COUP-TFII in Health and Disease

Abstract

The nuclear receptors (NRs) belong to a vast family of evolutionary conserved proteins acting as ligand-activated transcription factors. Functionally, NRs are essential in embryogenesis and organogenesis and in adulthood they are involved in almost every physiological and pathological process. Our knowledge of NRs action has greatly improved in recent years, demonstrating that both their expression and activity are tightly regulated by a network of signaling pathways, miRNA and reciprocal interactions. The Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII, NR2F2) is a NR classified as an orphan due to the lack of a known natural ligand. Although its expression peaks during development, and then decreases considerably, in adult tissues, COUP-TFII is an important regulator of differentiation and it is variably implicated in tissues homeostasis. As such, alterations of its expression or its transcriptional activity have been studied and linked to a spectrum of diseases in organs and tissues of different origins. Indeed, an altered COUP-TFII expression and activity may cause infertility, abnormality in the vascular system and metabolic diseases like diabetes. Moreover, COUP-TFII is actively investigated in cancer research but its role in tumor progression is yet to be fully understood. In this review, we summarize the current understanding of COUP-TFII in healthy and pathological conditions, proposing an updated and critical view of the many functions of this NR.

Keywords: COUP-TFII; EMT; NF-κB; NR2F2; angiogenesis; cancer; development; metabolism.

Figure 1

COUP-TFII protein and family relation. (A) The main isoforms of COUP-TF proteins possess the typical features of the NR domain structure of COUP-TFs nuclear receptor (NR). (B) Phylogram (guide tree) with cladogram branch length of the NR2F family showing that separation of COUP-TFIII from COUP-TFII and COUP-TFI is probably an early evolutionary event (data obtained from ClustalOmega alignment of human NR2F1, NR2F2 and NR2F6). Based on References [1,2,3].

Figure 2

COUP-TFII dimerization and mechanism of action. COUP-TFII may form homo- and heterodimers and may act as a transcriptional repressor or activator, in a cell-dependent manner. Natural ligands for COUP-TFII are unknown, but the NR may be activated by a high concentration of 9-cis-RA and inhibited by naphthol compounds. Based on References [3,23,24,25,26,27,28,29,30,31,32,33].

Figure 3

COUP-TFII and insulin in pancreatic β-cells. High glucose concentrations in the blood induce the release of insulin by β-cells and attenuate the expression of COUP-TFII. COUP-TFII is known to repress insulin genes, hence reducing the expression of COUP-TFII increases insulin gene expression but reduces insulin secretion. Interestingly, insulin in a paracrine manner further decreases COUP-TFII expression by nuclear exclusion of FOXO1 caused by AKT-mediated phosphorylation. HNF4α and COUP-TFII are reciprocally induced and sustain insulin secretion. Based on References [69,72,73,74].

Figure 4

Cell signaling determination of artery, vein and lymph identity. COUP-TFII is one of the main determinants of vein specification. Early in differentiation, COUP-TFII, under the control of BRG-1 and ETS members (ETS-1 and ETV1), induces the expression of vein markers and represses components of the Notch pathway. Later, together with Sox18, COUP-TFII allow the expression of Prox1 and regulates lymphatic vessels differentiation. Based on References [84,85,92,93,94,95,96,97,98,99]. Redrawn from [85], published by Elsevier, 2019.