MTA family of coregulators in nuclear receptor biology and pathology

Abstract

Nuclear receptors (NRs) rely on coregulators (coactivators and corepressors) to modulate the transcription of target genes. By interacting with nucleosome remodeling complexes, NR coactivators potentiate transcription, whereas corepressors inhibit transcription of the target genes. Metastasis-associated proteins (MTA) represent an emerging family of novel NR coregulators. In general, MTA family members form independent nucleosome remodeling and deacetylation (NuRD) complexes and repress the transcription of different genes by recruiting histone deacetylases onto their target genes. However, MTA1 also acts as a coactivator in a promoter-context dependent manner. Recent findings that repression of estrogen receptor transactivation functions by MTA1, MTA1s, and MTA2 and regulation of MTA3 by estrogen signaling have indicated the significance of these proteins in NR signaling. Here, we highlight the action of MTA proteins on NR signaling and their roles in pathophysiological conditions.

Figure 1. Comparison of structural domains among MTA family members and the components of the NuRD and Sin3 complexes.

A) Comparison of physical structures of the MTA family proteins. BAH, ELM and SANT domains located at the N-terminus are highly conserved, whereas the C-terminal region of MTA proteins is divergent. Identity (%), percentage of amino acid homology among MTA family members. ZnF, zinc finger; NLS-nuclear localization signal; AA, amino acids; PRO-rich, proline rich domain. B) Schematic representation of components of the NuRD complex, which is composed of seven polypeptides: Mi-2α/β, MTA1/2, MBDs, p66, HDACs (HDAC1 and 2), RbAp46 and RbAp48.

Figure 2. Cartoon showing the roles played by MTA family members in the nuclear receptor signaling pathway.

MTA1 and MTA1s are induced by various growth factors, Hypoxia and E2. MTA1 interacts with NuRD, while MTA2 associates with HDACs and represses E2-ERα transactivation at EREs. MTA1 also interacts with p300 and activates BCAS3 transcription. MTA1/2-HDACs complex also plays a role in stabilization of p53 and HIF1-α through acetylation. MTA3 is activated by ERα, associates with NuRD complex and represses Snail, an inhibitor of E-cad, and thereby promotes EMT.