Cigarette smoke disrupts the integrity of airway adherens junctions through the aberrant interaction of p120‐catenin with the cytoplasmic tail of MUC1

Zhang, Lili; Gallup, Marianne; Zlock, Lorna; Basbaum, Carol; Finkbeiner, Walter E.; McNamara, Nancy

doi:10.1002/path.4070

Cited by 41 publications

(54 citation statements)

References 41 publications

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“…Upon stimulation by Wnt ligands, b-catenin is stabilized and then translocates to the nucleus, where it binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors, activating the expression of Wnt target genes, promoting cell proliferation (15)(16)(17) and limiting cell differentiation (16,18), thus contributing to both airway (18,19) and alveolar epithelial repair (20)(21)(22) after injury. Consistent with this concept, activation of b-catenin signaling by lithium chloride attenuated elastase-induced experimental emphysema (21), suggesting that b-catenin signaling contributes to lung repair/regeneration in response to various injuries.…”

Section: Fam13amentioning

confidence: 99%

“…Stabilized b-catenin molecules translocate to the nucleus, where they activate the expression of Wnt target genes that promote cell proliferation (15-17) and limit cell differentiation (16,18). Therefore, activation of b-catenin signaling contributes to both airway (18,19) and alveolar epithelial cell repair (20)(21)(22) after various injuries (18,19,21,56). Our data suggest that reduced levels of FAM13A may promote lung repair by enhancing b-catenin signaling in CSexposed or PPE-treated lungs to promote epithelial proliferation and thereby limit emphysema development.…”

Section: /2mentioning

confidence: 99%

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A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin

Jiang¹,

Lao²,

Qiu³

et al. 2016

Am J Respir Crit Care Med

101

134

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Rationale: A genetic locus within the FAM13A gene has been consistently associated with chronic obstructive pulmonary disease (COPD) in genome-wide association studies. However, the mechanisms by which FAM13A contributes to COPD susceptibility are unknown.Objectives: To determine the biologic function of FAM13A in human COPD and murine COPD models and discover the molecular mechanism by which FAM13A influences COPD susceptibility. ) were generated and exposed to cigarette smoke. The lung inflammatory response and airspace size were assessed in Fam13a 2/2 and Fam13a 1/1 littermate control mice. Cellular localization of FAM13A protein and mRNA levels of FAM13A in COPD lungs were assessed using immunofluorescence, Western blotting, and reverse transcriptase-polymerase chain reaction, respectively. Immunoprecipitation followed by mass spectrometry identified cellular proteins that interact with FAM13A to reveal insights on FAM13A's function. ) were resistant to chronic cigarette smoke-induced emphysema compared with Fam13a 1/1 mice. In vitro, FAM13A interacts with protein phosphatase 2A and recruits protein phosphatase 2A with glycogen synthase kinase 3b and b-catenin, inducing b-catenin degradation. Fam13a 2/2 mice were also resistant to elastase-induced emphysema, and this resistance was reversed by coadministration of a b-catenin inhibitor, suggesting that FAM13A could increase the susceptibility of mice to emphysema development by inhibiting b-catenin signaling. Moreover, human COPD lungs had decreased protein levels of b-catenin and increased protein levels of FAM13A. Conclusions:We show that FAM13A may influence COPD susceptibility by promoting b-catenin degradation.

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Section: Fam13amentioning

confidence: 99%

Section: /2mentioning

confidence: 99%

A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin

Jiang¹,

Lao²,

Qiu³

et al. 2016

Am J Respir Crit Care Med

101

134

View full text Add to dashboard Cite

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“…Although the specific identity of signaling molecules that promote cell migration in the absence of p120ctn is unknown, we believe that Rac1 is an essential component. These data suggest that EGFR activation in response to smoke mediates membrane-to-cytoplasmic translocation of p120ctn 16,17 to facilitate Cdc42/Rac1 activation and cell migration. In contrast, we believe that Rac1 activation via an alternative, EGFR/p120ctn-independent pathway is normally suppressed by membrane p120ctn but disinhibited after its loss with tumor progression ( Figure 4D).…”

Section: Rac1 Modulates Smoke-induced Migrationmentioning

confidence: 81%

“…15e17 Loss of AJs was accompanied by the accumulation of p120ctn in the cytoplasm, 16,17 where it has been shown to interact with and inhibit RhoA activity. 12 To explore the potential role of p120ctn in regulating Rho GTPase activity during exposure to smoke, we examined its interaction with Rac1, Cdc42, and RhoA.…”

Section: Complex Formation In Response To Smoke Occurs In Conjunctionmentioning

confidence: 99%

Rac1 and Cdc42 Differentially Modulate Cigarette Smoke–Induced Airway Cell Migration through p120-Catenin–Dependent and –Independent Pathways

