Loss of LKB1 leads to impaired epithelial integrity and cell extrusion in the early mouse embryo

Krawchuk, Dayana; Anani, Shihadeh; Honma-Yamanaka, Nobuko; Polito, Samantha; Shafik, Marian; Yamanaka, Yojiro

doi:10.1242/jcs.162156

Cited by 14 publications

(6 citation statements)

References 51 publications

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“…1) were on cell number and anabolism, but the trophectoderm and cavitation appeared normal. This is in agreement with lack of effect of LKB1 knockout, and upstream positive regulator of AMPK, on blastocyst trophectoderm [49].…”

Section: Discussionsupporting

confidence: 89%

Two-cell embryos are more sensitive than blastocysts to AMPK-dependent suppression of anabolism and stemness by commonly used fertility drugs, a diet supplement, and stress

Bolnick

Abdulhasan

Kilburn

et al. 2017

J Assist Reprod Genet

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Section: Discussionsupporting

confidence: 89%

Two-cell embryos are more sensitive than blastocysts to AMPK-dependent suppression of anabolism and stemness by commonly used fertility drugs, a diet supplement, and stress

Bolnick

Abdulhasan

Kilburn

et al. 2017

J Assist Reprod Genet

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“…In C. elegans , during embryonic development, LKB1 activates Pig-1 and promotes a caspase independent cell extrusion process through cell detachment from the epithelium and endocytosis of cell-adhesion molecules [82]. In murine epithelia, LKB1 is required for regulating adherens junctions to prevent cell extrusion, as its loss leads to excess cell epithelial extrusion and disruption of epithelial integrity [92]. Alternatively, mammalian lkb1 mutations cause Peutz-Jeghers syndrome, where patients have high numbers of gastrointestinal polyps with a greater risk for many cancers.…”

Section: Pathologies Resulting From Defective Extrusionmentioning

confidence: 99%

Epithelial cell extrusion: Pathways and pathologies

Gudipaty

Rosenblatt

2017

Seminars in Cell & Developmental Biology

133

127

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To remove dying or unwanted cells from an epithelium while preserving the barrier function of the layer, epithelia use a unique process called cell extrusion. To extrude, the cell fated to die emits the lipid Sphingosine 1 Phosphate (S1P), which binds the G-protein-coupled receptor Sphingosine 1 Phosphate receptor 2 (S1P2) in the neighboring cells that activates Rho-mediated contraction of an actomyosin ring circumferentially and basally. This contraction acts to squeeze the cell out apically while drawing together neighboring cells and preventing any gaps to the epithelial barrier. Epithelia can extrude out cells targeted to die by apoptotic stimuli to repair the barrier in the face of death or extrude live cells to promote cell death when epithelial cells become too crowded. Indeed, because epithelial cells naturally turn over by cell death and division at some of the highest rates in the body, epithelia depend on crowding-induced live cell extrusion to preserve constant cell numbers. If extrusion is defective, epithelial cells rapidly lose contact inhibition and form masses. Additionally, because epithelia act as the first line of defense in innate immunity, preservation of this barrier is critical for preventing pathogens from invading the body. Given its role in controlling constant cell numbers and maintaining barrier function, a number of different pathologies can result when extrusion is disrupted. Here, we review mechanisms and signaling pathways that control epithelial extrusion and discuss how defects in these mechanisms can lead to multiple diseases. We also discuss tactics pathogens have devised to hijack the extrusion process to infect and colonize epithelia.

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“…Liver kinase B1 (LKB1) is a protein kinase also known as serine/threonine kinase 11 that is encoded by the STK11 gene in humans [ 1 ]. LKB1 is the homologue of par-4 in non-mammalian species [ 2 ] and can regulate early embryonic development in both mammals and non-mammals [ 2 – 4 ]. LKB1 has been linked to the regulation of epithelial integrity and polarity [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

The Prognostic Value of Decreased LKB1 in Solid Tumors: A Meta-Analysis

et al. 2016

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BackgroundLiver kinase B1 (LKB1) is a protein kinase that regulates the growth, integrity and polarity of mammalian cells. Recent studies have reported the prognostic value of decreased LKB1 expression in different tumors. However, the results of these studies remain controversial. Therefore, this meta-analysis was performed to more accurately estimate the role of decreased LKB1 in the prognostication of human solid tumors.MethodsA systematic literature search in the electronic databases PubMed, Embase, Web of Science and CNKI (updated to October 15, 2015) was performed to identify eligible studies. The overall survival (OS), relapse-free survival (RFS), disease-free survival (DFS) and clinicopathological features data were collected from these studies. The hazard ratios (HRs), odds ratios (ORs) and 95% confidence intervals (CIs) were calculated and pooled with a random-effects models using Stata12.0 software.ResultsA total of 14 studies covering 1915 patients with solid tumors were included in this meta-analysis. Decreased LKB1 was associated with poorer OS in both the univariate (HR: 1.86, 95%CI: 1.42–2.42, P<0.001) and multivariate (HR: 1.55, 95%CI: 1.09–2.21, P = 0.015) analyses. A subgroup analysis revealed that the associations between decreased LKB1 and poor OS were significant within the Asian region (HR 2.18, 95%CI: 1.66–2.86, P<0.001) and obvious for lung cancer (HR: 2.16, 95%CI: 1.47–3.18, P<0.001). However, the articles that involved analyses of both RFS and DFS numbered only 3, and no statistically significant correlations of decreased LKB1 with RFS or DFS were observed in this study. Additionally, the pooled odds ratios (ORs) indicated that decreased LKB1 was associated with larger tumor size (OR: 1.60, 95%CI: 1.09–2.36, P = 0.017), lymph node metastasis (OR: 2.41, 95%CI: 1.53–3.78, P<0.001) and a higher TNM stage (OR: 3.35, 95%CI: 2.20–5.09, P<0.001).ConclusionThese results suggest that decreased LKB1 expression in patients with solid tumors might be related to poor prognosis and serve as a potential predictive marker of poor clinicopathological prognostic factors. Additional studies are required to verify the clinical utility of decreased LKB1 in solid tumors.

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Loss of LKB1 leads to impaired epithelial integrity and cell extrusion in the early mouse embryo

Cited by 14 publications

References 51 publications

Two-cell embryos are more sensitive than blastocysts to AMPK-dependent suppression of anabolism and stemness by commonly used fertility drugs, a diet supplement, and stress

Two-cell embryos are more sensitive than blastocysts to AMPK-dependent suppression of anabolism and stemness by commonly used fertility drugs, a diet supplement, and stress

Epithelial cell extrusion: Pathways and pathologies

The Prognostic Value of Decreased LKB1 in Solid Tumors: A Meta-Analysis

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