Abstract
Discs large homolog 5 (Dlg5) is a member of the membrane-associated guanylate kinase adaptor family of proteins, some of which are involved in the regulation of epithelial-to-mesenchymal transition (EMT). Dlg5 has been described as a susceptibility gene for Crohn's disease; however, the physiological function of Dlg5 is unknown. We show here that transforming growth factor-β (TGF-β)-induced EMT suppresses Dlg5 expression in LLc-PK1 cells. Depletion of Dlg5 expression by knockdown promoted the expression of the mesenchymal marker proteins, fibronectin and α-smooth muscle actin, and suppressed the expression of E-cadherin. In addition, activation of JNK and p38, which are stimulated by TGF-β, was enhanced by Dlg5 depletion. Furthermore, inhibition of the TGF-β receptor suppressed the effects of Dlg5 depletion. These observations suggest that Dlg5 is involved in the regulation of TGF-βreceptor-dependent signals and EMT.
Highlights
Discs large homolog 5 (Dlg5)/placenta-dlg(p-dlg)/large type of p-dlg(lp-dlg)/KIAA0583 is a member of the membrane-associated guanylate kinase (MAGUK)adaptor family of proteins, in which some members are involved in the regulation of epithelial-to-mesenchymal transition (EMT) [1,2]
We first examined whether transforming growth factor-b (TGF-b)-induced EMT affects Dlg5 expression
Dlg5 is highly expressed in these cells as well as in kidney of humans and mice [11,13]
Summary
Discs large homolog 5 (Dlg5)/placenta-dlg(p-dlg)/large type of p-dlg(lp-dlg)/KIAA0583 (hereafter referred to as Dlg5) is a member of the membrane-associated guanylate kinase (MAGUK). Adaptor family of proteins, in which some members are involved in the regulation of EMT [1,2]. The MAGUK family of proteins shares at least one PDZ (PSD-95, Dlg, ZO-1) domain, an SH3 domain, and a guanylate kinase domain. Dlg was initially proposed to be one of five human homologs of the Drosophila Discs large (Dlg) protein, a tumor suppressor gene in imaginal discs, based on similarities in sequence and domain structure [3]. Recent computational analysis has revealed that Dlg does not belong to the DLG MAGUK subfamily defined by DLG1-4 in humans but rather has its own ortholog in other animals including Drosophila [4]. We have isolated Dlg as a binding protein for vinexin, a protein localized [15,16,19,20,21,22], the mechanisms regulating EMT are not fully understood
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