Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family

Abstract

The three homologous members of the p160 SRC family (SRC1, SRC2 and SRC3) mediate the transcriptional functions of nuclear receptors and other transcription factors, and are the most studied of all the transcriptional co-activators. Recent work has indicated that the SRCgenes are subject to amplification and overexpression in various human cancers. Some of the molecular mechanisms responsible for SRC overexpression, along with the mechanisms by which SRCs promote breast and prostate cancer cell proliferation and survival, have been identified, as have the specific contributions of individual SRC family members to spontaneous breast and prostate carcinogenesis in genetically manipulated mouse models. These studies have identified new challenges for cancer research and therapy.

Fig. 1

Molecular structure of SRCs and their functional mechanisms in steroid hormone-induced gene expression. The locations of basic structural and functional domains of SRCs are indicated. Upon hormone (H) binding, the hormone nuclear receptors (NR) expose their coactivator-binding motifs in their ligand-binding domains and allow SRCs to be recruited to the enhancer region of the NR target genes. SRCs further interact with CBP, p300, p/CAF, CARM1 and PRMT1 and recruit these common coactivators to the chromatin to build up a steroid receptor-directed transcriptional activation complex. This protein complex uses its protein acetyltransferase and methyltransferase activities to remodel the chromatin structure and to facilitate the assembly of general transcription factors and RNA polymerase II on the promoter for transcriptional activation. Of note, in addition to interactions between NR and the NRID domain of SRCs, interactions between NR and the bHLH/PAS domain of SRCs have been documented and may be important for function (see dotted line with arrowheads). Abbreviations: NRID, NR interaction domain; AD1 and AD2, activation domains 1 and 2; bHLH/PAS, the basis helix-loop-helix/Per-Ah receptor nuclear translocator-Sim domain; S/T, the serine and threonine-rich domain; L, L and L, the three LXXLL motifs responsible for interaction with nuclear receptors; Q, the glutamine-rich region; HAT, the histone acetyltransferase domain; CBP, the CREB (cAMP response element-binding protein) binding protein; p300, the 300 kDa protein homologous to CBP; p/CAF, the p300 and CBP-associated factor; CARM1, the coactivator-associated arginine methyltransferase 1; PRMT1, the protein arginine methyltransferase 1; TBP, the TATA binding protein; TAFIIs, TBP-associated general transcription factors (GTFs); Pol II, RNA polymerase II.

Fig. 2. Posttranslational modifications of SRCs

In general, phosphorylation results in activation of SRCs. In the case of SRC-3, phosphorylation determines the selectivity of SRC-3 for different transcription factors, promotes sequential ubiquitination of SRC-3 from mono-ubiquitination (activation) to poly-ubiquitination (degradation), and controls the duration of transcriptional activation by SRC-3. Conversely, de-phosphorylation by phosphatase (PPase) promotes SRC-3 sumoylation, stabilizes SRC-3 protein, and inhibits SRC-3 activity. Depending on specific kinases and phosphorylation sites, phosphorylation could either increase or decrease SRC-3 stability and cellular levels. Sumoylation enhances SRC-1 and SRC-2 activities (the “?” indicates that the conclusion is based on a limited amount of data), but it inhibits SRC-3 activity. SRC-3 acetylation and methylation cause a disassembly of the transcription complex and promote transcriptional termination.

Fig. 3. SRCs promote carcinogenesis through multiple pathways

Extracellular signals and their signaling pathways cause posttranslational modifications of SRCs, which regulate the cellular concentrations, activities and specificities of SRCs. In general, SRCs enhance steroid receptor functions and facilitate hormonal promotion of breast, prostate and ovarian cancers. Specifically, SRC-1 enhances Ets-2-mediated HER2 expression and PEA3-mediated Twist expression and upregulates CSF-1 expression to promote breast tumor cell migration, invasion and metastasis. MOZ and SRC-2 fusion gene causes AML (acute myeloid leukemia). SRC-3 upregulates its own expression through serving as a coactivator for E2F1 and SP1. The overexpressed SRC-3 enhances PEA3 and AP-1 mediated MMP expression to promote breast and prostate tumor cell metastasis. SRC-3 also enhances E2F1-mediated cell cycle progression and Gab2 expression that activates Akt. In addition, SRC-3 upregulates IGF-I, IRS-1 and IRS-2 to promote the IGF-I signaling pathway and to activate EGFR and ERBB2 to enhance Akt and MAPK activities, resulting in hyperactivation of Akt and MAPK which contribute to cancer cell proliferation, growth, survival, migration, invasion and metastasis.