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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-

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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.)

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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 that the assembly of collagen IV forms. Four of the mammalian subunits, a3A, network contributes to regulation of epithelial a4, b3, and g2, either arise from genes that are polarity (Wang et al. 1990) (F Moafi, J Mylly- shortened relative to those coding for canonical harju, and A Manninen et al., unpubl.). As the subunits, or are truncated by alternative splicing BM forms, interaction of laminins with its cell or posttranslational processing. Because each of surface receptors initiates intracellular signaling these shorter subunits lacks domains found in and alterations in the cytoskeleton (Colognato full-length laminin subunits, there are function- et al. 1999; Li et al. 2005). al implications in cells expressing them that re- The roles of laminin molecules lacking one main poorly understood (Miner and Yurchenco or more LN domains in the regulation or mod- 2004; Yurchenco 2011, 2015; Fahey and Degnan ulation of BM assembly is not completely clear. 2012). In mammals, laminin names reflect their Peter Yurchenco (2011) has suggested that lam- subunit composition such that laminin 511 inins such as Lm411, which lack an a subunit (hereafter Lm511) is made up of a5, b1, and LN domain, might form a loose network on the g1, whereas Lm3A32 is composed of a3A, b3, cell surface that is more dependent on the col- and g2 (Aumailley et al. 2005). The predomi- lagen IV network for its stability than one nant laminins expressed in mammalian epithe- formed by typical laminins. In cell cultures of lial cells are Lm111, Lm511, and Lm3A32. rat alveolar epithelial cells, Lm3A11, which also Mammalian laminins with the canonical lacks the a LN domain, appears to assemble structure are capable of polymerizing into a net- into fibrils, possibly driven by perlecan instead work that forms the backbone of the BM of or in addition to laminin–laminin interac- (Yurchenco 2011, 2015). Based on experiments tions. Such structures may transduce mechani- with cultured Schwann cells, the process of net- cal signals (Jones et al. 2005; Urich et al. 2011). work assembly is believed to be initiated by the Lm3A32, which lacks both a and g LN do-

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K.S. Matlin et al.

α1-laminin Collagen-IV

Polymerization Nidogen

γLN Perlecan γLN

γLN Anchorage

Integrin SGLs RTK DG Agrin F-actin Dystrophin/utrophin

Collagen-IV polymerization NC1

7S NC1 Lateral 2

Figure 2. The current model for assembly of laminin and the basement membrane. According to this model (upper panel), individual laminin molecules bind to the cell surface by interacting with sulfated glycolipids (SGLs) via laminin globular (LG) domains and then polymerize through interactions of laminin amino-terminal (LN) domains contributed by three laminin molecules (polymerization). This is followed by binding of dystro- glycan (DG), integrin, and agrin (a heparan sulfate proteoglycan) to LG domains, initiating signaling through receptor tyrosine kinases (RTKs). In this version of the model, the a1 LN domain also binds to SGLs and integrins, causing the assembled laminin network to flatten against the membrane. After assembly of laminin, collagen IV molecules intercalate into the laminin network, associate with integrins, and polymerize (lower panel). The collagen network is cross-linked to the laminin network by nidogen. Perlecan (another heparan sulfate proteoglycan) and agrin also help cross-link collagen to laminin, thereby stabilizing the basement mem- brane. (From Yurchenco 2011; reprinted, with permission, from Cold Spring Harbor Laboratory Press # 2011.)

mains, coexists in the BMs of the epidermis and lytically processed. On injury, however, both the some other tissues with the canonical laminin skin and kidney tubular epithelial cells express Lm511 (as well as Lm3A11), where it is linked to unprocessed (but still genetically truncated) the collagen IV network via nidogen (Tzu and Lm3A32, which is thought to stimulate cell mi- Marinkovich 2008). The a3A and g2 subunits gration to close the wound (Zuk and Matlin of Lm3A32 found in normal skin are proteo- 2002; Mak et al. 2006; Tzu and Marinkovich

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Laminin Polarization Cues

2008; Moyano et al. 2010; Greciano et al. 2012). MDCK cell cysts (O’Brien et al. 2001; Monte- Netrins, which are short, laminin-related pro- leon et al. 2012). teins possessing LN-like domains, have also been reported to regulate BM assembly LAMININ RECEPTORS IN EPITHELIAL CELLS (Schneiders et al. 2007). In Madin–Darby canine kidney (MDCK) Integrins constitute the major family of cellular cells, which form a continuous polarized epi- ECM receptors and many of the 24 known thelium in culture, the canonical laminin mammalian integrin ab-heterodimers have Lm511 is synthesized constitutively, whereas been reported to bind to laminin (Horwitz Lm3A32 is only expressed on disruption of et al. 1985; Languino et al. 1989; Ignatius et al. the epithelium, consistent with a role for 1990; Sonnenberg et al. 1990; Goodman et al. Lm3A32 in cell migration (Mak et al. 2006; 1991; Nishiuchi et al. 2006). Carboxy-terminal Moyano et al. 2010; Greciano et al. 2012). Gre- globular domains (particularly LG1-3) of the ciano et al. (2012) observed that the ability of laminin a chain serve as a binding site for at MDCK cells to undergo directional migration least a6b1-, a6b4-, a7b1-, and a3b1-integrins was dependent on the ratio of deposited Lm511 (Kikkawa et al. 2000; Nishiuchi et al. 2006). and Lm3A32. They hypothesized that Lm3A32 Although the expression pattern of integrins interacts with and destabilizes the Lm511 net- is cell-type dependent, normal epithelial cells work to generate a haptotactic gradient in the express several b1-integrins (typically a2b1, deposited extracellular matrix to facilitate direc- a3b1, and a6b1), a6b4, and aV-integrins tional migration, and speculated that effects on (aVb3, aVb5, aVb6, and aVb8) (Schoenen- the Lm511 network might be mediated by the berger et al. 1994; Howlett et al. 1995; Gilcrease b3 subunit of Lm3A32 (Greciano et al. 2012). 2007; Myllyma¨ki et al. 2011; Tera¨va¨inen et al. The plausibility of this hypothesis is uncertain. 2013). The above-mentioned b1-integrins and Purified Lm111, which resembles Lm511, will a6b4 all contribute to the establishment of api- assemble in solution in the presence of calcium cobasal polarity, particularly in three-dimen- in a manner analogous to network formation sional in vitro culture systems (Howlett et al. on the cell surface. Under these conditions, ad- 1995; Lohikangas et al. 2001; Weaver et al. dition of increasing concentrations of Lm3A32 2002; Yu et al. 2005; Myllyma¨ki et al. 2011). fails to inhibit Lm111 assembly, suggesting that Integrins link the extracellular matrix with the there is no interaction between the two different cellular actin cytoskeleton at integrin-linked ad- laminins that blocks ternary complex formation hesion complexes (ILACs; b1- and aV-inte- (Yurchenco and Cheng 1994; Cheng et al. grins) and with intermediate filament networks 1997). On the other hand, studies of molecular at hemidesmosomes (HDs; a6b4), thereby interactions between expressed LN domains forming a mechanical continuum connecting from a variety of laminin subunits indicate the ECM and epithelium (Kanchanawong that the b3 LN domain found in Lm3A32 is et al. 2010; Nahidiazar et al. 2015). ILACs are capable of interacting with other LN domains not mere mechanical links as they form large (Odenthal et al. 2004). Furthermore, purified multicomponent signaling platforms that regu- Lm3A32 disrupts a matrix of Lm111 assembled late essentially all aspects of cell behavior (Gei- on a glass coverslip, as monitored by atomic ger and Yamada 2011; Horton et al. 2015). force microscopy (Chiang et al. 2011). This po- However, mechanistic and proteomic studies tential modulation of network assembly by lam- of ILACs have been performed almost exclusive- inins like Lm3A32 is relevant to laminin’s pos- ly in fibroblasts seeded on fibronectin-coated sible role in epithelial polarization because substrates and, therefore, the function, dynam- evidence exists that only assembled laminin ics, and composition of ILACs on laminin re- can help to determine the apicobasal polarity mains poorly characterized (Geiger and Zaidel- axis (see below), and expression of Lm3A32 Bar 2012; Winograd-Katz et al. 2014; Horton has been reported during polarization of et al. 2015). b1- and a6b4-integrins colocalize

