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 p38MAPK-MK2 signaling pathway controls the phosphorylation of SRC-3 at S857 in a wide range of human cancer cells. Activation of the p38MAPK-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 p38MAPK-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.
Highlights
Steroid receptor coactivator-3 (SRC-3) regulates the activity of both nuclear hormone receptors and a number of key transcription factors
No phosphorylation was observed when a mutant version of the protein (GST-CBP-interacting domain (CID)-SRC-3 S857A), in which serine 857 was replaced with alanine was used as substrate (Fig. 1A)
These findings indicate that SRC-3 is phosphorylated at S857 by the extracellular regulated kinase 3 (ERK3) downstream effector MK5 rather than by ERK3 itself
Summary
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. 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 r eceptors[1], but is 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]. More recent data indicate that phosphorylation at S857 is essential for the ability of SRC-3 to promote lung and breast cancer progression and metastasis[23]. The data indicating that SRC-3 is a substrate for ERK3, could be an important step towards our understanding of the biological role of ERK33,24
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