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• W2044486518 abstract "Recent studies have greatly expanded our knowledge of initial events that lead to epithelial cell polarity. Epithelial polarity is defined, in part, by apical cell–cell tight junctions that separate the plasma membrane into the apical domain and the basolateral domain, as well as the zonula adherens that mediate intercellular adhesion. The process of epithelial polarization is closely coupled to the biogenesis of these junctions. Studies in mammalian epithelial cells and lower organisms have identified two evolutionarily conserved junctional complexes as important epithelia polarity regulators: the Crumbs complex and the partitioning defective complex. Disruption of the components of the two complexes leads to a disorder of epithelial cell polarity and defects in junction formation or maintenance. Recent discoveries have revealed more details of how the two junctional polarity complexes function to establish epithelial polarity. They also raised the question about the relationship between polarity and adhesion. Although it is widely accepted that cell–cell adhesion provides a landmark from which polarity can proceed, there are results pointing to the possibility that polarity complexes can regulate cell–cell adhesion. It seems likely that proteins that control cell adhesion and cell polarity work intimately together to establish final epithelial polarity. Recent studies have greatly expanded our knowledge of initial events that lead to epithelial cell polarity. Epithelial polarity is defined, in part, by apical cell–cell tight junctions that separate the plasma membrane into the apical domain and the basolateral domain, as well as the zonula adherens that mediate intercellular adhesion. The process of epithelial polarization is closely coupled to the biogenesis of these junctions. Studies in mammalian epithelial cells and lower organisms have identified two evolutionarily conserved junctional complexes as important epithelia polarity regulators: the Crumbs complex and the partitioning defective complex. Disruption of the components of the two complexes leads to a disorder of epithelial cell polarity and defects in junction formation or maintenance. Recent discoveries have revealed more details of how the two junctional polarity complexes function to establish epithelial polarity. They also raised the question about the relationship between polarity and adhesion. Although it is widely accepted that cell–cell adhesion provides a landmark from which polarity can proceed, there are results pointing to the possibility that polarity complexes can regulate cell–cell adhesion. It seems likely that proteins that control cell adhesion and cell polarity work intimately together to establish final epithelial polarity. The bodies of Metazoa enclose numerous highly organized cavities and compartments that are lined by sheets of epithelial cells. To protect the integrity of these cavities and compartments, epithelial cells have developed various intercellular junctions so that they are tightly packed and strongly adherent to one another. These junctions include the tight junctions (TJs) and the zonula adherens (ZA), which together comprise the apical junctional complexes. In addition to the protection function, epithelial cells are highly polarized and they mediate diverse polarized activities including absorption, secretion, transcellular transport, and sensation. The polarization of epithelial cells is reflected by the asymmetric distribution of proteins and lipids into the apical and basolateral surfaces. The apical domain faces the lumen while the basolateral domain consists of the basal domain that contacts the basement membrane and the lateral domain that contacts the neighboring cells. The process of apical–basal polarization is closely coupled to the establishment of the apical junctional complexes. The TJ, also referred to as the zonula occludens, is the apical most structure of the intercellular junctional complex. It carries out two important functions: first, it forms tight seals between epithelial cells and creates a selectively permeable barrier to diffusion through the intercellular space, namely the barrier function;1.Diamond J.M. Twenty-first Bowditch lecture. The epithelial junction: bridge, gate, and fence.Physiologist. 