Polarity Regulators and the Control of Epithelial Architecture, Cell Migration, and Tumorigenesis
Introduction
The generation of a functional three‐dimensional organ requires the cells within a tissue to undergo numerous changes and acquire different functional characteristics at specific developmental stages. In the case of epithelium, cells are required to proliferate, migrate, and form a stable functional barrier that can interact with vastly different microenvironments on each side of the tissue. During the development of an epithelial cancer, the regulation of each of these processes may be disrupted as cells lose normal tissue architecture (including apical–basal cell polarity), lose normal proliferation control, and may become invasive and motile. Thus, understanding the cellular machinery that controls cell polarity, proliferation, and motility is vital to our understanding of normal tissue homeostasis as well as the development and progression of malignant disease. Over the past decade, work in both Drosophila melanogaster and in mammalian model systems has coalesced to provide us with a clearer understanding of the mechanisms of polarity regulation and how the protein networks responsible for polarity establishment may impact on cell migration and tumorigenesis.
Section snippets
Regulation of Epithelial Cell Polarity
Cell polarity describes the asymmetrical distribution of cellular constituents including proteins, carbohydrates, and lipids to particular regions within a cell or group of cells. This asymmetry allows the formation of structurally and functionally distinct domains that cells must have to interact effectively with variable extracellular environments. Cell polarity takes on many forms but can be broadly classified into three types (illustrated schematically in Fig. 1): (1) apical–basal polarity
Polarity Regulators and Tumorigenesis
In addition to the essential role for polarity regulators in epithelial morphogenesis during eukaryotic development, many lines of evidence have implicated polarity proteins in the control of mammalian tumorigenesis (Bilder 2004, Humbert 2003). First, in Drosophila, Scribble, Dlg, and Lgl function as tumor suppressors to restrict neoplastic overgrowth of epithelium. Second, Scribble and Dlg mammalian homologues are targeted for degradation by the E6 oncoprotein from high‐risk (but not low‐risk)
Concluding Remarks
Polarity regulators of the Scribble and Par complexes function in many different cellular processes including apical–basal cell polarity, planar cell polarity, and cell migration and can have an impact on the development of aggressive cancers. Therefore, understanding the mechanisms of polarity regulation represents an important step in our knowledge of normal and aberrant cellular function. We expect that in the coming years, information gained from multiple “model” biological systems will
Acknowledgments
We would like to thank Anthony Brumby and Sarah Russell for critical reading of the manuscript and numerous discussions. P.O.H was supported by a Career Development Award from the Australian NHMRC and L.E.D. by a Postgraduate Cancer Research Scholarship from the Cancer Council Victoria. The studies that formed the foundation of this work were supported by grants from the Association for International Cancer Research and Cancer Council Victoria (P.O.H.).
References (237)
- et al.
Platelet‐derived growth factor and fibronectin‐stimulated migration are differentially regulated by the Rac and extracellular signal‐regulated kinase pathways
J. Biol. Chem.
(1997) - et al.
Mammalian Scribble forms a tight complex with the betaPIX exchange factor
Curr. Biol.
(2004) - et al.
LKB1 tumor suppressor protein: PARtaker in cell polarity
Trends Cell Biol.
(2004) - et al.
Discs lost, a novel multi‐PDZ domain protein, establishes and maintains epithelial polarity
Cell
(1999) PDZ proteins and polarity: Functions from the fly
Trends Genet.
(2001)- et al.
Regulation of Par6 by extracellular signals
Curr. Opin. Cell Biol.
(2006) - et al.
The apical disposition of the Caenorhabditis elegans intestinal terminal web is maintained by LET‐413
Dev. Biol.
(2004) Cell‐cell adhesion via the ECM: Integrin genetics in fly and worm
Matrix Biol.
(2000)- et al.
Suprabasal integrin expression in the epidermis of transgenic mice results in developmental defects and a phenotype resembling psoriasis
Cell
(1995) - et al.
