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Laminins in Epithelial Cell Polarization: Old Questions in Search of New Answers

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Laminins in Epithelial Cell Polarization: Old Questions in Search of New Answers Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Laminins in Epithelial Cell Polarization: Old Questions in Search of New Answers Karl S. Matlin,1 Satu-Marja Myllyma¨ki,2 and Aki Manninen2 1Department of Surgery, The University of Chicago, Chicago, Illinois 60637-1470 2Biocenter Oulu, Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu 90220, Finland Correspondence: [email protected] Laminin, a basement membrane protein discovered in 1979, was shortly thereafter impli- cated in the polarization of epithelial cells in both mammals and avarietyof lower organisms. To transduce a spatial cue to the intrinsic polarization machinery, laminin must polymerize into a dense network that forms the foundation of the basement membrane. Evidence sug- gests that activation of the small GTPase Rac1 by b1-integrins mobilizes laminin-binding integrins and dystroglycan to consolidate formation of the laminin network and initiate rearrangements of both the actin and microtubule cytoskeleton to help establish the apico- basal axis. A key coordinator of spatial signals from laminin is the serine–threonine kinase Par-1, which is known to affect dystroglycan availability, microtubule and actin organization, and lumen formation. The signaling protein integrin-linked kinase (ILK) may also play a role. Despite significant advances, knowledge of the mechanism by which assembled laminin produces a spatial signal remains fragmentary, and much more research into the complex functions of laminin in polarization and other cellular processes is needed. he evolution of epithelial cells made multi- the basement membrane to form a continuous, Tcellular organisms possible (Fahey and Deg- semipermeable cell layer or epithelium that nan 2010; Leys and Riesgo 2011). Epithelial shares the polarity of the individual cellular cells individually display a stable asymmetric constituents. This combination of collective organization or polarity, defined by a plasma cell polarity and a barrier created by the epithe- membrane differentiated into domains consist- lial layer divides multicellular organisms into ing of a free or apical surface, a lateral surface, compartments with different chemical compo- and a basal surface, each with a characteristic sitions and specialized functions, and separates protein and lipid composition. Polarity extends the inner milieu from the outside world. as well to the cytoplasm, with organelles ar- Polarization of epithelial cells occurs ranged along an axis running from the apical through the cooperation of intrinsic and extrin- to basal surface. Most significantly, epithelial sic polarization mechanisms (Nelson 2009). cells adhere to each other laterally and to an The intrinsic mechanism depends on mutually underlying extracellular matrix sheet known as antagonistic interactions among a series of cy- Editor: Keith E. Mostov Additional Perspectives on Cell Polarity available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a027920 1 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press K.S. Matlin et al. toplasmic polarization signaling proteins com- we present experimental evidence supporting monly divided into three groups called the Par, laminin’s role as an element of the extrinsic po- Scribbled, and Crumbs complexes, and activa- larization mechanism. Along the way we will tion of the small GTPases Rac1 and Cdc42 (Nel- highlight issues with experimental approaches son 2009). The extrinsic polarization mecha- that have, in our estimation, limited progress in nism, on the other hand, provides spatial this important area. orientation cues to the cell from the environ- ment, triggering the asymmetric distribution and activation of the complexes that make up THE LAMININ FAMILY the intrinsic mechanism. In early embryos, pri- All bilaterians express laminins that have a ca- mary spatial cues take a variety of forms. In nonical heterotrimeric structure consisting of Caenorhabditis elegans, for example, the sperm a, b, and g subunits assembled into a cross- entry point provides the cue, whereas in Dro- shaped molecule (Fig. 1) (Miner and Yurchenco sophila asymmetry is inherited epigenetically 2004; Fahey and Degnan 2012). The amino-ter- through the process of oogenesis (Deng and minal parts of each subunit form the three arms Ruohola-Baker 2000; Dawes and Munro 2011; Thompson 2012). In many, if not most, other cases involving polarization of epithelial cells, α1 CollV either initially