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in laminin patches observed in polarized 1988 that an antilaminin antibody blocked the MDCK epithelial cells, presumably demarcating differentiation and polarization of the primor- sites of cell-driven laminin assembly. Curiously, dial kidney epithelium in organ cultures of in- these laminin-rich patches are adjacent to, but duced metanephric mesenchyme (Klein et al. do not colocalize with, ILAC markers such as 1988). This finding was later buttressed by the talin, while they do overlap with an HD marker observation that an antibody against the a6 sub- plectin (SM Myllyma¨ki and A Manninen, un- unit of a laminin-binding integrin produced the publ.). HDs, in turn, are only found in epithelial same effect (Sorokin et al. 1990). At about the cells and their assembly depends on the unique same time, a variety of other studies appeared, cytoplasmic tail of the integrin b4 subunit, correlating the expression of laminin with epi- which supports interactions with the keratin thelial differentiation and polarization (Leivo cytoskeleton via the plakin family of cytoskeletal et al. 1980; Wang et al. 1990; Miner and Yur- linker proteins (Walko et al. 2015). Intermediate chenco 2004). filaments have unique mechanical properties During early mouse development, laminin but, unlike actin and microtubule polymers, does not appear to be required for initial blas- do not possess intrinsic polarity (Goldman tomere compaction and polarization at the et al. 2008; Li and Gundersen 2008). Neverthe- eight-cell stage before implantation, consistent less, a6b4-integrins are involved in the regula- with first detection of all three laminin subunits tion of apicobasal polarity, possibly by promot- at the 16-cell stage (Leivo et al. 1980; Fleming ing BM assembly or by modifying outside in and Johnson 1988; Miner and Yurchenco 2004). signaling from the laminin-rich ECM (Weaver Postimplantation studies based on homozygous et al. 2002; Myllyma¨ki et al. 2011). knockout of the gene for the g1 subunit, a com- Dystroglycan, heparan-sulfate proteogly- ponent of both Lm111 and Lm511, suggest that cans, and sulfated glycolipids all interact mainly laminin is critical for both BM assembly and with the LG4-5 domains of laminin a chains morphogenesis (Smyth et al. 1999; Miner and (Gee et al. 1993; Salmivirta et al. 1994; Ido Yurchenco 2004). 2004; Li et al. 2005). Similar to b1-integrins, Later work by Li and colleagues rigorously ab-heterodimeric dystroglycan also connects examined the role of laminin in epithelial po- with the actin cytoskeleton by interacting with larization using mouse embryoid bodies as a utrophin and/or dystrophin, particularly in model (Li et al. 2002, 2003). Embryoid bodies muscle tissues, where its main role is to are derived from suspended mouse embryonic strengthen the connection between the muscle stem cells, and when cultured recapitulate en- cell cytoskeleton and the surrounding BM dodermal and ectodermal differentiation (Mur- (Winder et al. 1995; Rybakova et al. 2000). Dys- ray and Edgar 2000; Li et al. 2003). Over a pe- troglycan is ubiquitously expressed in epithelial riod of 6–7 days, as the endoderm forms, a BM cells. At least in epidermis, dystroglycan localizes assembles between the endoderm and primitive to HDs, which strengthen the linkage between ectoderm. Through a process of cavitation and the epidermis and the underlying dermis (Her- apoptosis, a lumen opens in the cyst-like struc- zog et al. 2004). However, dystroglycan also in- ture and ectodermal cells polarize to produce an teracts with Par-1, component of the intrinsic epiblast (Murray and Edgar 2000; Li et al. 2003). polarization machinery, and might thereby reg- Li and colleagues (2002) used embryoid bodies ulate epithelial cell polarity and morphogenesis null for the expression of either b1-integrin, the (Bello et al. 2015; Peng et al. 2015) (see discus- laminin g1 subunit, or dystroglycan, to test the sion below). roles of laminin binding and assembly in epi- blast differentiation. In the absence of b1-inte- grin, neither epiblast differentiation nor BM LAMININ’S ROLE IN POLARIZATION assembly occurred; addition of exogenous lam- The first strong evidence that laminin is impor- inin under these conditions was, however, tant for epithelial polarization was the report in able to drive both. Li et al. also observed that

