DUSP3 regulates phosphorylation-mediated degradation of occludin and is required for maintaining epithelial tight junction

Abstract

Background Tight junctions (TJ) are multi-protein complexes that hold epithelial cells together and form structural and functional barriers for maintaining proper biological activities. Dual specificity phosphatase 3 (DUSP3), a suppressor of multiple protein tyrosine (Tyr) kinases, is decreased in lung cancer tissues. Here we demonstrated the role of DUSP3 in regulation of epithelial TJ. Methods Barrier functions of TJ were examined in wild-type or DUSP3-deficient lung epithelial cells. Animal and clinical data were analyzed for the association between DUSP3 deficiency and lung cancer progression. Proximity ligation assay, immunoblotting, and phosphatase assay were performed to study the effect of DUSP3 on the TJ protein occludin (OCLN). Mutations of Tyr residues on OCLN showed the role of Tyr phosphorylation in regulating OCLN. Results Compared to those of the DUSP3-expressing cells, we found the expression and distribution of ZO-1, a TJ-anchoring molecule, were abnormal in DUSP3-deficient cells. OCLN had an increased phosphorylation level in DUSP3-deficient cells. We identified that OCLN is a direct substrate of DUSP3. DUSP3 regulated OCLN ubiquitination and degradation through decreasing OCLN tyrosine phosphorylation directly or through suppressing focal adhesion kinase, the OCLN kinase. Conclusion Our study revealed that DUSP3 is an important TJ regulatory protein and its decrease may be involved in progression of epithelial cancers.

Loss of polarity protein Par3 in the intestinal epithelium promotes colitis‐associated colorectal cancer progression by damaging tight junction assembly

“…This suggests that the absence of Par3 may have little effect on the proliferation of epithelial cells, which requires further research. On the other hand, it has been demonstrated that the COOH terminus of occludin interacts with the Guk domain of ZO‐1, which is essential for occludin recruitment to TJs assemblies 36,37 . Moreover, there was evidence that disrupted ZO‐1 could significantly increase the permeability of the epithelial barrier 38 .…”

DUSP3 modulates IRES‐dependent translation of mRNAs through dephosphorylation of the HNRNPC protein in cells under genotoxic stimulus

“…A single catalytic domain within DUSP3 dephosphorylates tyrosine and threonine residues in targets such as MAPK (ERK, SAPK/JNK, p38), which are associated with cell proliferation, differentiation, and stress response (Denu et al., 1995; Schumacher et al., 2002; Todd et al., 2002). In addition to MAPKs, DUSP3 interacts with other substrates including STAT5, ERBB2 receptor, STAT3, and occludin, thereby mediating cell cycle, proliferation, senescence, and regulation of immune responses (Alonso et al., 2003; Cerignoli et al., 2006; Chou et al., 2022; Hoyt et al., 2007; Jeffrey et al., 2007; Kim et al., 2020; Rahmouni et al., 2006; Wang et al., 2011).…”

Dual-specificity phosphatases 22-deficient T cells contribute to the pathogenesis of ankylosing spondylitis

“…DUSPs are able to regulate the activities of MAP kinases [ 1 – 3 ], which play central roles of thymocyte development, T helper (Th) cell polarization, and T cell signaling [ 4 , 5 ]. DUSPs also can dephosphorylate non-MAP kinase proteins, such as TAK1, occludin, and focal adhesion kinase (FAK) [ 1 , 6 – 8 ]. DUSP4 negatively regulates CD4 + T cell proliferation through dephosphorylating STAT5 [ 1 ].…”