Zhang

Gallup

Zlock

et al. 2013

The American Journal of Pathology

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The adherens junction protein p120-catenin (p120ctn) shuttles between E-cadherinebound and cytoplasmic pools to regulate E-cadherin/catenin complex stability and cell migration, respectively. When released from the adherens junction, p120ctn promotes cell migration through modulation of the Rho GTPases Rac1, Cdc42, and RhoA. Accordingly, the down-regulation and cytoplasmic mislocalization of p120ctn has been reported in all subtypes of lung cancers and is associated with grave prognosis. Previously, we reported that cigarette smoke induced cytoplasmic translocation of p120ctn and cell migration, but the underlying mechanism was unclear. Using primary human bronchial epithelial cells exposed to smoke-concentrated medium (Smk), we observed the translocation of Rac1 and Cdc42, but not RhoA, to the leading edge of polarized and migrating human bronchial epithelial cells. Rac1 and Cdc42 were robustly activated by smoke, whereas RhoA was inhibited. Accordingly, siRNA knockdown of Rac1 or Cdc42 completely abolished Smk-induced cell migration, whereas knockdown of RhoA had no effect. p120ctn/Rac1 double knockdown completely abolished Smk-induced cell migration, whereas p120ctn/Cdc42 double knockdown did not. These data suggested that Rac1 and Cdc42 coactivation was essential to smoke-promoted cell migration in the presence of p120ctn, whereas migration proceeded via Rac1 alone in the absence of p120ctn. Thus, Rac1 may provide an omnipotent therapeutic target in reversing cell migration during the early (intact p120ctn) and late (loss of p120ctn) stages of lung carcinogenesis. (Am J Pathol 2013 http://dx.doi.org/10.1016/j.ajpath.2013 Cigarette smoke contains >4000 active constituents, !60 of which are established carcinogens and/or mutagens. 1 With a 20-fold greater risk of lung cancer and accounting for 87% of lung cancererelated deaths, 2 smoking continues to represent the single most important carcinogenic exposure. Because treatment of lung cancer is largely ineffective, recent research has been focused on efforts to identify and reverse early events leading to the initiation of lung cancer by smoke. 3 Emerging evidence suggests that smoke mediates epithelial-mesenchymal transition (EMT) and pretumor cell migration by disrupting cell-cell adhesion in polarized mucosal epithelia. 4,5 During EMT, cells switch from a polarized immobile epithelial phenotype to a highly motile fibroblast phenotype. 6 Unregulated EMT confers epithelial cells with stem cellelike properties capable of self-renewal, metastasis, and resistance to apoptosis. 6,7 Little is known about how smoke mediates EMT during the early stages of lung cancer.E-cadherin (E-cad)ebased adherens junctions (AJs) interact with catenins to modulate cell-cell adhesion. 8 Structural analysis by X-ray crystallography revealed that p120-catenin (p120ctn) binds to the juxtamembrane domain of E-cad, where it regulates stability and turnover of E-cad by concealing the juxtamembrane domain residues implicated in endocytosis and ubiquitination of E-cad. 9,10 The disruption ...

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“…mammospheres were not formed from a single cell, they do appear to induce a type of metaplasia. Metaplasia is associated with changes in polarity, such as a breakdown of cell-cell junctions, which is a phenotype observed when polarity proteins are lost [47][48][49].…”

Section: Discussionmentioning

confidence: 99%

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2016

Oncotarget

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We have previously demonstrated that Llgl1 loss results in a gain of mesenchymal phenotypes and a loss of apicobasal and planar polarity. We now demonstrate that these changes represent a fundamental shift in cellular phenotype. Llgl1 regulates the expression of multiple cell identity markers, including CD44, CD49f, and CD24, and the nuclear translocation of TAZ and Slug. Cells lacking Llgl1 form mammospheres, where survival and transplantability is dependent upon the Epidermal Growth Factor Receptor (EGFR). Additionally, Llgl1 loss allows cells to grow in soft-agar and maintain prolonged survival as orthotopic transplants in NOD-SCID mice. Lineage tracing and wound healing experiments demonstrate that mammosphere survival is due to enhanced EGF-dependent migration. The loss of Llgl1 drives EGFR mislocalization and an EGFR mislocalization point mutation (P667A) drives these same phenotypes, including activation of AKT and TAZ nuclear translocation. Together, these data indicate that the loss of Llgl1 results in EGFR mislocalization, promoting pre-neoplastic changes.

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Cigarette smoke disrupts the integrity of airway adherens junctions through the aberrant interaction of p120‐catenin with the cytoplasmic tail of MUC1

Cited by 41 publications

References 41 publications

A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin

A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin

Rac1 and Cdc42 Differentially Modulate Cigarette Smoke–Induced Airway Cell Migration through p120-Catenin–Dependent and –Independent Pathways

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