically to the transcription of targeted genes, they have different mechanisms of activation. AF-1 activity is highly dependent on phosphorylation of serine 118 by mitogen-activated protein kinase (MAPK) (18). In contrast, the more potent AF-2 is activated by the binding of estrogenic ligands (3).ER-mediated gene transcription is regulated at yet another level depending on the ligand; ER interacts with corepressors or coactivators that inhibit or enhance its activity on target genes. In the absence of ligand, ER is sequestered in the nucleus by interaction with heat shock proteins (29, 33). When activated by agonist ligand binding, ER exerts its action by promoting chromatin remodeling and stimulating the basal transcriptional machinery through interaction with a variety of coactivators (1, 14-16, 23, 27, 28, 34). One of the best-characterized groups of NR coactivators is the p160 family. When bound to agonists such as estradiol, ER AF-2 engages signature motifs (LXXLL) in the center of the p160 molecule (11). Recent studies have shown that the AF-1 domain of ER also interacts with p160 coactivators (40, 42), though the interaction seems to occur at a different site found in the C terminus of the p160 molecule. The p160 coactivators also contain two activation domains, AD1 and AD2, which are localized in the C terminus (6,7,41) and bind the secondary coactivators p300/CREB binding protein (CBP) and coactivator-associated arginine methyltransferase 1 (CARM1), respectively. Thus, AD1 and AD2 act as signal output domains in the process of transcriptional activation (22). Mutations in the AD1 region greatly reduced or eliminated the ability of p160 proteins to bind CBP or p300 and to serve as coactivators f...

Inverse relationship between ER-β and SRC-1 predicts outcome in endocrine-resistant breast cancer

“…The relationship between SRC-1 response to the steroid environment and HER2 status is an interesting one, as p160 proteins are known to be phosphorylated via the MAP kinase pathway (Font de Mora and Brown, 2000;Rowan et al, 2000). Taken together, these data provide further evidence of the proposed crosstalk between growth factor receptor pathways and activation of steroid receptor coactivator proteins (Johnston et al, 2003;Osborne et al, 2003).…”

Non-genomic actions of androgens

“…The steroid receptor coactivator (SRC) family of transcriptional coactivators is a target of MAPK phosphorylation. Phosphorylation of SRCs results in an increased ability of these coactivators to recruit additional coregulatory complexes to the DNA-bound receptor [66] [ 67; 68]. It is possible that androgens can induce an autocrine type of feed-forward loop in which androgen-bound AR stimulates the MAPK pathway through direct interaction with cSrc kinase, resulting in phosphorylation of AR and AR coactivators and enhancement of AR transcriptional activity [69; 70; 71].…”

Interactions between the estrogen receptor, its cofactors and microRNAs in breast cancer

“…The gene encoding PPARBP is localized on chromosome 17q12, in close proximity to the HER2/neu amplicon (ERBB2), which is frequently amplified in breast cancer [32]. It is suggested that coactivator upregulation and kinase hyperactivation are part of an integrated mechanism in promoting carcinogenesis [33,34].…”

“…This action is thought to result after phosphorylation of the ER outside the nucleus i.e., in the cytoplasm or cell membrane, leading to activation of tyrosine kinase receptors such as insulin-like growth factor 1 receptor (IGF-1R), epidermal growth factor receptor (EGFR) and HER2/neu [52]. These receptors then initiate the activation of key downstream signaling kinases such as ERK1,2 mitogen-activated protein kinase (MAPK) and AKT, which in turn phosphorylate and activate the ER and/or its coactivators [34]. This ligand-independent cross talk between the ER and growth factor signaling pathways can sustain activation of pathway signaling and the survival of breast cancer by enhancing the estrogen agonist activity of tamoxifen [53].…”