Phosphorylation of the WASP‐VCA domain increases its affinity for the Arp2/3 complex and enhances actin polymerization by WASP
Mol. Cell
(2003)
Integrin‐mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCzeta
Cell
Rho family proteins in cell adhesion and cell migration
Eur. J. Cancer
Alpha 6 beta 4 and alpha 6 beta 1 integrins associate with ErbB‐2 in human carcinoma cell lines
Exp. Cell Res.
Structurally conserved interaction of Lgl family with SNAREs is critical to their cellular function
Curr. Biol.
Isoforms of the polarity protein par6 have distinct functions
J. Biol. Chem.
Assembly of epithelial tight junctions is negatively regulated by Par6
Curr. Biol.
Hemipterous encodes a novel Drosophila MAP kinase kinase, required for epithelial cell sheet movement
Cell
Nuclear movement regulated by Cdc42, MRCK, myosin, and actin flow establishes MTOC polarization in migrating cells
Cell
Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac‐dependent cell migration
J. Biol. Chem.
The Drosophila tumor suppressor gene, dlg, is involved in structural plasticity at a glutamatergic synapse
Curr. Biol.
Ras redux: Rethinking how and where Ras acts
Curr. Opin. Genet. Dev.
The Scribble and Par complexes in polarity and migration: Friends or foes?
Trends Cell Biol.
Sequential roles of Cdc42, Par‐6, aPKC, and Lgl in the establishment of epithelial polarity during Drosophila embryogenesis
Dev. Cell
Paxillin serves as an ERK‐regulated scaffold for coordinating FAK and Rac activation in epithelial morphogenesis
Mol. Cell
The genomic response of the Drosophila embryo to JNK signaling
Dev. Cell
Regulators of endocytosis maintain localized receptor tyrosine kinase signaling in guided migration
Dev. Cell
Laminin and beta1 integrins are crucial for normal mammary gland development in the mouse
Dev. Biol.
Bazooka is a permissive factor for the invasive behavior of discs large tumor cells in Drosophila ovarian follicular epithelia
Development
Multiple requirements for the receptor serine/threonine kinase thick veins reveal novel functions of TGF beta homologs during Drosophila embryogenesis
Development
Scribble protein domain mapping reveals a multistep localization mechanism and domains necessary for establishing cortical polarity
J. Cell Sci.
Epithelial Bmpr1a regulates differentiation and proliferation in postnatal hair follicles and is essential for tooth development
Development
Par6‐aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control
Nat. Cell Biol.
The Drosophila tumor suppressor gene lethal(2)giant larvae is required for the emission of the decapentaplegic signal
Development
Drosophila Stardust is a partner of Crumbs in the control of epithelial cell polarity
Nature
The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl
Nature
Epithelial polarity and proliferation control: Links from the Drosophila neoplastic tumor suppressors
Genes Dev.
Localization of apical epithelial determinants by the basolateral PDZ protein Scribble
Nature
Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors
Science
Integrated activity of PDZ protein complexes regulates epithelial polarity
Nat. Cell Biol.
Epidermal growth factor promotes the chemotactic migration of cultured rat intestinal epithelial cells
J. Cell. Physiol.
The AF‐6 homolog canoe acts as a Rap1 effector during dorsal closure of the Drosophila embryo
Genetics
A new diploid nontumorigenic human breast epithelial cell line isolated and propagated in chemically defined medium
In Vitro Cell Dev. Biol.
Null mutations in the alpha PS2 and beta PS integrin subunit genes have distinct phenotypes
Development
Scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila
EMBO J.
Using Drosophila melanogaster to map human cancer pathways
Nat. Rev. Cancer
Human papillomavirus type 18: Association with poor prognosis in early stage cervical cancer
J. Natl. Cancer Inst.
Coexistence of K‐ras mutations and HPV infection in colon cancer
BMC Cancer
Craniofacial dysmorphogenesis including cleft palate in mice with an insertional mutation in the discs large gene
Mol. Cell. Biol.
Cdc42 controls the polarity of the actin and microtubule cytoskeletons through two distinct signal transduction pathways
J. Cell Sci.
Epidermal growth factor receptor‐mediated cell motility: Phospholipase C activity is required, but mitogen‐activated protein kinase activity is not sufficient for induced cell movement
J. Cell Biol.
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