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JUP, a homologue of β-catenin, is a cell-cell junction protein involved in adhesion junction and desmosome composition. JUP may have a controversial role in different malignancies dependence of its competence with or collaboration with β-catenin as a transcription factor. In this study, we focused on the role of JUP in tumor progress and metastasis of GC. We investigated whether that the function of JUP is related to its cellular location in GC development process from epithelium-like, low malignant GC to advanced EMT-phenotypic GC. Gradual loss of membrane and/or cytoplasm JUP was closely correlated with GC malignancy and poor prognostics. Knockdown of JUP in epithelium-like GC cells causes EMT and promotes GC cell migration and invasion. Ectopic expression of wild JUP in malignant GC cells led to an attenuated malignant phenotype such as reduced cell invasive potential. In mechanism, loss of membrane and/or cytoplasm JUP abolished the restrain of JUP to EGFR at cell membrane and resulted in increased p-AKT levels and AKT/GSK3β/β-catenin signaling activity. In addition, nuclear JUP interacts with nuclear β-catenin and TCF4 and played a synergistic role with β-catenin in promoting TCF4 transcription and its downstream target MMP7 expression to fuel GC cell invasion. [ABSTRACT FROM AUTHOR]

Salt-inducible kinase 2 (SIK2) is abundant in adipocytes, but downregulated in adipose tissue from individuals with obesity and insulin resistance. Moreover, SIK isoforms are required for normal insulin signalling and glucose uptake in adipocytes, but the underlying molecular mechanisms are currently not known. The adherens junction protein JUP, also termed plakoglobin or γ-catenin, has recently been reported to promote insulin signalling in muscle cells. The objective of this study was to analyse if JUP is required for insulin signalling in adipocytes and the underlying molecular mechanisms of this regulation. Co-expression of SIK2 and JUP mRNA levels in adipose tissue from a human cohort was analysed. siRNA silencing and/or pharmacological inhibition of SIK2, JUP, class IIa HDACs and CRTC2 was employed in 3T3-L1- and primary rat adipocytes. JUP protein expression was analysed by western blot and mRNA levels by qPCR. Insulin signalling was evaluated by western blot as levels of phosphorylated PKB/Akt and AS160, and by monitoring the uptake of 3H-2-deoxyglucose. mRNA expression of SIK2 correlated with that of JUP in human adipose tissue. SIK2 inhibition or silencing resulted in downregulation of JUP mRNA and protein expression in 3T3-L1- and in primary rat adipocytes. Moreover, JUP silencing reduced the expression of PKB and the downstream substrate AS160, and consequently attenuated activity in the insulin signalling pathway, including insulin-induced glucose uptake. The known SIK2 substrates CRTC2 and class IIa HDACs were found to play a role in the SIK-mediated regulation of JUP expression. These findings identify JUP as a novel player in the regulation of insulin sensitivity in adipocytes, and suggest that changes in JUP expression could contribute to the effect of SIK2 on insulin signalling in these cells. • JUP/plakoglobin is decreased after SIK2 inhibition in adipocytes. • JUP silencing results in diminished insulin signalling and glucose uptake. • CRTCs are likely involved in SIK2-mediated JUP downregulation. • JUP is a novel molecular target downstream SIK2 in adipocytes. [ABSTRACT FROM AUTHOR]