Steroid receptor coactivator-1 SRC

A series of proteins or protein complexes with coactivator function for nuclear receptors has been identified that specifically interact with the activated, liganded receptor. The most abundant ones are now included in the pl60 family of coactivators with the steroid receptor coactivator 1, SRC-1, as a well-characterized member. Another group of coactivators is present as multiprotein complexes like the TRAP complex (TRAP, thyroid hormone receptor activating protein). A common receptor interaction motif LXXLL is found on these coactivators which mediates at least part of the interaction with the AF2 domain of the receptor. 

The pl60 family of coactivators including steroid receptor coactivator 1 (SRC-1), TIF/GRIP (SRC-2), and ACTR/pCIP (SRC-3) [24] stimulates the transcriptional activity of nuclear receptors. The pi60 family of coactivators has three LXXLL motifs in the receptor-interacting domain (RID) that interacts with the AF-2 domain of nuclear receptors. SRC-1 is a weak HAT that interacts with p300/CBP and recruits CARM-1. 

Fig. 7. Model for activation by coactivators (A) and inhibition by corepressors (B) of transcription. Abbreviations CBP/p300, cAMP response element binding protein SRC-1, steroid receptor coactivator 1 TBP, TATA-binding protein TAF, TBP-associated factor pol II, RNA polymerase II N-CoR, nuclear receptor corepressor SMRT, silencing mediator of retinoic and thyroid hormone receptors.

The two ERs share many functional characteristics based on their well conserved modular structure. As summarized above, AF-2 is responsible for estrogen-dependent activation through recruitment of coactivator proteins including members of the steroid receptor coactivator (SRC) family (Anzick et al., 1997 Chen et al., 1997 Hong et al., 1996 Kamei et al., 1996 Li et al., 1997 Onate et al., 1995 Torchia et al., 1997 Voegel et al., 1996). On the other hand, AF-1 activity is constitutive and ligand-independent (Berry et al., 1990 Kumar et al., 1987 Metzger et al., 1995). 

Our observations suggest that Ser-106 and Ser-124 are both required in vivo to fully recruit SRC-1. In addition, when cells were treated with factors known to activate Ras, such as EGF or IGF-1 (data not shown), the in vivo interaction between SRC-1 and ER(3 was also enhanced, thus mimicking the results obtained in the presence of activated Ras. This study demonstrates for the first time that phosphorylation of the AF-1 domain of a member of the nuclear receptor superfamily enhances the recruitment of a steroid receptor coactivator (SRC-1) and provides a molecular basis for ligand-independent activation of ER(3 via the MAPK cascade. 

Coactivators enhancing the transcriptional activity of steroid hormone receptors activators include SRC-1 (steroid-receptor co-activator 1) or TEF2 (transcriptional intermediary factor 2), which are recruited by the DNA/ steroid hormone receptor complex. Their main role is to attract other transcriptional coactivators with histone acetyltransferase activity in order to decondense chromatin and allow for the binding of components of the general transcription apparatus. 

Li H, Gomes PJ, Chen JD. 1997. RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc. Natl. Acad. Sci. USA 94 8479-84... 

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