Faulty Epithelial Polarity Genes and Cancer

Tervonen, Topi A.; Partanen, Juhaní; Saarikoski, Sirkku T.; Myllynen, Mikko; Marques, Elsa; Paasonen, Katriina; Moilanen, Anu-Maarit; Wohlfahrt, Gerd; Kovanen, Panu E.; Klefström, Juha

doi:10.1016/b978-0-12-385524-4.00003-9

Cited by 18 publications

(18 citation statements)

References 317 publications

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“…lethal giant larvae encodes a protein, Lgl, rich in WD40 repeats, predicted to fold into two b-propeller domains at the N-terminus. Lgl mammalian orthologues, Lgl-1 and Lgl-2, also contain WD40 repeats and have distinct expression patterns (Dow and Humbert, 2007;Tervonen et al, 2011). Fly and human proteins show the significant global sequence similarity of 62.5% if conservative aminoacid changes are taken into account, and we found conclusive evidence of the functional conservation between the two proteins in the full rescue of the Drosophila lgl mutant by the human Lgl-1 cDNA (Grifoni et al, 2004).…”

Section: The Scribble/discs Large/lethal Giant Larvae Complexsupporting

confidence: 53%

“…Similarly, CRB3 complexes with the PDZ domain of Std mammalian homologue Pals1 (Protein associated with lin seven 1). The third component is encoded by dpatj gene in Drosophila and two mammalian homologues, PATJ (Pals-Associated Tight Junction Protein) and MUPP1 (MUlti-PDZ domain Protein 1), are also known to interact with Crb intracellular portion (Dow and Humbert, 2007;Tervonen et al, 2011).…”

Section: The Crumbs/stardust/patj Complexmentioning

confidence: 99%

“…In mammals one Baz homologue (Par3), three Par6 homologues (Par6a, b and g) and two aPKC homologues (aPKCl/i and aPKCz) have been found with differential expression patterns but mostly redundant functions. In mammalian cells this complex localises at tight junctions and is required for AJs formation as it is in Drosophila (Dow and Humbert, 2007;Tervonen et al, 2011).…”

Section: The Bazooka/par6/apkc Complexmentioning

confidence: 99%

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Connecting epithelial polarity, proliferation and cancer in Drosophila: the many faces of lgl loss of function

Grifoni

Froldi²,

Pession³

2013

Int. J. Dev. Biol.

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Loss of cell polarity is a prominent feature of epithelial cancers. Several tumour-suppressor genes are indeed involved in establishing and maintaining a correct apical-basal polarity suggesting that a link exists between disruption of epithelial polarity and the control of cell proliferation. Nevertheless, the molecular basis of this link is only beginning to be unveiled. In Drosophila, the tumour suppressor gene lethal giant larvae (lgl) is widely used as a genetic tool in cancer modelling: its loss of function causes neoplastic growth of the imaginal tissues, larval epithelial organs from which adult structures originate. These mutant epithelia are characterised by loss of cell polarity and tissue architecture as well as hyperproliferation. We observed that in a clonal context, the ability of lgl mutant cells to express their neoplastic potential correlates with the levels of the oncoprotein Myc, a master regulator of cell growth and proliferation. Malignant, polarity-deficient mutant cells upregulate Myc and are able to overcome the tumour-suppressive defences imposed by the surrounding wild-type tissue. How does the loss of lgl function induce an increase in Myc levels? The answer to this question came from the finding that Lgl is an upstream regulator of the Hippo pathway, a highly conserved signalling network that controls proliferation of epithelial cells and organ size. The core of this pathway responds to several upstream regulators and converges on the inhibition of a transcriptional co-factor, Yorkie, which, as we and others have shown, is a direct regulator of the myc promoter. In this review we discuss the key findings that contributed to the identification of this regulatory network that links cell polarity to cell proliferation control.

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Section: The Scribble/discs Large/lethal Giant Larvae Complexsupporting

confidence: 53%

Section: The Crumbs/stardust/patj Complexmentioning

confidence: 99%

Section: The Bazooka/par6/apkc Complexmentioning

confidence: 99%

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Connecting epithelial polarity, proliferation and cancer in Drosophila: the many faces of lgl loss of function

Grifoni

Froldi²,

Pession³

2013

Int. J. Dev. Biol.