1977; 20: 10-18PubMed Google Scholar second, it physically separates the apical and basolateral membranes and prevents the intermixing of the components of the two membrane domains, namely the fence function.2.Dragsten P.R. Blumenthal R. Handler J.S. Membrane asymmetry in epithelia: is the tight junction a barrier to diffusion in the plasma membrane?.Nature. 1981; 294: 718-722Crossref PubMed Google Scholar TJs are revealed to be the tight apposition of neighboring epithelial cells in conventional electron micrographs, while in freeze-fracture electron micrographs, they appear as a continuous network of parallel and interconnected strands that circumscribe the apex of lateral membranes.3.Claude P. Morphological factors influencing transepithelial permeability: a model for the resistance of the zonula occludens.J Membr Biol. 1978; 39: 219-232Crossref PubMed Scopus (425) Google Scholar TJs are composed of three families of transmembrane proteins: occludin, claudins, and junctional adhesion molecules. They reach across the intercellular space and connect the membranes of adjacent epithelial cells (reviewed in Shin et al.4.Shin K. Fogg V.C. Margolis B. Tight junctions and cell polarity.Annu Rev Cell Dev Biol. 2006; 22: 207-235Crossref PubMed Scopus (372) Google Scholar). The functional equivalent structure in Drosophila epithelia is the septate junction, which lies basal to the ZA and has a different molecular composition.5.Knust E. Bossinger O. Composition and formation of intercellular junctions in epithelial cells.Science. 2002; 298: 1955-1959Crossref PubMed Scopus (282) Google Scholar The adhesion between epithelial cells is primarily contributed by the ZA, which is also called the adherens junction in vertebrates. It is an adhesive belt that encircles the cell just below the apical surface, and it lays basal to TJs in mammalian epithelial cells. Cadherins represent the primary structural component of ZA and their calcium-dependent trans-dimerization provides the adhesion between neighboring epithelial cells. Cryo-electron microscopy of the adherens junction reveals rod-like structures extending from the extracellular surface into the intercellular space, and it is suggested that they represent the extracellular domains of E-cadherin.6.Miyaguchi K. Ultrastructure of the zonula adherens revealed by rapid-freeze deep-etching.J Struct Biol. 2000; 132: 169-178Crossref PubMed Scopus (41) Google Scholar Other adherens junction transmembrane components include Nectins and nectin-like molecules, and they trans-interact in a calcium-independent manner.7.Nakanishi H. Takai Y. Roles of nectins in cell adhesion, migration and polarization.Biol Chem. 2004; 385: 885-892Crossref PubMed Scopus (37) Google Scholar The apical junctional complexes are dynamic structures. They undergo dramatic rearrangement and redistribution during embryonic development. The cytoplasmic domains of the junctional structural components are associated with various adaptor proteins as well as signaling elements, and they are linked to the cytoskeleton. These connections integrate the dynamics of cell–cell junctions with a number of cellular processes such as migration, proliferation, differentiation as well as pathological processes that include tumor cell metastasis, infiltration, and microbial infections. The formation of junctional complexes is intimately linked to cell polarization. Recent studies in mammalian systems and lower organisms have revealed several evolutionarily conserved protein complexes that regulate cell polarization. The complicated interplay among these complexes and their orderly function regulate the establishment of epithelial cell polarity and the cell–cell junctions. Studies of the apical membrane domain have focused on two major complexes, the Crumbs (CRB) complex and the partitioning defective (PAR) complex.8.Margolis B. Borg J.P. Apicobasal polarity complexes.J Cell Sci. 2005; 118: 5157-5159Crossref PubMed Scopus (76) Google Scholar These complexes are important in recognizing the