Abstract
A unique heterodimerization pathway involving orphan receptors TR2 and TR4 is demonstrated. TR2 and TR4 preferentially form heterodimers in solution as well as on DNA elements containing a direct repeat-5 (DR5). The in vitro interaction between TR2 and TR4 is demonstrated by the yeast and the mammalian two-hybrid interaction assays, the pull-down assay, and the gel mobility shift assay. The in vivo interaction is demonstrated by following the intracellular localization of fusion receptors tagged with a green fluorescent protein. The dimerization is mediated by the ligand binding domains, and the three leucine residues on helix 10 of TR2 are critical for this interaction. In addition, coexpression of these two receptors exerts a much stronger repressive activity on a DR5-containing reporter than expressing either receptor alone. In the developing testis, TR2 and TR4 are coexpressed in the same testicular cell populations and exhibit a parallel pattern of expression along development. The preferential heterodimerization between TR2 and TR4 and their coexistence in specific germ cell populations suggest a physiological role of TR2/TR4 heterodimers in germ cell development.
Highlights
Family provides the common partners for all the nuclear receptors that are able to form heterodimers
We have identified two isoforms of this receptor, one encoding 590 amino acid residues designated as TR2-11-f and the other encoding 256 amino acid residues as a result of early termination, designated as TR2–11-t [7]
In several reporter systems, such as a reporter controlled by a direct repeat-5 (DR5)-type RA response element (RARE) of the RAR gene [7] and a reporter controlled by a DR4-type hormone response element of the mouse cellular retinoic acid binding protein I (CRABP-I) gene, we have shown that TR2, but not TR2-11-t, strongly represses the activities of these reporters [8]
Summary
Family provides the common partners for all the nuclear receptors that are able to form heterodimers. The biological functions of several orphan receptors have been revealed in gene-targeted mice and by linkage analysis. From an adult testis cDNA library, we have identified several positive clones, including the orphan receptor TR4, or TAK1 [10, 11], suggesting an interaction between TR2 and TR4 mediated by the LBD. TR4 receptor has been shown to function as a repressor for several reporters, including SV40 promoter and RAR/RXR- and T3R-mediated signaling pathways [11, 12]. Neither TR2 nor TR4 forms heterodimer with the RXR members Instead, these two receptors preferentially interact with each other and exert a
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