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“…Alterations in cell morphology and motility occur during normal organ tissue remodeling, but deregulation of these processes contributes to pathological outcomes including tumorigenesis (Tervonen et al, 2011). The cytoskeleton is highly malleable and responds to extracellular signals by reorganizing its structure to effect changes in cell shape and drive migration (Gardel et al, 2010;Harris et al, 2009;Ridley et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

PDZ-RhoGEF is essential for CXCR4-driven breast tumor cell motility through spatial regulation of RhoA

Struckhoff

Rana

Kher

et al. 2013

Journal of Cell Science

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SummaryThe CXCL12-CXCR4 chemokine signaling pathway is a well-established driver of cancer progression. One key process promoted by CXCR4 stimulation is tumor cell motility; however, the specific signaling pathways leading to migration remain poorly understood. Previously, we have shown that CXCL12 stimulation of migration depends on temporal regulation of RhoA. However, the specific RhoGEF that translates CXCR4 signaling into RhoA activity and cell motility is unknown. We screened the three regulator of Gprotein signaling RhoGEFs (LSC, LARG and PRG) and found that PRG selectively regulated the migration and invasion of CXCR4-overexpressing breast tumor cells. Interestingly, we found that PDZ-RhoGEF (PRG) was required for spatial organization of F-actin structures in the center, but not periphery of the cells. The effects on the cytoskeleton were mirrored by the spatial effects on RhoA activity that were dependent upon PRG. Loss of PRG also enhanced adherens junctions in the epithelial-like MCF7-CXCR4 cell line, and inhibited directional persistence and polarity in the more mesenchymal MDA-MB-231 cell line. Thus, PRG is essential for CXCR4-driven tumor cell migration through spatial regulation of RhoA and the subsequent organization of the cytoskeletal structures that support motility. Furthermore, immunohistochemical analysis of human breast tumor tissues shows a significant increase of PRG expression in the invasive areas of the tumors, suggesting that this RhoGEF is associated with breast tumor invasion in vivo.

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“…The role of core polarity genes and surrounding regulatory networks in cancer has been recently comprehensively covered in many reviews. This emerging field of research continues to inspire investigators as it holds promise for identifying novel, fundamentally important pathways contributing to tumour progression and invasion as well as new therapies to fight cancer [7,9,[34][35][36]. This review focuses on liver kinase B1, serine-threonine kinase 11 (LKB1/STK11), which is a human homologue of PAR-4.…”

Section: Loss Of Epithelial Polarity In Cancermentioning

confidence: 99%

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

Partanen

Tervonen

Klefström

2013

Phil. Trans. R. Soc. B

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The PAR clan of polarity regulating genes was initially discovered in a genetic screen searching for genes involved in asymmetric cell divisions in the Caenorhabditis elegans embryo. Today, investigations in worms, flies and mammals have established PAR proteins as conserved and fundamental regulators of animal cell polarization in a broad range of biological phenomena requiring cellular asymmetries. The human homologue of invertebrate PAR-4, a serine–threonine kinase LKB1/STK11, has caught attention as a gene behind Peutz–Jeghers polyposis syndrome and as a bona fide tumour suppressor gene commonly mutated in sporadic cancer. LKB1 functions as a master regulator of AMP-activated protein kinase (AMPK) and 12 other kinases referred to as the AMPK-related kinases, including four human homologues of PAR-1. The role of LKB1 as part of the energy sensing LKB1-AMPK module has been intensively studied, whereas the polarity function of LKB1, in the context of homoeostasis or cancer, has gained less attention. Here, we focus on the PAR-4 identity of LKB1, discussing the weight of evidence indicating a role for LKB1 in regulation of cell polarity and epithelial integrity across species and highlight recent investigations providing new insight into the old question: does the PAR-4 identity of LKB1 matter in cancer?

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Faulty Epithelial Polarity Genes and Cancer

Cited by 18 publications

References 317 publications

Connecting epithelial polarity, proliferation and cancer in Drosophila: the many faces of lgl loss of function

Connecting epithelial polarity, proliferation and cancer in Drosophila: the many faces of lgl loss of function

PDZ-RhoGEF is essential for CXCR4-driven breast tumor cell motility through spatial regulation of RhoA

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

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