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b1-integrin-null epiblasts do not express the sional polarized cysts with apical surfaces facing laminin a1 subunit, explaining the absence of the lumen and basal surfaces facing the sur- endogenous assembled laminin in this mutant rounding extracellular matrix (Fig. 3) (O’Brien and indicating that b1-integrin is not essential et al. 2001; Yu et al. 2005). At the same time, a for anchorage of laminin to the cell surface in continuous BM composed of endogenous this model. Dystroglycan-null end-binding pro- Lm511 and collagen IV,as well as other compo- teins (EBs) assembled laminin and had prop- nents, assembles on the outer surface of the cyst erly polarized epiblasts although their survival (O’Brien et al. 2001; Yu et al. 2005). In cells was affected. Addition of exogenous laminins expressing a dominant negative (dn) form of unable to polymerize failed to stimulate differ- the small GTPase Rac1, or treated with a func- entiation of a polarized epiblast, strongly sug- tion-blocking antibody directed against b1-in- gesting that laminin assembly into a network tegrin, the polarity of cells in the cyst is inverted was critical for polarization (Li et al. 2002, and disorganized such that apical proteins now 2003). Proper epiblast polarization in laminin- appear on the side of the cyst facing the extra- supplemented b1-integrin and dystroglycan- cellular matrix. At the same time, laminin and null EBs suggests that the basal polarity cue collagen IV still surround the cyst, but appear from laminin can be conveyed by multiple lam- diffuse and disassembled (Fig. 3) (O’Brien et al. inin receptors. 2001; Yu et al. 2005). In cells expressing dnRac1, Studies in both Drosophila and C. elegans inverted polarity can be partially rescued by ad- also support a role for laminin in epithelial dif- dition of exogenous Lm111 to the collagen gel ferentiation and polarization. As mentioned (O’Brien et al. 2001). Inversion caused by anti- previously, both organisms express two differ- b1-integrin, on the other hand, can be rescued ent laminin a subunits and single b and g sub- by expression of constitutively active Rac1 or by units (Fahey and Degnan 2012). Consequently, inhibition of the RhoA/ROCK1/myosin-II cas- deletion or mutation of the b subunit permits cade (Yu et al. 2008). Significantly, these manip- the roles of any possible laminin polymers to be ulations also rescue laminin assembly into a probed. In Drosophila, mutation of the LanB1 BM-like structure surrounding the cyst (Yu gene prevented BM from forming, but did not et al. 2005). The investigators of these studies inhibit embryogenesis. Nevertheless, organo- suggest that an integrin containing the b1sub- genesis was generally abnormal with defects unit, likely a2b1, interacts with collagen I mol- noted in adhesion, cell migration, and tubulo- ecules in the gel to activate Rac1, as supported genesis (Urbano et al. 2009). Surprisingly, lam- also by more recent studies (Myllyma¨ki et al. inin was not required for gastrulation, leading 2011; Tera¨va¨inen et al. 2013). Rac1 signaling, the investigators to postulate that laminin is re- then, in some manner, facilitates laminin assem- quired only during epithelialization, which oc- bly resulting in the transmission of a spatial cue curs after gastrulation in Drosophila (Urbano to cells that leads to the correct polar orientation et al. 2009). In C. elegans, mutation of the b (Yu et al. 2005). The role of Rac1 was challenged subunit gene lam-1, prevented the polarization by a recent study on mammary epithelial cells in of pharyngeal precursor cells, as judged by api- which mammary acinar morphogenesis was un- cal localization of the polarity protein Par3. affected by deletion of Rac1, whereas b1-inte- Laminin was, however, not universally required grins were still essential (Akhtar and Streuli 2013). because the intestinal epithelium was able to Another recent report relating MDCK cell differentiate and polarize in its absence (Ras- cyst orientation and the integrity of the BM is mussen et al. 2012). generally consistent with the conclusions of the The linkage between epithelial polarization previously discussed studies, but also illustrates and laminin assembly was also shown in studies potential pitfalls of experimental systems used of MDCK cell cysts. When individual MDCK for three-dimensional culture. Monteleon et al. cells are suspended in a gel of type I, interstitial (2012) observed that MDCK cells grown in Ma- collagen, they proliferate to form three-dimen- trigel, a commercial product derived from the

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Control β1KD Lm111 and collagen IV rich matrix of the EHS- sarcoma, show inverted polarity when the ex- pression of the Arf6 small-GTPase is suppressed with siRNA. They showed that this inversion is related to Rac1 inactivation, and is reversed by Rac1 activation, consistent with the findings of pcx F-actin DAPI Yu, O’Brien, and colleagues (O’Brien et al. 2001; Control β1KD Yu et al. 2005, 2008). However, O’Brien et al. grew MDCK cell cysts in type I collagen gels, not Matrigel, and were able to rescue the inverted polarity phenotype by addition of Lm111 to the collagen gel. In the case of Monteleon et al. (2012) inversion that they link to Rac1 inacti-

LN γ 1 F-actin DAPI vation occurs even though MDCK cell cysts are Control β1KD immersed in the Lm111 provided by Matrigel, a discrepancy that they fail to note. Furthermore, they also observe the “assembly” of endogenous Lm332 (presumably Lm3A32) in normal MDCK cell cysts grown in Matrigel, as well as its lack of organization in inverted cysts, with- out accounting for the inability of Lm332 to γ LN 1 assemble like other canonical laminins or the correlation of Lm332 expression in MDCK cells with loss of epithelial integrity (Cheng et al. 1997; Zuk and Matlin 2002; Mak et al. 2006; Moyano et al. 2010). More broadly considered, the use of Matrigel in three-dimensional cul- Max. intensity proj.Max. Optical slice tures for experiments that probe the role of lam- inin and BM assembly in epithelial polarization Figure 3. Laminin is deposited in a basement mem- is problematic. The presence of large amounts brane-like pattern in three-dimensional cultures of of Lm111 in Matrigel can potentially drive lam- Madin–Darby canine kidney (MDCK) epithelial cells. When MDCK cells are grown in collagen gels, inin assembly by mass action under circum- they form polarized cysts with the apical surface fac- stances when assembly of endogenous laminins ing the lumen of the cyst and the basal surface facing might be inhibited, suppressing certain pheno- the collagen gel. Normal (control) cultures are shown types and confounding interpretation of results. on the left and MDCK cells in which expression of the Furthermore, at least in the case of MDCK cells, b1-integrin subunit (part of collagen and laminin Lm511, and not Lm111, is the normal canonical receptors) is suppressed by siRNA are shown on the laminin that the cells express, and the naı¨ve as- right. In controls, the apical protein podocalyxin (pcx) and actin are detected on the apical surface sumption that Lm111 can fully substitute for by confocal fluorescence microscopy, whereas lami- Lm511 may introduce further complications nin, detected with an antibody to the g1 subunit into experiments. (LNg1), forms a thin basal layer. The distribution of laminin is more easily seen in both an optical slice and a projection assembled from a through-focal se- HOW DOES LAMININ ACT AS A SPATIAL ries of optical slices in the two lower control panels. CUE? Knockdown of b1-integrin disrupts overall cyst mor- phology and inverts polarity of actin and pcx, and Based on the previous discussion, it seems likely disturbs the distribution of laminin (right panels) that laminin acts as spatial cue during polariza- (SM Myllyma¨ki and M Manninen, unpubl.; see also tion of epithelial cells, but only when it is as- Yu et al. 2005). Scale bars, 10 mm. sembled, presumably into a structure involving

