Rho/Rho-associated Kinase-II Signaling Mediates Disassembly of Epithelial Apical Junctions

Samarin, Stanislav; Ivanov, Andrei I.; Flatau, Gilles; Parkos, Charles A.; Nusrat, Asma

doi:10.1091/mbc.e07-04-0315

Cited by 117 publications

(101 citation statements)

References 70 publications

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“…GEF-H1 is also activated by various pathogens, junction dissociation, and tissue disruption (28,30,40,41). Moreover, ZONAB is stimulated by reduced expression of ZO-1, a cellular inhibitor of the transcriptional and posttranscriptional function of ZONAB, linking it to the integrity of tight junctions (10).…”

Section: Discussionmentioning

confidence: 99%

Stress- and Rho-activated ZO-1–associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival

Nie

Balda

Matter

2012

Proc. Natl. Acad. Sci. U.S.A.

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A central component of the cellular stress response is p21 WAF1/CIP1 , which regulates cell proliferation, survival, and differentiation. Inflammation and cell stress often up-regulate p21 posttranscriptionally by regulatory mechanisms that are poorly understood. ZO-1-associated nucleic acid binding protein (ZONAB)/DbpA is a Y-box transcription factor that is regulated by components of intercellular junctions that are affected by cytokines and tissue damage. We therefore asked whether ZONAB activation is part of the cellular stress response. Here, we demonstrate that ZONAB promotes cell survival in response to proinflammatory, hyperosmotic, and cytotoxic stress and that stress-induced ZONAB activation involves the Rho regulator GEF-H1. Unexpectedly, stress-induced ZONAB activation does not stimulate ZONAB's activity as a transcription factor but leads to the posttranscriptional up-regulation of p21 protein and mRNA. Up-regulation is mediated by ZONAB binding to specific sites in the 3′-untranslated region of the p21 mRNA, resulting in mRNA stabilization and enhanced translation. Binding of ZONAB to mRNA is activated by GEF-H1 via Rho stimulation and also mediates Ras-induced p21 expression. We thus identify a unique type of stress and Rho signaling activated pathway that drives mRNA stabilization and translation and links the cellular stress response to p21 expression and cell survival.epithelia | RhoGTPases | tight junction | necrosis | apoptosis C ells developed regulatory pathways that are activated in response to proinflammatory challenges, adverse extracellular conditions, and cytotoxic stress to ensure cell survival and tissue integrity. These pathways regulate expression of genes encoding factors required to cope with stress conditions and involve transcription factors that stimulate the synthesis of mRNAs encoding proteins required for specific responses. However, expression of many crucial stress-induced genes is regulated posttranscriptionally by mechanisms that are not well understood.A central regulator of cell proliferation and survival is p21 WAF1/CIP1

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Section: Discussionmentioning

confidence: 99%

Stress- and Rho-activated ZO-1–associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival

Nie

Balda

Matter

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…In that study, stressinduced reorganization of F-actin was prevented by Rho kinase inhibition, suggesting a role for Rho activation in the cytoskeletal changes observed in C18 KO cells. Higher Rho activity affects the cytoskeleton via Rho-associated kinase-mediated phosphorylation of cytoskeletal regulatory components (47), which can result in increased paracellular permeability (48). Rho activity is regulated by guanine-exchange factors (e.g., GEF-H1) that can be sequestered by TJ proteins (e.g., cingulin) (49).…”

Section: Changes In Expression/localization Of Other Tjs and Tj-assocmentioning

confidence: 99%

Knockout Mice Reveal Key Roles for Claudin 18 in Alveolar Barrier Properties and Fluid Homeostasis

Flodby

Luo

et al. 2014

Am J Respir Cell Mol Biol

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Claudin proteins are major constituents of epithelial and endothelial tight junctions (TJs) that regulate paracellular permeability to ions and solutes. Claudin 18, a member of the large claudin family, is highly expressed in lung alveolar epithelium. To elucidate the role of claudin 18 in alveolar epithelial barrier function, we generated claudin 18 knockout (C18 KO) mice. C18 KO mice exhibited increased solute permeability and alveolar fluid clearance (AFC) compared with wild-type control mice. Increased AFC in C18 KO mice was associated with increased b-adrenergic receptor signaling together with activation of cystic fibrosis transmembrane conductance regulator, higher epithelial sodium channel, and Na-K-ATPase (Na pump) activity and increased Na-K-ATPase b1 subunit expression. Consistent with in vivo findings, C18 KO alveolar epithelial cell (AEC) monolayers exhibited lower transepithelial electrical resistance and increased solute and ion permeability with unchanged ion selectivity. Claudin 3 and claudin 4 expression was markedly increased in C18 KO mice, whereas claudin 5 expression was unchanged and occludin significantly decreased. Microarray analysis revealed changes in cytoskeletonassociated gene expression in C18 KO mice, consistent with observed F-actin cytoskeletal rearrangement in AEC monolayers. These findings demonstrate a crucial nonredundant role for claudin 18 in the regulation of alveolar epithelial TJ composition and permeability properties. Increased AFC in C18 KO mice identifies a role for claudin 18 in alveolar fluid homeostasis beyond its direct contributions to barrier properties that may, at least in part, compensate for increased permeability.

