Zonula Occludens Proteins in Cancer

González‐Mariscal, Lorenza; Miranda, Jael; Ortega-Olvera, José Mario; Gallego-Gutiérrez, Helios; Raya‐Sandino, Arturo; Vargas-Sierra, Orlando

doi:10.1007/s40139-016-0109-3

Cited by 8 publications

(10 citation statements)

References 105 publications

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“…Zonula occludens proteins ZO-1, ZO-2, and ZO-3 belong to the membrane associated guanylate kinase homologue (MAGUK) protein family and are concentrated at the cytoplasmic face of tight junctions (TJs) in epithelial cells. Although these proteins share a core of common structural and functional domains and interacting partners, they also exhibit particular features that give rise to certain non-redundant functions among these proteins (for review see [[1,2]]). This review concentrates on ZO-2 and its non-canonical role in gene transcription, cell proliferation, and modulation of cell size, cytoarchitecture, and cancer.…”

Section: Introductionmentioning

confidence: 99%

ZO-2 Is a Master Regulator of Gene Expression, Cell Proliferation, Cytoarchitecture, and Cell Size

González‐Mariscal

Gallego-Gutiérrez

González-González

et al. 2019

IJMS

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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.

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Section: Introductionmentioning

confidence: 99%

ZO-2 Is a Master Regulator of Gene Expression, Cell Proliferation, Cytoarchitecture, and Cell Size

González‐Mariscal

Gallego-Gutiérrez

González-González

et al. 2019

IJMS

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“…, 1993). TJs are composed of a complex group of proteins including transmembrane proteins such as claudins, j unctional adhesion molecules, occludin, tricellulin and marvel-D3, and a vast array of cytoplasmic proteins that link the integral TJ proteins to the actomyosin cytoskeleton (Gonzalez-Mariscal, 2016a,b).…”

Section: Introductionmentioning

confidence: 99%

Activation of the Ca²⁺sensing receptor and the PKC/WNK4 downstream signaling cascade induces incorporation of ZO-2 to tight junctions and its separation from 14-3-3

Amaya

Alarcón

Martín-Tapia

et al. 2019

MBoC

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Zonula occludens-2 (ZO-2) is a tight junction (TJ) cytoplasmic protein, whose localization varies according to cell density and Ca2+ in the media. In cells cultured in low calcium (LC), ZO-2 displays a diffuse cytoplasmic distribution, but activation of the Ca2+ sensing receptor (CaSR) with Gd3+ triggers the appearance of ZO-2 at the cell borders. CaSR downstream signaling involves activation of protein kinase C, which phosphorylates and activates with no lysine kinase-4 that phosphorylates ZO-2 inducing its concentration at TJs. In LC, ZO-2 is protected from degradation by association to 14-3-3 proteins. When monolayers are transferred to normal calcium, the complexes ZO-2/14-3-3ζ and ZO-2/14-3-3σ move to the cell borders and dissociate. The 14-3-3 proteins are then degraded in proteosomes, whereas ZO-2 integrates to TJs. From the plasma membrane residual ZO-2 is endocyted and degradaded in lysosomes. The unique region 2 of ZO-2, and S261 located within a nuclear localization signal, are critical for the interaction with 14-3-3 ζ and σ and for the efficient nuclear importation of ZO-2. These results explain the molecular mechanism through which extracellular Ca2+ triggers the appearance of ZO-2 at TJs in epithelial cells and reveal the novel interaction between ZO-2 and 14-3-3 proteins, which is critical for ZO-2 protection and intracellular traffic.

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“…Consequently, beta catenin-mediated reduced ZO-1 expression is associated with enhanced proliferation of colorectal epithelial cells[ 12 ]. In contrast, the ectopic introduction of ZO-1 showed reduced cell proliferation and transformation in MDCK cells[ 13 ]. Moreover, ZO-1 knockout mice showed embryonic lethality due to abnormal angiogenesis and embryonic cells apoptosis in the yolk sac[ 13 ].…”

Section: Zo Proteins As Regulators Of Cell Proliferationmentioning

confidence: 99%

“…In contrast, the ectopic introduction of ZO-1 showed reduced cell proliferation and transformation in MDCK cells[ 13 ]. Moreover, ZO-1 knockout mice showed embryonic lethality due to abnormal angiogenesis and embryonic cells apoptosis in the yolk sac[ 13 ]. Apart from protein-binding domains, ZO-1 contains nuclear localization signal (NLS) and nuclear export signal (NES).…”

Section: Zo Proteins As Regulators Of Cell Proliferationmentioning

confidence: 99%

Role of zonula occludens in gastrointestinal and liver cancers

Ram¹,

Vairappan²

2022

WJCC

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A growing body of evidence suggests that tight junction (TJ) proteins play a crucial role in the pathogenesis of various diseases, including gastrointestinal (GI) cancer and hepatocellular carcinoma (HCC). TJ proteins primarily maintain the epithelial and endothelial cells intact together through integral proteins however, recent reports suggest that they also regulate gene expression necessary for cell proliferation, angiogenesis, and metastasis through adapter proteins such as zonula occludens (ZO). ZO proteins are membrane-associated cytosolic scaffolding proteins that modulate cell proliferation by interacting with several transcription factors. Reduced ZO proteins in GI cancer and HCC are correlated with tumor development and poor prognosis. Pubmed has searched for using the keyword ZO and gastric cancer, ZO and cancer, and ZO and HCC for the last ten years to date. This review summarized the role of ZO proteins in cell proliferation and their expression in GI cancer and HCC. Furthermore, therapeutic interventions targeting ZO in GI and liver cancers are reviewed.

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Zonula Occludens Proteins in Cancer

Cited by 8 publications

References 105 publications

ZO-2 Is a Master Regulator of Gene Expression, Cell Proliferation, Cytoarchitecture, and Cell Size

ZO-2 Is a Master Regulator of Gene Expression, Cell Proliferation, Cytoarchitecture, and Cell Size

Activation of the Ca²⁺sensing receptor and the PKC/WNK4 downstream signaling cascade induces incorporation of ZO-2 to tight junctions and its separation from 14-3-3

Role of zonula occludens in gastrointestinal and liver cancers

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Zonula Occludens Proteins in Cancer

Cited by 8 publications

References 105 publications

ZO-2 Is a Master Regulator of Gene Expression, Cell Proliferation, Cytoarchitecture, and Cell Size

ZO-2 Is a Master Regulator of Gene Expression, Cell Proliferation, Cytoarchitecture, and Cell Size

Activation of the Ca2+sensing receptor and the PKC/WNK4 downstream signaling cascade induces incorporation of ZO-2 to tight junctions and its separation from 14-3-3

Role of zonula occludens in gastrointestinal and liver cancers

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Activation of the Ca²⁺sensing receptor and the PKC/WNK4 downstream signaling cascade induces incorporation of ZO-2 to tight junctions and its separation from 14-3-3