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Laminin Polarization Cues

ternary complexes between laminin molecules serine–threonine kinase identified through as found in authentic BMs. This raises two ques- the same mutant screens of C. elegans that tions: First, is the assembly of laminin regulated found other Par protein components of the in- by the cell, or is it driven solely by mass action trinsic polarization machinery (Nelson 2009; when the density of laminin bound to the cell Roignot et al. 2013). In polarized epithelial cells, surface reaches a certain threshold? Second, Par-1 binds to the basolateral plasma membrane once laminin is engaged with its receptors, but is prevented from accumulating in the api- how does it communicate with the polarization cal part of the cell by phosphorylation with machinery to orient the cell? atypical protein kinase C (aPKC), a component A likely answer to the first question is that of the apical Par polarity complex (Hurov et al. laminin assembly may initially be driven by 2004; Roignot et al. 2013). There is evidence mass action, but its transformation into a sol- that Par-1 regulates the formation of apical lu- id-state signaling platform appears to be regu- mens in both MDCK cell monolayers overlaid lated through engagement of laminin receptors with collagen and three-dimensional cyst cul- with the actin cytoskeleton and the generation tures in collagen gels (Cohen et al. 2004, 2007, of specific signals. Workby Yurchenco has clear- 2011; La´zaro-Die´guez et al. 2013). The level of ly shown that laminin assembly on cell surfaces Par-1 activity seems to be critical to this process, can be driven by addition of exogenous mole- because overexpression of Par-1 can induce cules (Colognato et al. 1999; Li et al. 2005). In MDCK cells to form lateral, hepatocyte-like lu- one case in particular, when exogenous laminin mens instead of showing normal apicobasal po- was added to myotubes capable of synthesizing larized organization. only small amounts of endogenous laminin, it Most significantly, Par-1 appears to be in- bound to the cell surface and was observed by volved in both laminin assembly and transduc- light microscopy to transition from an initial tion of polarizing signals from the BM to the aggregated, reticular distribution to a more fo- cell. Masuda-Hirata and colleagues found that cal, repeating polygonal pattern after more than Par-1 binds to the utrophin subunit of the dys- 4 hours in culture (Colognato et al. 1999). For- troglycan laminin receptor (Masuda-Hirata mation of the pattern on the cell surface re- et al. 2009; Yamashita et al. 2010). They further quired laminin polymerization, because it did reported that Par-1 both regulates the localiza- not happen with a modified laminin incapable tion of dystroglycan and the accumulation of of polymerization, but was also dependent on laminin on the basal surface (Masuda-Hirata actin and tyrosine phosphorylation because cy- et al. 2009). Other, more recent, results are con- tochalasin and a pan-tyrosine kinase inhibitor sistent with these observations (Lewandowski blocked the rearrangement. This suggests that and Piwnica-Worms 2014). Cohen and col- conversion of the nascent laminin network into leagues observed that overexpression of Par-1 a more functional configuration is an active in MDCK cells affected the distribution of lam- process (Colognato et al. 1999). The work of inin on the basal surfaces of MDCK cell cysts in Li et al. (2005) further refined this sequence of collagen gels (Cohen et al. 2011). In the latter events by demonstrating that laminin initially case, this is likely related to Par-1 regulation of concentrates and begins to assemble on the cell the actin cytoskeleton. Par-1 phosphorylates surface by binding to sulfated glycolipids. Sub- and inactivates insulin receptor tyrosine kinase sequently, integrin and dystroglycan receptors substrate 53 (IRSp53), a protein responsible for interact with the adherent laminin, and activate mediating actin microfilament reorganization signaling through tyrosine kinases. in response to Rac1 and cdc42, as well as gua- The answer to the second question likely nine nucleotide exchange factor H1 (GEF-H1), involves the polarization protein Par-1 (Ma- which regulates RhoA-dependent actin cyto- suda-Hirata et al. 2009; Cohen et al. 2011; skeleton restructuring (Scita et al. 2008; Cohen Yamahashi et al. 2011; Sato et al. 2013; Lewan- et al. 2011; Yamahashi et al. 2011). Cohen et al. dowski and Piwnica-Worms 2014). Par-1 is a found that knockdown of IRSp53 mimicked the

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effects of Par-1 overexpression on laminin dep- had no defect in BM assembly, but the epiblast osition (Cohen et al. 2011). failed to polarize (Sakai et al. 2003). These results suggest a possible role for Par- 1 as a central modulator of spatial cues from A WORKING MODEL laminin to the polarizing epithelial cell (Ma- suda-Hirata et al. 2009; Cohen et al. 2011; Lew- The studies reviewed here suggest a model for andowski and Piwnica-Worms 2014). Not only how laminin provides a spatial cue to facilitate is there evidence of Par-1 involvement in the apicobasal polarization of epithelial cells (Fig. activity and localization of laminin receptors, 4). When epithelial cells initially adhere to ECM but also in the transduction of laminin signals proteins, whether collagen, laminin, or others, through the cytoskeleton. In addition to regu- through engagement of integrin receptors, the lating actin reorganization, Par-1 also alters mi- small GTPase Rac1 is activated. As secreted lam- crotubule dynamics through phosphorylation inin accumulates, it is initially concentrated on of microtubule-binding proteins, affecting the the cell surface by binding to sulfated glycolip- realignment of microtubules from a centroso- ids. The activities of Rac1 and Par-1, as well as mal focus to a vertical array that parallels the signals from receptor tyrosine kinases, then mo- apicobasal axis in polarized cells (Cohen et al. bilize both integrin and dystroglycan laminin 2004; La´zaro-Die´guez et al. 2013; Sato et al. receptors to reorganize and stabilize the nascent 2013). As epithelial polarization proceeds, Par- laminin network. At the same time, collagen IV 1 seems to balance the various factors transduc- and other components of the BM intercalate ing basal polarization signals—both too little into the laminin network. Once engaged, sig- and too much Par-1 activity can be disruptive nals from the laminin receptors, again modu- to organization of the laminin matrix and lated by Par-1 together with ILK, lead to the downstream effects on polarization (Masuda- reorganization of the microtubule and actin cy- Hirata et al. 2009; Cohen et al. 2011). toskeletons to establish the apicobasal axis. The above data favor a role for dystroglycan This model is consistent with observations in promoting laminin assembly yet do not ex- that inhibition of Rac1 or blockade of b1-inte- clude a role for integrins, particularly in con- grins disrupts both laminin assembly and po- veying polarity signals once the laminin net- larization (O’Brien et al. 2001; Yu et al. 2005), as work has formed. Depletion of both b1- and well as a variety of findings linking Par-1 activity b4-integrins in MDCK cells (that still express to apical lumen formation, actin and microtu- dystroglycan) results in inverted polarity in Ma- bule reorganization, and dystroglycan availabil- trigel-embedded MDCK cells in which abun- ity and activity (Cohen et al. 2004, 2007, 2011; dant exogenous laminin is present (Myllyma¨ki Masuda-Hirata et al. 2009; La´zaro-Die´guez et al. 2011). Moreover, depletion of either the et al. 2013; Sato et al. 2013; Lewandowski and b1- or a3-integrin subunit interferes with lu- Piwnica-Worms 2014). The model presupposes men formation in Matrigel cultures. the basal secretion of laminin, which may be Akhtar and colleagues reported that inte- under the control of regulators of membrane grin-linked kinase (ILK), a pseudokinase adap- trafficking Crag and Rab10, and ultimately tor protein that binds directly to the cytoplas- phosphoinositides, which are critical for epithe- mic tails of b1- and b3-integrins, orchestrates lial polarization (Gassama-Diagne et al. 2006; endocytosis of apical membrane proteins away Martin-Belmonte et al. 2007; Denef et al. 2008; from the laminin-rich basal domain in mam- Lerner et al. 2013; Devergne et al. 2014). What is mary epithelial cells (Akhtar and Streuli 2013). not accounted for by this model is any possible ILK accomplished this by capturing microtu- role for nonpolymerizing laminins such as bule plus ends at integrin adhesions via interac- Lm3A32 in the regulation of laminin assembly tions with EBs, resulting in alignment of micro- (Odenthal et al. 2004; Chiang et al. 2011; Gre- tubules along the apicobasal polarity axis. In ciano et al. 2012). This laminin is expressed by line with these data, ILK-null embryoid bodies epithelial cells like MDCK in a regulated fashion

