Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4

Partanen, Juhaní; Tervonen, Topi A.; Klefström, Juha

doi:10.1098/rstb.2013.0111

Cited by 26 publications

(24 citation statements)

References 122 publications

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“…Another example of a molecule involved in maintenance of cell adhesions is the mammalian LKB1, a serine-threonine kinase that is required for correct polarization of epithelial cells [90]. LKB1 is also a tumor suppressor protein that functions by phosphorylating several downstream kinases, including AMPK, MARK, and MELK (Pig-1) [91].…”

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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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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“…LKB1 (also known as STK11 in mammals and PAR-4 in invertebrates) is a serine-threonine kinase required for correct polarization of many cell types in both invertebrates and vertebrates (reviewed in Partanen et al, 2013). Invertebrate par-4 is part of the partitioning-defective group of genes and is required for polarized asymmetrical division in Caenorhabditis elegans embryos (Kemphues et al, 1988;Watts et al, 2000) and polarization of Drosophila oocytes, follicle cells and retinal cells (Amin et al, 2009;Martin and St Johnston, 2003).…”

Section: Introductionmentioning

confidence: 99%

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

Krawchuk

Anani

Honma-Yamanaka

et al. 2015

Journal of Cell Science

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LKB1/PAR-4 is essential for the earliest polarization steps in Caenorhabditis elegans embryos and Drosophila oocytes. Although LKB1 (also known as STK11) is sufficient to initiate polarity in a single mammalian intestinal epithelial cell, its necessity in the formation and maintenance of mammalian epithelia remains unclear. To address this, we completely remove LKB1 from mouse embryos by generating maternal-zygotic Lkb1 mutants and find that it is dispensable for polarity and epithelia formation in the early embryo. Instead, loss of Lkb1 leads to the extrusion of cells from blastocyst epithelia that remain alive and can continue to divide. Chimeric analysis shows that Lkb1 is cell-autonomously required to prevent these extrusions. Furthermore, heterozygous loss of Cdh1 exacerbates the number of extrusions per blastocyst, suggesting that LKB1 has a role in regulating adherens junctions in order to prevent extrusion in epithelia.

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“…Therefore, the data are consistent with a view that hepsin primarily influences the tumour initiation and early progression phases, which are also known bottlenecks for Mycdependent tumourigenesis. 27,39 In MCF10A mammary epithelial cells, hepsin induced striking cellular changes commonly associated with the invasive phenotype. Overexpression of hepsin endowed cells with a strong capacity to proteolytically activate HGF, which further activated MET kinase in an autocrine and paracrine manner.…”

Section: Discussionmentioning

confidence: 99%

Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion

et al. 2015

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Hepsin belongs to a family of cell-surface serine proteases, which have sparked interest as therapeutic targets because of the accessibility of extracellular protease domain for inhibitors. Hepsin is frequently amplified and/or overexpressed in epithelial cancers, but it is not clear how enhanced hepsin expression confers a potential for oncogenicity. We show that hepsin is consistently overexpressed in more than 40% of examined breast cancers, including all major biological subtypes. The effects of doxycycline-induced hepsin overexpression were examined in mammary epithelial organoids, and we found that induced hepsin acutely downmodulates its cognate inhibitor, hepatocyte growth factor (HGF) activator inhibitor type 1 (HAI-1). Hepsin-induced depletion of cellular HAI-1 led to a sharp increase in pericellular serine protease activity. The derepressed hepsin proteolytically activated downstream serine proteases, augmented HGF/MET signalling and caused deterioration of desmosomes and hemidesmosomes; structures important for cell cohesion and cell-basement membrane interaction. Moreover, chronic induction of hepsin considerably shortened the latency of Myc-dependent tumourigenesis in the mouse mammary gland. The serine protease and uPA system inhibitor WX-UK1, identified as a micromolar range hepsin inhibitor, prevented hepsin from augmenting HGF/MET signalling and disrupting desmosomes and hemidesmosomes. The findings suggest that the oncogenic activity of hepsin arises not only from elevated expression level but also from depletion of HAI-1, events which together trigger gain-of-function activity impacting HGF/MET signalling and epithelial cohesion. Thus, hepsin overexpression is a major oncogenic conferrer to a serine protease activity involved in breast cancer dissemination.

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Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4

Cited by 26 publications

References 122 publications

Epithelial cell extrusion: Pathways and pathologies

Epithelial cell extrusion: Pathways and pathologies

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

Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion

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