Steroid receptor coactivator (SRC) family: masters of systems biology

Abstract

The three members of the p160 family of steroid receptor coactivators (SRC-1, SRC-2, and SRC-3) steer the functional output of numerous genetic programs and serve as pleiotropic rheostats for diverse physiological processes. Since their discovery ∼15 years ago, the extraordinary sum of examination of SRC function has shaped the foundation of our knowledge for the now 350+ coregulators that have been identified to date. In this perspective, we retrace our steps into the field of coregulators and provide a summary of selected seminal work that helped define the SRCs as masters of systems biology.

FIGURE 1.

Steroid/nuclear receptor publications. A graphical analysis of publications on steroid/nuclear receptors as they relate to influential findings in the field is presented. Discoveries listed include identification of a receptor for estrogens (1962) (82), identification of estrogen stimulation of gene expression (1968–1972) (83, 84), molecular DNA cloning of the first gene (1972) (85), partial purification of NRs (1974) (86–88), identification of estrogen-responsive genes (1976) (89), identification of hormone-response elements (HRE) (1982) (90), cloning of the first full-length NRs (1985) (91), determination of the first x-ray crystal structure of NRs (1991) (92–94), development of the first nuclear receptor knock-out (KO) mouse (1993) (95), cloning of the first SRC (1995) (20), development of the first coactivator (CoA) knock-out mouse (1998) (60), and identification of metabolic functions (F(x)s) for nuclear receptors (1997) (96). These data were compiled from PubMed. The asterisk indicates a predicted estimate for the number of publications for 2010.

FIGURE 2.

Molecular structure and interacting partners of human SRC-3. Conserved functional domains of human SRC-3 include the bHLH/PAS domain, a serine/threonine (S/T)-rich domain, a nuclear receptor-interacting domain (RID) (where L = LXXLL), the CBP/p300 interaction domain (CID), a polyglutamate region (Q), and a histone acetyltransferase (HAT) domain. This representation is not to scale and is an incomplete list of known interacting proteins. Asterisks indicate proteins that have been validated to interact specifically with SRC-3Δ4. AD, activation domain; AR, androgen receptor; PR, progesterone receptor; GR, glucocorticoid receptor; TR, thyroid receptor; CoCoA, co-coactivator; aPKC, atypical PKC; EGFR, EGF receptor; FAK, focal adhesion kinase.

FIGURE 3.

Molecular functions of SRC-3. Presented is a schematic representation of how PTMs selectively code the numerous molecular functions of SRC-3, which include, but are not limited to, amplification of steroid- and mitogen-mediated gene transcription, regulation of RNA splicing, translational corepression, modulation of energy homeostasis, and control of cellular motility. TNFR, TNF receptor; EGFR, EGF receptor; FAK, focal adhesion kinase; CoCoA, co-coactivator; Ub, ubiquitin; TBP, TATA-binding protein; TAFIIs, TATA-binding protein-associated factors; Pol II, RNA polymerase II; PPTases, phosphatases; GTF, general transcription factor.