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Laminin Polarization Cues

A Partially polarized Laminin DG Integrin Sulfo- lipid

Microtubule Actin

ILK Rac* Rac* ILK Rac* Par1 Par1 ILK Par1

ECM

B Polarized

Par1 ILK ILK ILK Par1 ILK Par1

Assembled laminin ECM

Figure 4. A preliminary model for the induction of epithelial polarity by laminin. Epithelial cells adhere to each other and extracellular matrix (ECM) proteins such as collagen and fibronectin through integrins, and activate Rac1 (RacÃ), leading to alterations in cortical actin. Secreted laminin attaches to the basal surface via sulfated glycolipids. As the amount of laminin accumulates, it begins to polymerize and bind to integrins and dystro- glycan (DG). The activities of Rac1 and Par-1, then mobilize both integrin and DG laminin receptors to reorganize and stabilize the nascent laminin network (assembled laminin). At the same time, collagen IV and other components of the basement membrane intercalate into the laminin network (not illustrated). Once engaged, signals from the laminin receptors, again modulated by Par-1 together with integrin-linked kinase (ILK), lead to the reorganization of the microtubule and actin cytoskeletons to establish the apicobasal axis, leading to full polarization.

(Yu et al. 2005; Mak et al. 2006; Moyano et al. lial polarization, is a robust property. Condi- 2010), and is capable of disrupting laminin net- tions of in vitro culture can circumvent or works (Chiang et al. 2011), but its presence is mask processes that are important in vivo, mak- often ignored by investigators in favor of a focus ing signaling mechanisms from laminin hard to on single, canonical laminins. unravel. Furthermore, laminin molecules are Spatial signaling to epithelial cells from the difficult to study because of their large size extracellular matrix, like other aspects of epithe- and complex domain structure. Even with the

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many tour de force studies of Peter Yurchenco Colognato H, Winkelmann D, Yurchenco P. 1999. Laminin and his colleagues (McKee et al. 2009), the de- polymerization induces a receptor cytoskeleton network. J Cell Biol 145: 619–631. tailed organization, permeability, and mechan- Dawes AT, Munro EM. 2011. PAR-3 oligomerization may ical properties of laminin networks and the provide an actin-independent mechanism to maintain overall BM are essentially unknown. Despite distinct par protein domains in the early Caenorhabditis these many obstacles, more work to understand elegans embryo. Biophys J 101: 1412–1422. this essential, solid-state-signaling platform is Denef N, Chen Y, Weeks SD, Barcelo G, Schu¨pbach T. 2008. Crag regulates epithelial architecture and polarized dep- justified and urgently needed. osition of basement membrane proteins in Drosophila. Dev Cell 14: 354–364. Deng WM, Ruohola-Baker H. 2000. Laminin A is required for follicle cell-oocyte signaling that leads to establish- ACKNOWLEDGMENTS ment of the anterior–posterior axis in Drosophila. Curr Biol 10: 683–686. This article is dedicated to the memories of Devergne O, Tsung K, Barcelo G, Schu¨pbach T. 2014. Polar- Elizabeth (Betty) Hay and Peter Ekblom, and ized deposition of basement membrane proteins depends on phosphatidylinositol synthase and the levels of phos- to the many colleagues over the years that con- phatidylinositol 4,5-bisphosphate. Proc Natl Acad Sci tributed to our work on integrins and laminins 111: 7689–7694. in epithelial cells. Research in the authors’ lab- Ekblom P, Alitalo K, Vaheri A, Timpl R, Saxen L. 1980. oratories was supported by grants from the Na- Induction of a basement membrane glycoprotein in em- tional Institutes of Health (K.S.M.) and Acade- bryonic kidney: Possible role of laminin in morphogen- esis. Proc Natl Acad Sci 77: 485–489. my of Finland (140974, 263770, 135560; A.M. Fahey B, Degnan BM. 2010. Origin of animal epithelia: In- and S.-M.M.). sights from the sponge genome. Evol Dev 12: 601–617. Fahey B, Degnan BM. 2012. Origin and evolution of laminin gene family diversity. Mol Biol Evol 29: 1823–1836. Fleming TP, Johnson MH. 1988. From egg to epithelium. REFERENCES Annu Rev Cell Biol 4: 459–485. Gassama-Diagne A, Yu W, ter Beest M, Martin-Belmonte F, Akhtar N, Streuli CH. 2013. An integrin-ILK-microtubule Kierbel A, Engel J, Mostov K. 2006. Phosphatidylinositol- network orients cell polarity and lumen formation in 3,4,5-trisphosphate regulates the formation of the baso- glandular epithelium. Nat Cell Biol 15: 17–27. lateral plasma membrane in epithelial cells. Nat Cell Biol Aumailley M, Bruckner-TudermanL, Carter W,Deutzmann 8: 963–970. R, Edgar D, Ekblom P, Engel J, Engvall E, Hohenester E, Gee SH, Blacher RW, Douville PJ, Provost PR, Yurchenco Jones J, et al. 2005. A simplified laminin nomenclature. PD, Carbonetto S. 1993. Laminin binding protein 120 Matrix Biol 24: 326–332. from brain is closely related to the dystrophin-associated Bello V,Moreau N, Sirour C, Hidalgo M, Buisson N, Darri- glycoprotein, dystroglycan, and binds with high affinity bere T. 2015. The dystroglycan: Nestled in an adhesome to the major heparin binding domain of laminin. J Biol during embryonic development. Dev Biol 401: 132–142. Chem 268: 14972–14980. Cheng Y, Champliaud M, Burgeson R, Marinkovich M, Geiger B, Yamada KM. 2011. Molecular architecture and Yurchenco P. 1997. Self-assembly of laminin isoforms. function of matrix adhesions. Cold Spring Harb Perspect J Biol Chem 272: 31525–31532. Biol 3: a005033. Chiang LY, Poole K, Oliveira BE, Duarte N, Sierra YAB, Geiger T, Zaidel-Bar R. 2012. Opening the floodgates: Pro- Bruckner-Tuderman L, Koch M, Hu J, Lewin GR. 2011. teomics and the integrin adhesome. Curr Opin Cell Biol Laminin-332 coordinates mechanotransduction and 24: 562–568. growth cone bifurcation in sensory neurons. Nat Neurosci 14: 993–1000. Gilcrease MZ. 2007. Integrin signaling in epithelial cells. Cancer Lett 247: 1–25. Cohen D, Brennwald PJ, Rodriguez-Boulan E, Mu¨sch A. 2004. Mammalian PAR-1 determines epithelial lumen Goldman RD, Grin B, Mendez MG, Kuczmarski ER. 2008. polarity by organizing the microtubule cytoskeleton. Intermediate filaments: Versatile building blocks of cell J Cell Biol 164: 717–727. structure. Curr Opin Cell Biol 20: 28–34. Cohen D, Tian Y, Mu¨sch A. 2007. Par1b promotes hepatic- Goodman SL, Aumailley M, von der Mark H. 1991. Multiple type lumen polarity in Madin Darby canine kidney cells cell surface receptors for the short arms of laminin: a1b1 via myosin II- and E-cadherin-dependent signaling. Mol integrin and RGD-dependent proteins mediate cell at- Biol Cell 18: 2203–2215. tachment only to domains III in murine tumor laminin. Cohen D, Fernandez D, La´zaro-Die´guez F, Mu¨sch A. 2011. J Cell Biol 113: 931–941. The serine/threonine kinase Par1b regulates epithelial Greciano PG, Moyano JV, Buschmann MM, Tang J, Lu Y, lumen polarity via IRSp53-mediated cell–ECM signal- Rudnicki J, Manninen A, Matlin KS. 2012. Laminin 511 ing. J Cell Biol 192: 525–540. partners with laminin 332 to mediate directional migra-