initial polarization cues, and they play a pivotal role in regulating the establishment of apical junctional complexes. Work in both the mammalian and Drosophila systems have demonstrated that the CRB complex and the PAR complex have a conserved function in the establishment and maintenance of apical–basal polarity. In this review, the composition and function of these complexes will be summarized, with an emphasis on recent literature that highlight novel aspects of their structure and function. The CRB complex is composed of three proteins: CRB, protein associated with Lin Seven 1 (PALS1), and PALS1-associated tight junction protein (PATJ) (see Figure 1). In Drosophila, CRB is localized to the apical membrane and the subapical region. The subapical region represents a spot where the apical membrane ends and the lateral membrane begins. In mammalian cells, this is the site of the TJ, but in Drosophila no junction is localized at this point. In Drosophila, CRB is an important apical membrane determinant, as the plasma membrane-associated expression of CRB is necessary and sufficient to confer apical character on a membrane domain, and overexpression of CRB results in an expansion of the apical plasma membrane with concomitant reduction of the basolateral domain.9.Wodarz A. Hinz U. Engelbert M. Knust E. Expression of crumbs confers apical character on plasma membrane domains of ectodermal epithelia of Drosophila.Cell. 1995; 82: 67-76Abstract Full Text PDF PubMed Scopus (437) Google Scholar Drosophila CRB is a transmembrane protein with 30 EGF-like and 4 laminin A G-domain-like repeats in its extracellular domain. The exact function of this large extracellular domain is not clear, since a truncated form of CRB devoid of the entire extracellular domain is sufficient to rescue the CRB mutant Drosophila embryo.9.Wodarz A. Hinz U. Engelbert M. Knust E. Expression of crumbs confers apical character on plasma membrane domains of ectodermal epithelia of Drosophila.Cell. 1995; 82: 67-76Abstract Full Text PDF PubMed Scopus (437) Google Scholar The short cytoplasmic domain of CRB contains two functionally important motifs.10.Klebes A. Knust E. A conserved motif in Crumbs is required for E-cadherin localisation and zonula adherens formation in Drosophila.Curr Biol. 2000; 10: 76-85Abstract Full Text Full Text PDF PubMed Google Scholar The 4.1/ezrin/radaxin/moesin (FERM) domain-binding motif of zebrafish CRB binds an FERM protein Moe, and it has been shown recently that Yurt, the Drosophila ortholog of zebrafish Moe, interacts with the Drosophila CRB FERM-binding motif.11.Jensen A.M. Westerfield M. Zebrafish mosaic eyes is a novel FERM protein required for retinal lamination and retinal pigmented epithelial tight junction formation.Curr Biol. 2004; 14: 711-717Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar,12.Laprise P. Beronja S. Silva-Gagliardi N.F. et al.The FERM protein Yurt is a negative regulatory component of the Crumbs complex that controls epithelial polarity and apical membrane size.Dev Cell. 2006; 11: 363-374Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar This interaction is conserved between the mammalian Yurt orthologs YMO1 and EHM2 and the mammalian CRB proteins, and it may be part of a negative feedback loop that regulates CRB activity.12.Laprise P. Beronja S. Silva-Gagliardi N.F. et al.The FERM protein Yurt is a negative regulatory component of the Crumbs complex that controls epithelial polarity and apical membrane size.Dev Cell. 2006; 11: 363-374Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar The C-terminal postsynaptic density/discs large/zonula occludens (PDZ) domain-binding motif, on the other hand, is recognized by the PDZ domain of Stardust, the Drosophila homolog of PALS1.13.Bachmann A. Schneider M. Theilenberg E. et al.Drosophila Stardust is a partner of Crumbs in the control of epithelial cell polarity.Nature. 2001; 414: 638-643Crossref PubMed Scopus (175) Google Scholar,14.Hong Y. Stronach B. Perrimon N. et al.Drosophila Stardust interacts with Crumbs to control polarity of epithelia but not neuroblasts.Nature. 