Phosphorylation of steroid receptor coactivator-3 (SRC-3) at serine 857 is regulated by the p38MAPK-MK2 axis and affects NF-κB-mediated transcription

Abstract

Steroid receptor coactivator-3 (SRC-3) regulates the activity of both nuclear hormone receptors and a number of key transcription factors. It is implicated in the regulation of cell proliferation, inflammation and in the progression of several common cancers including breast, colorectal and lung tumors. Phosphorylation is an important regulatory event controlling the activities of SRC-3. Serine 857 is the most studied phospho-acceptor site, and its modification has been reported to be important for SRC-3-dependent tumor progression. In this study, we show that the stress-responsive p38 MApK-MK2 signaling pathway controls the phosphorylation of SRC-3 at S857 in a wide range of human cancer cells. Activation of the p38 MApK-MK2 pathway results in the nuclear translocation of SRC-3, where it contributes to the transactivation of NF-kB and thus regulation of IL-6 transcription. The identification of the p38 MApK-MK2 signaling axis as a key regulator of SRC-3 phosphorylation and activity opens up new possibilities for the development and testing of novel therapeutic strategies to control both proliferative and metastatic tumor growth. The steroid receptor coactivator 3 (SRC-3) is a transcriptional coactivator of the p160 family encoded by the gene nuclear receptor coactivator 3 (NCOA3). It was originally identified as a coactivator for nuclear receptors 1 , but is now recognized as a coactivator of several other transcription factors including E2F transcription factor 1 (E2F1) 2 , polyomavirus enhancer activator 3 (PEA3) 3 , activator protein-1 (AP-1) 4,5 , and nuclear factor-κB (NF-κB) 6,7. Based on this broad spectrum of transcriptional activities, SRC-3 has been shown to play important roles in a wide range of physiological processes, such as cell proliferation, cell survival, mammary gland development 8 and metabolism 9. Since 1997, when SRC-3 was found to be amplified in breast cancer 10 its role in cancer progression has been broadly investigated. It has been shown to be implicated in hormone-related cancers, such as endometrial 11 , ovarian 12 , prostate 13 and breast cancer 14 , but also in in hormone-independent cancer types such as esophageal, squamous cell, colorectal, hepatocellular, pancreatic and non-small cell lung cancer 15. SRC-3 modulates various processes, for example cell proliferation 16 , development of metastasis 17 , and resistances to anti-cancer drugs 18,19. The function of the SRC-3 protein is highly regulated by post-transcriptional modifications through phosphorylation. SRC-3 is phosphorylated at multiple residues mediated by distinct protein kinases, suggesting that SRC-3 might be controlled by several different signaling pathways in health and disease 20,21. Among the different phosphorylation sites, the most frequently reported modification of SRC-3 is the phosphorylation at serine 857 (S857) 22. This phosphorylation has been shown to be important for regulation of estrogen receptor, androgen receptor and NF-κB-mediated transcription 20. In addition, more recent data indicate that phosp...

SRC‐3 Knockout Attenuates Myocardial Injury Induced by Chronic Intermittent Hypoxia in Mice

“…Furthermore, HIF-1 α is an important transcription factor involved in oxidative stress and that many of its downstream targets are closely related to CVDs [ 6 ]. It is easy to come up with SRC-3 may regulate the downstream NF- κ B signaling pathways [ 45 ] (Figures 7(a) and 7(b) ), inflammatory, and iNOS by recruitment to the promoters of HIF-1 α . We postulate that SRC-3 contributes to the pathogenesis of CVDs through activating HIF-1 α and NF- κ B, as well as promoting oxidative stress and inflammation.…”

Epigenetic DNA Methylation of EBI3 Modulates Human Interleukin-35 Formation via NFkB Signaling: A Promising Therapeutic Option in Ulcerative Colitis

“…However, the effect was not as potent as the IκB kinase inhibitor BMS-345541, which almost completely abolished the effect. As several studies have demonstrated that the expression of EBI3 through various stimuli is regulated by NFκB and not via MAPK [ 37 , 48 , 49 ] and also because the link between p38 signaling and NFκB-mediated gene expression is well known [ 50 , 51 , 52 ], the results suggest that part of the NFκB effect is mediated via p38 MAPK.…”

SRC-3, a Steroid Receptor Coactivator: Implication in Cancer

“…According to reports, the most common phosphorylation site of SRC-3 is S857 [ 29 ]. Recently, two signaling axes were found to regulate phosphorylation of SRC-3 at this site [ 30 , 31 ]. Dasgupta et al performed a kinome-wide RNA interference-based screening to identify fuctose-2,6-bisphosphatase 4 (PFKFB4) that phosphorylates SRC-3 at S857 and promotes the intrinsic SRC-3 transcriptional activity [ 30 ].…”

“…Based on in vitro phosphorylation assay, Shrestha et al indicated that MK2 was responsible for phosphorylation of SRC-3 at S857 and p38 is the upstream of MK2. Activation of the p38-MK2 signaling leaded to the nuclear translocation of SRC-3, which contributed to NF-kB activation and downstream target expression [ 31 ]. In conclusion, PTMs are critical molecular events, which change SRC-3 conformation and generate diverse SRC-3 properties by regulating its stability, localization and interacting partners, consequently exerting pivotal roles in regulating the functions of SRC-3.…”