during development or in adults Polym. (sulfatide) following injuries that disrupt polarity, there is LN Perl evidence that cell adhesion to both other cells LEa Nd1 and to the basement membrane (BM) protein L4a laminin provide spatial cues. Polym. Polym. LEb Laminin was discovered by Rupert Timpl in LEa LEa 1979 during biochemical analysis of a matrix- LN L4b L4a LN LF like material secreted by the EHS mouse sar- β1 γ1 coma (Timpl et al. 1979). When used for immunohistochemistry, specific antibodies against this protein showed that laminin is lo- calized in the BMs underlying epithelia and sur- Agrin rounding nerves and muscle fibers. In the 1980s, Coiled-coil Peter Ekblom implicated laminin in the differ- entiation and polarization of the primordial kidney epithelium from induced metanephric mesenchyme in the mouse (Ekblom et al. LG α6β1 1 3 1980; Klein et al. 1988). Since then, further re- α6β4 2 αDG, search in mammals and lower organisms has α7β1 5 4 sulfatides (SGL) HS consistently supported the idea that laminin fa- cilitates epithelial polarization. How laminin Figure 1. The structure of a canonical laminin mole- accomplishes this remains, however, unclear. cule, using Lm111 as an example. Note the three In this article, we review the evidence that laminin amino-terminal (LN) or polymerization do- laminin plays a critical role in the polarization of mains on the a1, b1, and g1 subunits, and the lam- epithelial cells. We first describe the complex inin globular (LG) domains on the carboxyl terminus laminin family and how laminins contribute of the a1 subunit. The binding sites of integrins, to the assembly and overall structure of the a-dystroglycan (aDG), and sulfated glycolipids (SGLs) as well heparan sulfates to LG domains are BM. We then focus on laminin receptors ex- indicated. Nd1 refers to the binding site of nidogen, a pressed in epithelial cells, including both inte- protein that cross-links collagen type IV (CollIV) to grins and dystroglycan, and on their atypical laminin. (From Yurchenco 2015; reprinted, with per- distributions and functions in epithelia. Finally, mission, from Elsevier # 2015.) 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a027920 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Laminin Polarization Cues of the cross and the carboxy-terminal regions binding of individual laminin molecules to ga- associate into the stem through coiled-coil in- lactosyl-sulfatide, a membrane glycolipid, fol- teractions. The amino termini of all three chains lowed by recruitment of dystroglycan and inte- are folded into homologous laminin amino-ter- grins, other laminin receptors (Li et al. 2005). minal (LN) domains. These mediate intermo- As the concentration of bound laminin on the lecular interactions that drive the assembly of cell surface increases, individual laminin mole- laminin networks and the formation of BMs. cules associate with each other by formation of The carboxyl terminus of the a chain consists ternary complexes between LN domains from of a series of five laminin globular (LG) do- a, b, and g subunits contributed by three dif- mains that mediate the interaction of laminin ferent laminin molecules (Fig. 2). This loose with cell surface receptors. Recent analysis indi- laminin network is then stabilized by intercala- cates that even the sponge Amphimedon queens- tion and assembly of a separate collagen IV net- landica has laminin-related genes whose prod- work that is cross-linked to the laminin network ucts are theoretically capable of assembling into by the protein nidogen. Other proteins, such a cross-like structure similar to bilaterian lami- as the proteoglycan perlecan, bind to the cell nin, linking the evolution of laminins to that surface and insert themselves into the overall of the earliest metazoans (Fahey and Degnan structure (Yurchenco 2011, 2015). In the ab- 2012). C. elegans and Drosophila, two inverte- sence of laminin, no assembly of collagen IV brate model organisms commonly used to occurs; conversely, detectable BMs can be study epithelial polarization, express the mini- formed without collagen IV, consistent with a mal set of conserved laminin chains, designated fundamental role for laminin (Li et al. 2002; types a1/2, a3/5, b, and g, and resulting, when Poschl 2004). Nevertheless, the BMs assembled assembled, in two different laminin molecules in the absence of collagen IV have structural (Fahey and Degnan 2012). In mammals, the abnormalities leading to functional defects in laminin family is expanded to five a, four b, the epithelium (Poschl 2004). Moreover, in vi- and three g chains, yielding at least 16 different tro studies hint
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