Introduction Protein-protein interaction and signaling crosstalk contribute to the regulation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) and broaden their cellular function. Area covered This review covers key historic discoveries and recent advances in our understanding of the broad function of PXR and CAR and their regulation by protein-protein interaction and signaling crosstalk. Expert opinion PXR and CAR were first discovered as xenobiotic receptors. However, it is clear that PXR and CAR perform a much broader range of cellular functions through protein-protein interaction and signaling crosstalk, which typically mutually affect the function of all the partners involved. Future research on PXR and CAR should, therefore, look beyond their xenobiotic function.
Symplekin is multifunctional protein localized to both the tight junction and the nucleus with known roles in mRNA polyadenylation, proliferation, differentiation and tumorigenesis. Functions of symplekin at tight junctions have not been systematically investigated. In this study, increased expression of symplekin was observed during the formation of tight junctions in cultured HT-29 and HepG2 epithelial cells. Repression of symplekin by RNAi increased the permeability of epithelial monolayers, disrupted cellular polarity, and decreased the expression of the tight junction protein ZO-1. Moreover, symplekin was co-localized with ZO-1 at tight junctions and co-immunoprecipitated with ZO-1, indicating that ZO-1 and symplekin form complexes. In conclusion, symplekin expression regulates the assembly of tight junctions, thus helps to maintain the integrity of the epithelial monolayer and cellular polarity.
Symplekin is a multifunctional protein that localizes to both tight junctions and the nucleus in polarized epithelial cells, with confirmed roles in mRNA maturation, transcriptional modulation and tight-junction assembly. However, the mechanisms governing its subcellular distribution and related functions remain unclear. In this study, we found that symplekin primarily localizes to the nuclei of cultured dedifferentiated colorectal cancer cells, and nuclear symplekin showed higher phosphorylation and binding affinity with YBX3 than its membrane fraction. Moreover, the accumulation of nuclear symplekin promoted cell proliferation and dedifferentiation as well as β-catenin transactivation in vitro. Nuclear symplekin acts as a transcriptional co-activator for the expression of many cell cycle-related genes. Furthermore, extracellular signal-regulated kinase (ERK) phosphorylated symplekin at T1257 to facilitate its nuclear accumulation upon epidermal growth factor (EGF) stimulation. Meanwhile, reduction of total symplekin also induced certain epithelial-mesenchymal transition features in HT-29 cells. Taken together, our results confirm the coordinated roles of symplekin in cell junctions and gene transcription, which are related to its subcellular localization. The significance of nuclear symplekin in tumorigenesis is also highlighted, and ERK-dependent phosphorylation represents a mechanism for its subcellular sorting.Symplekin is expressed in a wide range of cell types and participates in cytoplasmic mRNA polyadenylation 1 , cell proliferation 2 , differentiation 3 , mitosis 4 and tumorigenesis 5 . Previously, we confirmed the role of symplekin in cell tight-junction (TJ) assembly and polarity maintenance 6 . Among peripheral TJ proteins, Zonula Occludin-1 (ZO-1), Y-box transcriptional factor 3 (YBX3, also known as CSDA, DBPA or ZONAB) and symplekin have been reported to form functional protein complexes and to shuttle between the junctional plaques and the nucleus 2, 6, 7 . In addition to polarized epithelial cells, symplekin localizes exclusively to the nucleus of tight-junctionless cells, emphasizing its vital roles in the nucleus 8 . However, the underlying mechanism, including the translocation of symplekin, is poorly understood. By comparing nuclear and extra-nuclear symplekin, we observed that nuclear symplekin exhibited increased phosphorylation in the present study. Post-translational modifications such as phosphorylation, glycosylation, and ubiquitylation have emerged as dynamic and essential regulators for target proteins sorting and relocalization to participate in various cellular events 9 . The phosphorylation of several junctional components, such as ZO-1, occludin and β-catenin, has also been shown to determine their subcellular distrbutions [10][11][12] . We found that extracellular epidermal growth factor (EGF) signals induced the phosphorylation of symplekin on specific residues, followed by nuclear translocation, with nuclear symplekin serving as a trans-activator to promote cell proliferation ...
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