RESUMEN
ZO-2 is a cytoplasmic protein of tight junctions (TJs). Here, we describe ZO-2 involvement in the formation of the apical junctional complex during early development and in TJ biogenesis in epithelial cultured cells. ZO-2 acts as a scaffold for the polymerization of claudins at TJs and plays a unique role in the blood-testis barrier, as well as at TJs of the human liver and the inner ear. ZO-2 movement between the cytoplasm and nucleus is regulated by nuclear localization and exportation signals and post-translation modifications, while ZO-2 arrival at the cell border is triggered by activation of calcium sensing receptors and corresponding downstream signaling. Depending on its location, ZO-2 associates with junctional proteins and the actomyosin cytoskeleton or a variety of nuclear proteins, playing a role as a transcriptional repressor that leads to inhibition of cell proliferation and transformation. ZO-2 regulates cell architecture through modulation of Rho proteins and its absence induces hypertrophy due to inactivation of the Hippo pathway and activation of mTOR and S6K. The interaction of ZO-2 with viral oncoproteins and kinases and its silencing in diverse carcinomas reinforce the view of ZO-2 as a tumor regulator protein.
Asunto(s)
Regulación de la Expresión Génica , Transducción de Señal , Proteína de la Zonula Occludens-2/genética , Proteína de la Zonula Occludens-2/metabolismo , Actomiosina/metabolismo , Animales , Apoptosis/genética , Proliferación Celular , Forma de la Célula , Tamaño de la Célula , Desarrollo Embrionario/genética , Humanos , Proteínas Nucleares/metabolismo , Especificidad de Órganos/genética , Unión Proteica , Transporte de Proteínas , Uniones Estrechas/metabolismo , Transcripción Genética , Proteína de la Zonula Occludens-2/químicaRESUMEN
Silencing Zonula occludens 2 (ZO-2), a tight junctions (TJ) scaffold protein, in epithelial cells (MDCK ZO-2 KD) triggers: 1) Decreased cell to substratum attachment, accompanied by reduced expression of claudin-7 and integrin ß1, and increased vinculin recruitment to focal adhesions and stress fibers formation; 2) Lowered cell-cell aggregation and appearance of wider intercellular spaces; 3) Increased RhoA/ROCK activity, mediated by GEF-HI recruitment to cell borders by cingulin; 4) Increased Cdc42 activity, mitotic spindle disorientation and the appearance of cysts with multiple lumens; 5) Increased Rac and cofilin activity, multiple lamellipodia formation and random cell migration but increased wound closure; 6) Diminished cingulin phosphorylation and disappearance of planar network of microtubules at the TJ region; and 7) Increased transepithelial electrical resistance at steady state, coupled to an increased expression of ZO-1 and claudin-4 and a decreased expression of claudin-2 and paracingulin. Hence, ZO-2 is a crucial regulator of Rho proteins activity and the development of epithelial cytoarchitecture and barrier function.
Asunto(s)
Uniones Estrechas/metabolismo , Proteína de la Zonula Occludens-1/genética , Proteína de la Zonula Occludens-2/genética , Proteína de Unión al GTP rac1/genética , Proteína de Unión al GTP rhoA/genética , Animales , Claudina-2/metabolismo , Claudina-4/genética , Claudina-4/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Perros , Células Epiteliales/metabolismo , Humanos , Células de Riñón Canino Madin Darby , Fosforilación , Uniones Estrechas/genética , TransfecciónRESUMEN
ZO-2 is a peripheral tight junction protein that belongs to the membrane-associated guanylate kinase protein family. Here, we explain the modular and supramodular organization of ZO-2 that allows it to interact with a wide variety of molecules, including cell-cell adhesion proteins, cytoskeletal components, and nuclear factors. We also describe how ZO proteins evolved through metazoan evolution and analyze the intracellular traffic of ZO-2, as well as the roles played by ZO-2 at the plasma membrane and nucleus that translate into the regulation of proliferation, cell size, and apoptosis. In addition, we focus on the impact of ZO-2 expression on male fertility and on maladies like cancer, cholestasis, and hearing loss.
Asunto(s)
Apoptosis , Proliferación Celular , Expresión Génica , Uniones Estrechas/metabolismo , Proteína de la Zonula Occludens-2/metabolismo , Animales , Tamaño de la Célula , Humanos , Infertilidad Masculina/genética , Masculino , Proteína de la Zonula Occludens-2/genéticaRESUMEN
We have studied the expression of the tight junction proteins (TJ) occludin, claudin-1 and ZO-2 in the epidermis of female mice. We observed a peak of expression of these proteins at postnatal day 7 and a decrease in 6 week-old mice to values similar to those found in newborn animals. We explored if the expression of the E6 oncoprotein from high-risk human papilloma virus type 16 (HPV16) in the skin of transgenic female mice (K14E6), altered TJ protein expression in a manner sensitive to ovarian hormones. We observed that in ovariectomized mice E6 up-regulates the expression of occludin and ZO-2 in the epidermis and that this effect was canceled by 17ß-estradiol. Progesterone instead induced occludin and ZO-2 over-expression. However, the decreased expression of occludin and ZO-2 induced by 17ß-estradiol in the epidermis was not overturned by E6 or progesterone. In addition, we employed MDCK cells transfected with E6, and observed that ZO-2 delocalizes from TJs and accumulates in the cell nuclei due to a decrease in the turnover rate of the protein. These results reinforce the view of 17ß-estradiol and E6 as risk factors for the development of cancer through effects on expression and mislocalization of TJ proteins.