2001; 414: 634-638Crossref PubMed Scopus (160) Google Scholar The CRB–Stardust interaction is important for the biogenesis of the ZA, which is a pivotal step in the establishment of epithelial integrity.15.Grawe F. Wodarz A. Lee B. et al.The Drosophila genes crumbs and stardust are involved in the biogenesis of adherens junctions.Development. 1996; 122: 951-959PubMed Google Scholar,16.Tepass U. Crumbs, a component of the apical membrane, is required for zonula adherens formation in primary epithelia of Drosophila.Dev Biol. 1996; 177: 217-225Crossref PubMed Scopus (153) Google Scholar Three mammalian CRB proteins have been identified, all of which consist of a transmembrane domain and an intracellular domain with the conserved FERM- and PDZ-binding motifs. CRB1 is the human ortholog of Drosophila CRB, and it is expressed primarily in the eye and brain. Mutations in CRB1 cause various diseases including Leber congenital amaurosis and retinitis pigmentosa.17.den Hollander A.I. ten Brink J.B. de Kok Y.J. et al.Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12).Nat Genet. 1999; 23: 217-221Crossref PubMed Scopus (250) Google Scholar,18.den Hollander A.I. Heckenlively J.R. van den Born L.I. et al.Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene.Am J Hum Genet. 2001; 69: 198-203Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar CRB2 has not been extensively characterized to date. CRB3 is expressed ubiquitously in epithelial tissues, and unlike Drosophila CRB and the other two mammalian CRB proteins has a very short extracellular domain. CRB3 is localized to the apical membrane of mammalian epithelial cells and concentrated to TJs, where it interacts with PALS1 with its C-terminal PDZ-binding motif.19.Roh M.H. Makarova O. Liu C.J. et al.The Maguk protein, Pals1, functions as an adapter, linking mammalian homologues of Crumbs and Discs Lost.J Cell Biol. 2002; 157: 161-172Crossref PubMed Scopus (221) Google Scholar,20.Makarova O. Roh M.H. Liu C.J. et al.Mammalian Crumbs3 is a small transmembrane protein linked to protein associated with Lin-7 (Pals1).Gene. 2003; 302: 21-29Crossref PubMed Scopus (115) Google Scholar Overexpression of CRB3 in Madin–Darby canine kidney (MDCK) cells leads to delayed TJ formation and a disruption of cell polarity.21.Lemmers C. Michel D. Lane-Guermonprez L. et al.CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells.Mol Biol Cell. 2004; 15: 1324-1333Crossref PubMed Scopus (156) Google Scholar,22.Roh M.H. Fan S. Liu C.J. Margolis B. The Crumbs3-Pals1 complex participates in the establishment of polarity in mammalian epithelial cells.J Cell Sci. 2003; 116: 2895-2906Crossref PubMed Scopus (119) Google Scholar Introducing CRB3 into the mammary epithelial MCF10A cells, which express little endogenous CRB3, induces the formation of TJs.23.Fogg V.C. Liu C.J. Margolis B. Multiple regions of Crumbs3 are required for tight junction formation in MCF10A cells.J Cell Sci. 2005; 118: 2859-2869Crossref PubMed Scopus (75) Google Scholar CRB3 has also been shown to localize to the primary cilia and it is required for ciliogenesis of MDCK cells.24.Fan S. Hurd T.W. Liu C.J. et al.Polarity proteins control ciliogenesis via kinesin motor interactions.Curr Biol. 2004; 14: 1451-1461Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar PALS1 is a membrane-associated guanylate kinase protein. It consists of two L27 domains, a PDZ domain, an SH3 domain, a band 4.1-binding domain, and a GUK domain.25.Kamberov E. Makarova O. Roh M. et al.Molecular cloning and characterization of Pals, proteins associated with mLin-7.J Biol Chem. 2000; 275: 11425-11431Crossref PubMed Scopus (121) Google Scholar The two L27 domains mediate its interaction with PATJ and Lin-7, respectively,19.Roh M.H. Makarova O. Liu C.J. et al.The Maguk protein, Pals1, functions as an adapter, linking mammalian homologues of Crumbs and Discs Lost.J Cell Biol. 2002; 157: 161-172Crossref PubMed Scopus (221) Google Scholar,25.Kamberov E. Makarova O. Roh M. et al.Molecular cloning and characterization of Pals, proteins associated with mLin-7.J Biol Chem. 2000; 275: 11425-11431Crossref PubMed Scopus (121) Google Scholar and the PDZ domain binds CRB3 in mammalian epithelial cells.19.Roh M.H. Makarova O. Liu C.J. et al.The Maguk protein, Pals1, functions