12 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

tion of Madin–Darby canine kidney epithelial cells. Mol mechanism for polarized basement membrane secretion Biol Cell 23: 121–136. during organ morphogenesis. Dev Cell 24: 159–168. Herzog C, Has C, Franzke CW, Echtermeyer FG, Schlo¨tzer- Lewandowski KT, Piwnica-Worms H. 2014. Phosphoryla- Schrehardt U, Kra¨ger S, Gustafsson E, Fa¨ssler R, Bruck- tion of the E3 ubiquitin ligase RNF41 by the kinase Par- ner-Tuderman L. 2004. Dystroglycan in skin and cutane- 1b is required for epithelial cell polarity. J Cell Sci 127: ous cells: b subunit is shed from the cell surface. J Invest 315–327. Dermatol 122: 1372–1380. Leys SP,Riesgo A. 2011. Epithelia, an evolutionary novelty of Horton ER, Byron A, Askari JA, Ng DHJ, Millon-Fre´millon metazoans. J Exp Zool B Mol Dev Evol 318: 438–447. A, Robertson J, Koper EJ, Paul NR, WarwoodS, Knight D, Li R, Gundersen GG. 2008. Beyond polymer polarity: How et al. 2015. Definition of a consensus integrin adhesome the cytoskeleton builds a polarized cell. Nat Rev Mol Cell and its dynamics during adhesion complex assembly and Biol 9: 860–873. disassembly. Nat Cell Biol 17: 1577–1587. Li S, Harrison D, Carbonetto S, Fassler R, Smyth N, Edgar D, Horwitz A, Duggan K, Greggs R, Decker C, Buck C. 1985. Yurchenco P.2002. Matrix assembly, regulation, and sur- The cell substrate attachment (CSAT) antigen has prop- vival functions of laminin and its receptors in embryonic erties of a receptor for laminin and fibronectin. J Cell Biol stem cell differentiation. J Cell Biol 157: 1279–1290. 101: 2134–2144. Li S, Edgar D, Fassler R, Wadsworth W, Yurchenco P. 2003. Howlett AR, Bailey N, Damsky C, Petersen OW, Bissell MJ. The role of laminin in embryonic cell polarization and 1995. Cellular growth and survival are mediated by b1 tissue organization. Dev Cell 4: 613–624. integrins in normal human breast epithelium but not in Li S, Liquari P, McKee K, Harrison D, Patel R, Lee S, Yur- breast carcinoma. J Cell Sci 108: 1945–1957. chenco P.2005. Laminin-sulfatide binding initiates base- Hurov JB, Watkins JL, Piwnica-Worms H. 2004. Atypical ment membrane assembly and enables receptor signaling PKC phosphorylates PAR-1 kinases to regulate localiza- in Schwann cells and fibroblasts. J Cell Biol 169: 179–189. tion and activity. Curr Biol 14: 736–741. Lohikangas L, Gullberg D, Johansson S. 2001. Assembly of Ido H. 2004. Molecular dissection of the a-dystroglycan- laminin polymers is dependent on b1-integrins. Exp Cell and integrin-binding sites within the globular domain Res 265: 135–144. of human laminin-10. J Biol Chem 279: 10946–10954. Mak GZ, Kavanaugh GM, Buschmann MM, Stickley SM, Ignatius MJ, Large TH, Houde M, Tawil JW, Barton A, Esch Koch M, Goss KH, Waechter H, Zuk A, Matlin KS. 2006. F,Carbonetto S, Reichardt LF.1990. Molecular cloning of Regulated synthesis and functions of laminin 5 in polar- the rat integrin a1-subunit: A receptor for laminin and ized Madin–Darby canine kidney epithelial cells. Mol collagen. J Cell Biol 111: 709–720. Biol Cell 17: 3664–3677. Jones JCR, Lane K, Hopkinson SB, Lecuona E, Geiger RC, Martin-Belmonte F, Gassama A, Datta A, Yu W, Rescher U, Dean DA, Correa-Meyer E, Gonzales M, Campbell K, Gerke V, Mostov K. 2007. PTEN mediated apical segre- gation of phosphoinositides controls epithelial morpho- Sznajder JI, et al. 2005. Laminin-6 assembles into multi- genesis through Cdc42. Cell 128: 383–397. molecular fibrillar complexes with perlecan and partici- pates in mechanical-signal transduction via a dystrogly- Masuda-Hirata M, Suzuki A, Amano Y,YamashitaK, Ide M, can-dependent, integrin-independent mechanism. J Cell Yamanaka T, Sakai M, Imamura M, Ohno S. 2009. Intra- Sci 118: 2557–2566. cellular polarity protein PAR-1 regulates extracellular laminin assembly by regulating the dystroglycan com- Kanchanawong P, Shtengel G, Pasapera AM, Ramko EB, plex. Genes Cells 14: 835–850. Davidson MW,Hess HF,Waterman CM. 2010. Nanoscale architecture of integrin-based cell adhesions. Nature 468: McKee K, Capizzi S, Yurchenco P. 2009. Scaffold-forming 580–584. and adhesive contributions of synthetic laminin-binding proteins to basement membrane assembly. J Biol Chem Kikkawa Y,Sanzen N, Fujiwara H, Sonnenberg A, Sekiguchi 284: 8984–8994. K. 2000. Integrin binding specificity of laminin-10/11: Miner JH, Yurchenco PD. 2004. Laminin functions in tissue Laminin-10/11 are recognized by a3b1, a6b1 and a6b4 morphogenesis. Annu Rev Cell Dev Biol 20: 255–284. integrins. J Cell Sci 113: 869–876. Monteleon CL, Sedgwick A, Hartsell A, Dai M, Whittington Klein G, Langegger M, Timpl R, Ekblom P. 1988. Role of C, Voytik-Harbin S, D’Souza-Schorey C. 2012. Establish- laminin a chain in the development of epithelial cell ing epithelial glandular polarity: Interlinked roles for polarity. Cell 55: 331–341. ARF6, Rac1, and the matrix microenvironment. Mol Languino LR, Gehlsen KR, Wayner E, Carter WG, Engvall E, Biol Cell 23: 4495–4505. a b Ruoslahti E. 1989. Endothelial cells use 2 1 integrin as a Moyano JV,Greciano PG, Buschmann MM, Koch M, Matlin laminin receptor. J Cell Biol 109: 2455–2462. KS. 2010. Autocrine transforming growth factor-b1 acti- La´zaro-Die´guez F, Cohen D, Fernandez D, Hodgson L, van vation mediated by integrin aVb3 regulates transcrip- IJzendoorn SCD, Mu¨sch A. 2013. Par1b links lumen po- tional expression of laminin-332 in Madin–Darby ca- larity with LGN-NuMA positioning for distinct epithelial nine kidney epithelial cells. Mol Biol Cell 21: 3654–3668. cell division phenotypes. J Cell Biol 203: 251–264. Murray P, Edgar D. 2000. Regulation of programmed cell Leivo I, Vaheri A, Timpl R, Wartiovaara J. 1980. Appearance death by basement membranes in embryonic develop- and distribution of collagens and laminin in the early ment. J Cell Biol 150: 1215–1221. mouse embryo. Dev Biol 76: 100–114. Myllyma¨ki SM, Tera¨va¨inen TP,Manninen A. 2011. Two dis- Lerner DW, McCoy D, Isabella AJ, Mahowald AP, Gerlach tinct integrin-mediated mechanisms contribute to apical GF,Chaudhry TA,Horner DS. 2013. A Rab10-dependent lumen formation in epithelial cells. PLoS ONE 6: e19453.

Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a027920 13 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press

K.S. Matlin et al.

Nahidiazar L, Kreft M, van den Broek B, Secades P,Manders MDCK cells and transformed MDCK cells lacking apical EMM, Sonnenberg A, Jalink K. 2015. The molecular ar- polarity. J Cell Sci 107: 527–541. chitecture of hemidesmosomes, as revealed with super- Scita G, Confalonieri S, Lappalainen P, Suetsugu S. 2008. resolution microscopy. J Cell Sci 128: 3714–3719. IRSp53: Crossing the road of membrane and actin dy- Nelson WJ. 2009. Remodeling epithelial cell organization: namics in the formation of membrane protrusions. Transitions between front–rear and apical–basal polari- Trends Cell Biol 18: 52–60. ty. Cold Spring Harb Perspect Biol 1: a000513. Smyth N, Vatansever HS, Murray P,Meyer M, Frie C, Pauls- Nishiuchi R, Takagi J, Hayashi M, Ido H, Yagi Y, Sanzen N, son M, Edgar D. 1999. Absence of basement membranes Tsuji T, Yamada M, Sekiguchi K. 2006. Ligand-binding after targeting the LAMC1 gene results in embryonic le- specificities of laminin-binding integrins: A comprehen- thality due to failure of endoderm differentiation. J Cell sive survey of laminin–integrin interactions using re- Biol 144: 151–160. combinant a3b1, a6b1, a7b1 and a6b4 integrins. Ma- trix Biol 25: 189–197. Sonnenberg A, Linders CJ, Modderman PW, Damsky CH, Aumailley M, Timpl R. 1990. Integrin recognition of dif- O’Brien LE, Jou TS, Pollack AL, Zhang Q, Hansen SH, ferent cell-binding fragments of laminin (P1, E3, E8) and Yurchenco P,Mostov KE. 2001. Rac1 orientates epithelial evidence that a6b1 but not a6b4 functions as a major apical polarity through effects on basolateral laminin as- receptor for fragment E8. J Cell Biol 110: 2145–2155. sembly. Nat Cell Biol 3: 831–838. Sorokin L, Sonnenberg A, Aumailley M, Timpl R, Ekblom P. Odenthal U, Haehn S, Tunggal P, Merkl B, Schomburg D, Frie C, Paulsson M, Smyth N. 2004. Molecular analysis of 1990. Recognition of the laminin E8 cell-binding site by laminin N-terminal domains mediating self-interac- an integrin possessing the a6 subunit is essential for tions. J Biol Chem 279: 44504–44512. epithelial polarization in developing kidney tubules. J Cell Biol 111: 1265–1273. Peng J, Awad A, Sar S, Hamze Komaiha O, Moyano R, Rayal A, Samuel D, Shewan A, Vanhaesebroeck B, Mostov K, et Te r a¨va¨inen TP, Myllyma¨ki SM, Friedrichs J, Strohmeyer N, al. 2015. Phosphoinositide 3-kinase p110d promotes lu- Moyano JV, Wu C, Matlin KS, Muller DJ, Manninen A. men formation through the enhancement of apico–basal 2013. aV-integrins are required for mechanotransduc- polarity and basal membrane organization. Nat Commun tion in MDCK epithelial cells. PLoS ONE 8: e71485. 6: 5937. Thompson BJ. 2012. Cell polarity: Models and mechanisms Poschl E. 2004. Collagen IV is essential for basement mem- from yeast, worms and flies. Development 140: 13–21. brane stability but dispensable for initiation of its assem- Timpl R, Rohde H, Robey PG, Rennard SI, Foidart JM, bly during early development. Development 131: 1619– Martin GR. 1979. Laminin—A glycoprotein from base- 1628. ment membranes. J Biol Chem 254: 9933–9937. Rasmussen JP, Reddy SS, Priess JR. 2012. Laminin is re- Tzu J, Marinkovich MP.2008. Bridging structure with func- quired to orient epithelial polarity in the C. elegans phar- tion: Structural, regulatory, and developmental role of ynx. Development 139: 2050–2060. laminins. Int J Biochem Cell Biol 40: 199–214. Roignot J, Peng X, Mostov K. 2013. Polarity in mammalian Urbano J, Torgler C, Molnar C, Tepass U, Lo´pez-Varea A, epithelial morphogenesis. Cold Spring Harb Perspect Biol Brown N, de Celis J, Martı´n-Bermudo M. 2009. Dro- 5: a013789. sophila laminins act as key regulators of basement mem- Rybakova IN, Patel JR, Ervasti JM. 2000. The dystrophin brane assembly and morphogenesis. Development 136: complex forms a mechanically strong link between the 4165–4176. sarcolemma and costameric actin. J Cell Biol 150: 1209– Urich D, Eisenberg JL, Hamill KJ, Takawira D, Chiarella SE, 1214. Soberanes S, Gonzalez A, Koentgen F, Manghi T, Hop- Sakai T, Li S, Docheva D, Grashoff C, Sakai K, Kostka G, kinson SB, et al. 2011. Lung-specific loss of the laminin Braun A, Pfeifer A, Yurchenco PD, Fa¨ssler R. 2003. In- a3 subunit confers resistance to mechanical injury. J Cell tegrin-linked kinase (ILK) is required for polarizing the Sci 124: 2927–2937. epiblast, cell adhesion, and controlling actin accumula- tion. Genes Dev 17: 926–940. Walko G, Castan˜o´n MJ, Wiche G. 2015. Molecular architec- ture and function of the hemidesmosome. Cell Tissue Res Salmivirta M, Mali M, Heino J, Hermonen J, Jalkanen M. 360: 363–378. 1994. A novel laminin-binding form of syndecan-1 (cell surface proteoglycan) produced by syndecan-1 cDNA- Wang AZ, Ojakian GK, Nelson WJ. 1990. Steps in the mor- transfected NIH-3T3 cells. Exp Cell Res 215: 180–188. phogenesis of a polarized epithelium. I: Uncoupling the Sato Y,Akitsu M, Amano Y,YamashitaK, Ide M, Shimada K, roles of cell–cell and cell–substratum contact in estab- Yamashita A, Hirano H, Arakawa N, Maki T, et al. 2013. lishing plasma membrane polarity in multicellular epi- The novel PAR-1-binding protein MTCL1 has crucial thelial (MDCK) cysts. J Cell Sci 95: 137–151. roles in organizing microtubules in polarizing epithelial Weaver VM, Lelie`vre S, Lakins JN, Chrenek MA, Jones cells. J Cell Sci 126: 4671–4683. JCR, Giancotti F, Werb Z, Bissell MJ. 2002. b4 inte- Schneiders F,Maertens B, Bose K, Li Y,Brunken W,Paulsson grin-dependent formation of polarized three-dimen- M, Smyth N, Koch M. 2007. Binding of netrin-4 to lam- sional architecture confers resistance to apoptosis in inin short arms regulates basement membrane assembly. normal and malignant mammary epithelium. Cancer J Biol Chem 282: 23750–23758. Cell 2: 205–216. Schoenenberger CA, Zuk A, Zinkl GM, Kendall D, Matlin Winder SJ, Gibson TJ, Kendrick-Jones J. 1995. Dystrophin KS. 1994. Integrin expression and localization in normal and utrophin: The missing links! FEBS Lett 369: 27–33.