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“…The formation of epithelia depends on the development of specific cell-cell adhesion structures between neighboring cells and the establishment of cell polarity. An intricate spatial regulation of Rho activity and its downstream effectors Rho-kinase (ROCK) and diaphanous (Dia) was implicated in the stabilization and maintenance of tight junctions and adherens junctions (Sahai and Marshall, 2002;Aijaz et al, 2005;Ozdamar et al, 2005;Samarin et al, 2007;Yamada and Nelson, 2007;Fang et al, 2008;Homem and Peifer, 2008). These junctional complexes are not only important for the barrier function of epithelia, but they also regulate cell proliferation and differentiation .…”

Section: Introductionmentioning

confidence: 99%

Myosin IXa Regulates Epithelial Differentiation and Its Deficiency Results in Hydrocephalus

Abouhamed

Grobe

San

et al. 2009

MBoC

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The ependymal multiciliated epithelium in the brain restricts the cerebrospinal fluid to the cerebral ventricles and regulates its flow. We report here that mice deficient for myosin IXa (Myo9a), an actin-dependent motor molecule with a Rho GTPase-activating (GAP) domain, develop severe hydrocephalus with stenosis and closure of the ventral caudal 3rd ventricle and the aqueduct. Myo9a is expressed in maturing ependymal epithelial cells, and its absence leads to impaired maturation of ependymal cells. The Myo9a deficiency further resulted in a distorted ependyma due to irregular epithelial cell morphology and altered organization of intercellular junctions. Ependymal cells occasionally delaminated, forming multilayered structures that bridged the CSF-filled ventricular space. Hydrocephalus formation could be significantly attenuated by the inhibition of the Rho-effector Rho-kinase (ROCK). Administration of ROCK-inhibitor restored maturation of ependymal cells, but not the morphological distortions of the ependyma. Similarly, down-regulation of Myo9a by siRNA in Caco-2 adenocarcinoma cells increased Rho-signaling and induced alterations in differentiation, cell morphology, junction assembly, junctional signaling, and gene expression. Our results demonstrate that Myo9a is a critical regulator of Rho-dependent and -independent signaling mechanisms that guide epithelial differentiation. Moreover, Rho-kinases may represent a new target for therapeutic intervention in some forms of hydrocephalus. INTRODUCTIONThe development and homeostasis of multicellular organisms depends on coordinated cell shape changes that are coupled with alterations in intracellular organization. The dynamic organization of the actin cytoskeleton accounts for many cell shape changes. A multitude of proteins can directly or indirectly modify the dynamics and organization of the actin cytoskeleton. Among these proteins are monomeric GTPases and the superfamily of myosin molecules. The myosin superfamily of actin-based molecular motors is subdivided into more than 30 classes (Odronitz and Kollmar, 2007). The class IX of myosin molecules includes in mammals two members, Myo9a (myr 7) and Myo9b (myr 5), that are both expressed in a number of differentially spliced variants (Bähler, 2008). The Myo9a protein, previously also called myr 7, is expressed during development and in many adult tissues, most abundantly in brain and testis (Chieregatti et al., 1998;Gorman et al., 1999). Class IX myosins comprise in addition to their myosin head domain a tail region that encompasses a C1 domain and a Rho GTPaseactivating protein (RhoGAP) domain (Reinhard et al., 1995;Chieregatti et al., 1998). The RhoGAP domain negatively regulates the monomeric Rho GTPase by accelerating its rate of GTP-hydrolysis, switching it from the active GTP-bound form to the inactive GDP-bound form. The RhoGTPases are known to be important regulators of cell morphogenesis, cell migration, and cell proliferation (Jaffe and Hall, 2005). They are inactivated under spatial and temporal con...

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Rho/Rho-associated Kinase-II Signaling Mediates Disassembly of Epithelial Apical Junctions

Cited by 117 publications

References 70 publications

Stress- and Rho-activated ZO-1–associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival

Stress- and Rho-activated ZO-1–associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival

Knockout Mice Reveal Key Roles for Claudin 18 in Alveolar Barrier Properties and Fluid Homeostasis

Myosin IXa Regulates Epithelial Differentiation and Its Deficiency Results in Hydrocephalus

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