as an adapter, linking mammalian homologues of Crumbs and Discs Lost.J Cell Biol. 2002; 157: 161-172Crossref PubMed Scopus (221) Google Scholar,20.Makarova O. Roh M.H. Liu C.J. et al.Mammalian Crumbs3 is a small transmembrane protein linked to protein associated with Lin-7 (Pals1).Gene. 2003; 302: 21-29Crossref PubMed Scopus (115) Google Scholar The function of the C-terminal SH3, band 4.1-binding, and GUK domains is not known, but a recent report shows that they are an essential part of the PALS1 protein.26.Wang Q. Chen X.W. Margolis B. PALS1 regulates E-cadherin trafficking in mammalian epithelial cells.Mol Biol Cell. 2007; 18: 874-885Crossref PubMed Scopus (51) Google Scholar In addition to these domains, the N-terminal U1 region of both PALS1 and Stardust binds PAR6 (see below).27.Hurd T.W. Gao L. Roh M.H. et al.Direct interaction of two polarity complexes implicated in epithelial tight junction assembly.Nat Cell Biol. 2003; 5: 137-142Crossref PubMed Scopus (280) Google Scholar,28.Wang Q. Hurd T.W. Margolis B. Tight junction protein Par6 interacts with an evolutionarily conserved region in the amino terminus of PALS1/stardust.J Biol Chem. 2004; 279: 30715-30721Crossref PubMed Scopus (61) Google Scholar RNA interference-mediated inhibition of PALS1 expression in mammalian epithelial cells leads to severe defects in cell–cell junction formation and cell polarity.26.Wang Q. Chen X.W. Margolis B. PALS1 regulates E-cadherin trafficking in mammalian epithelial cells.Mol Biol Cell. 2007; 18: 874-885Crossref PubMed Scopus (51) Google Scholar,29.Straight S.W. Shin K. Fogg V.C. et al.Loss of PALS1 expression leads to tight junction and polarity defects.Mol Biol Cell. 2004; 15: 1981-1990Crossref PubMed Scopus (105) Google Scholar Stardust, the Drosophila ortholog of PALS1, acts downstream of CRB to regulate the formation of the ZA and epithelial morphogenesis in flies, and the mutations in Stardust produce a phenotype nearly identical to that of the CRB mutant.30.Tepass U. Knust E. Crumbs and stardust act in a genetic pathway that controls the organization of epithelia in Drosophila melanogaster.Dev Biol. 1993; 159: 311-326Crossref PubMed Scopus (118) Google Scholar The PALS1 ortholog in zebrafish is Nagie Oko. It is essential in the biogenesis of photoreceptor cells in the retina,31.Wei X. Malicki J. Nagie Oko, encoding a MAGUK-family protein, is essential for cellular patterning of the retina.Nat Genet. 2002; 31: 150-157Crossref PubMed Scopus (132) Google Scholar and it is required for myocardial coherence and heart tube elongation in concert with Heart and Soul/PKCτ.32.Rohr S. Bit-Avragim N. Abdelilah-Seyfried S. Heart and soul/PRKCi and nagie oko/Mpp5 regulate myocardial coherence and remodeling during cardiac morphogenesis.Development. 2006; 133: 107-115Crossref PubMed Scopus (57) Google Scholar A recent report suggests that Na+,K+-ATPase acts in the same genetic pathway as Nagie Oko in cardiac morphogenesis.33.Cibrian-Uhalte E. Langenbacher A. Shu X. et al.Involvement of zebrafish Na+,K+ ATPase in myocardial cell junction maintenance.J Cell Biol. 2007; 176: 223-230Crossref PubMed Scopus (18) Google Scholar PATJ, the third member of the CRB complex, contains 1 L27 domain at the N terminus and 10 PDZ domains. It interacts with PALS1 through L27 domain dimerization,19.Roh M.H. Makarova O. Liu C.J. et al.The Maguk protein, Pals1, functions as an adapter, linking mammalian homologues of Crumbs and Discs Lost.J Cell Biol. 2002; 157: 161-172Crossref PubMed Scopus (221) Google Scholar,34.Lemmers C. Medina E. Delgrossi M.H. et al.hINADl/PATJ, a homolog of discs lost, interacts with crumbs and localizes to tight junctions in human epithelial cells.J Biol Chem. 2002; 277: 25408-25415Crossref PubMed Scopus (111) Google Scholar and this interaction is important for the stability of PATJ in mammalian epithelial cells.26.Wang Q. Chen X.W. Margolis B. PALS1 regulates E-cadherin trafficking in mammalian epithelial cells.Mol Biol Cell. 2007; 18: 874-885Crossref PubMed Scopus (51) Google Scholar,29.Straight S.W. Shin K. Fogg V.C. et al.Loss of PALS1 expression leads to tight junction and polarity defects.Mol Biol Cell. 2004; 15: 1981-1990Crossref PubMed