14 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

Winograd-Katz SE, Fa¨ssler R, Geiger B, Legate KR. 2014. Yu W, Shewan AM, Brakeman P,Eastburn DJ, Datta A, Bry- The integrin adhesome: From genes and proteins to hu- ant DM, Fan QW, Weiss WA, Zegers MMP, Mostov KE. man disease. Nat Rev Mol Cell Biol 15: 273–288. 2008. Involvement of RhoA, ROCK I and myosin II in Yamahashi Y, Saito Y, Murata-Kamiya N, Hatakeyama M. inverted orientation of epithelial polarity. EMBO Rep 9: 2011. Polarity-regulating kinase partitioning-defective 923–929. 1b (PAR1b) phosphorylates guanine nucleotide ex- Yurchenco PD. 2011. Basement membranes: Cell scaffold- change factor H1 (GEF-H1) to regulate RhoA-dependent ings and signaling platforms. Cold Spring Harb Perspect actin cytoskeletal reorganization. J Biol Chem 286: Biol 3: a004911. 44576–44584. Yurchenco PD. 2015. Integrating activities of laminins that Yamashita K, Suzuki A, Satoh Y, Ide M, Amano Y, Masuda- drive basement membrane assembly and function. Curr Hirata M, Hayashi YK, Hamada K, Ogata K, Ohno S. Topic Membr 76: 1–30. 2010. The 8th and 9th tandem spectrin-like repeats of utrophin cooperatively form a functional unit to interact Yurchenco P,Cheng Y.1994. Laminin self-assembly: A three- with polarity-regulating kinase PAR-1b. Biochem Biophys arm interaction hypothesis for the formation of a net- Res Commun 391: 812–817. work in basement membranes. Contrib Nephrol 107: 47– Yu W,Datta A, Leroy P,O’Brien LE, Mak GZ, Jou TS, Matlin 56. KS, Mostov KE, Zegers MMP. 2005. b1-Integrin orients Zuk A, Matlin KS. 2002. Induction of a laminin isoform and epithelial polarity via Rac1 and laminin. Mol Biol Cell 16: a3b1-integrin in renal ischemic injury and repair in vivo. 433–445. Am J Physiol Renal Physiol 283: F971–F984.

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

Karl S. Matlin, Satu-Marja Myllymäki and Aki Manninen

Cold Spring Harb Perspect Biol published online February 3, 2017

Subject Collection Cell Polarity

Regulation of Cell Polarity by Exocyst-Mediated The Crumbs3 Polarity Protein Trafficking Ben Margolis Noemi Polgar and Ben Fogelgren Phosphoinositides and Membrane Targeting in Microtubule Motors in Establishment of Epithelial Cell Polarity Cell Polarity Gerald R. Hammond and Yang Hong Geri Kreitzer and Monn Monn Myat Trafficking Ion Transporters to the Apical Role of Polarity Proteins in the Generation and Membrane of Polarized Intestinal Enterocytes Organization of Apical Surface Protrusions Amy Christine Engevik and James R. Goldenring Gerard Apodaca Signaling Networks in Epithelial Tube Formation Polarized Exocytosis Ilenia Bernascone, Mariam Hachimi and Fernando Jingwen Zeng, Shanshan Feng, Bin Wu, et al. Martin-Belmonte Making Heads or Tails of It: Cell−Cell Adhesion in Regulation of Transporters and Channels by Cellular and Supracellular Polarity in Collective Membrane-Trafficking Complexes in Epithelial Migration Cells Jan-Hendrik Venhuizen and Mirjam M. Zegers Curtis T. Okamoto Laminins in Epithelial Cell Polarization: Old Membrane Transport across Polarized Epithelia Questions in Search of New Answers Maria Daniela Garcia-Castillo, Daniel J.-F. Karl S. Matlin, Satu-Marja Myllymäki and Aki Chinnapen and Wayne I. Lencer Manninen Epithelial Morphogenesis during Liver Mechanisms of Cell Polarity−Controlled Epithelial Development Homeostasis and Immunity in the Intestine Naoki Tanimizu and Toshihiro Mitaka Leon J. Klunder, Klaas Nico Faber, Gerard Dijkstra, et al. Targeting the Mucosal Barrier: How Pathogens The Biology of Ciliary Dynamics Modulate the Cellular Polarity Network Kuo-Shun Hsu, Jen-Zen Chuang and Ching-Hwa Travis R. Ruch and Joanne N. Engel Sung

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