Scopus (105) Google Scholar PATJ serves as a scaffold and its multiple PDZ domains interact with various junction structural components, peripheral proteins, and signaling elements, which include claudin-1, zonula occludens-3, and angiomotin.35.Roh M.H. Liu C.J. Laurinec S. Margolis B. The carboxyl terminus of zona occludens-3 binds and recruits a mammalian homologue of discs lost to tight junctions.J Biol Chem. 2002; 277: 27501-27509Crossref PubMed Scopus (102) Google Scholar,36.Wells C.D. Fawcett J.P. Traweger A. et al.A Rich1/Amot complex regulates the Cdc42 GTPase and apical-polarity proteins in epithelial cells.Cell. 2006; 125: 535-548Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar Knockdown of PATJ in MDCK cells leads to a delay in TJ formation and cell polarity defects,37.Shin K. Straight S. Margolis B. PATJ regulates tight junction formation and polarity in mammalian epithelial cells.J Cell Biol. 2005; 168: 705-711Crossref PubMed Scopus (114) Google Scholar and the adenovirus protein E4-ORF1 induces the disassembly of TJs by interacting with PATJ and sequestering it from the junctions.38.Latorre I.J. Roh M.H. Frese K.K. et al.Viral oncoprotein-induced mislocalization of select PDZ proteins disrupts tight junctions and causes polarity defects in epithelial cells.J Cell Sci. 2005; 118: 4283-4293Crossref PubMed Scopus (72) Google Scholar Drosophila PATJ (DmPATJ), on the other hand, is a much smaller protein with only four PDZ domains besides the L27 domain. DmPATJ stabilizes the CRB complex and is required for rhabdomere stalk membrane maintenance during photoreceptor development.39.Richard M. Grawe F. Knust E. DPATJ plays a role in retinal morphogenesis and protects against light-dependent degeneration of photoreceptor cells in the Drosophila eye.Dev Dyn. 2006; 235: 895-907Crossref PubMed Scopus (57) Google Scholar Moreover, DmPATJ has been shown to interact with Frizzled, and it recruits atypical protein kinase C (aPKC) to Frizzled, resulting in the inhibition of Frizzled activity.40.Djiane A. Yogev S. Mlodzik M. The apical determinants aPKC and dPatj regulate Frizzled-dependent planar cell polarity in the Drosophila eye.Cell. 2005; 121: 621-631Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar This study indicates that DmPATJ could be a linker between the apical–basal polarity pathway and the planar cell polarity pathway. Recent work indicates that PATJ plays a role in regulating the exocytosis of CRB3. Michel et al.41.Michel D. Arsanto J.P. Massey-Harroche D. et al.PATJ connects and stabilizes apical and lateral components of tight junctions in human intestinal cells.J Cell Sci. 2005; 118: 4049-4057Crossref PubMed Scopus (70) Google Scholar reported that knockdown of PATJ in Caco2 cells causes the mislocalization of CRB3. CRB3 accumulates in a subapical compartment, and the CRB3-positive compartment partially overlaps with early endosomes indicated by EEA1 staining. Our group observed similar CRB3 retention in PATJ-depleted MDCK cells, and the defect can be rescued when exogenous PATJ is re-introduced (unpublished data). These results suggest that PATJ can control the formation of the apical membrane by regulating CRB3 exocytosis. It was also recently reported that a Drosophila syntaxin mutant leads to expansion of the apical membrane similar to that of CRB overexpression, presumably because defective endocytosis leads to excessive CRB on the apical membrane.42.Lu H. Bilder D. Endocytic control of epithelial polarity and proliferation in Drosophila.Nat Cell Biol. 2005; 7: 1232-1239Crossref PubMed Scopus (46) Google Scholar Therefore, it appears that a balance between exocytosis and endocytosis of CRB is critical for the proper maintenance of the apical membrane domain. The six par genes and protein kinase C3 were uncovered in a screen for defects in zygotic-axis specification in Caenorhabditis elegans.43.Kemphues K.J. Priess J.R. Morton D.G. Cheng N.S. Identification of genes required for cytoplasmic localization in early C. elegans embryos.Cell. 1988; 52: 311-320Abstract Full Text PDF PubMed Scopus (509) Google Scholar The par genes encode primarily scaffolding proteins and serine–threonine kinases.44.Macara I.G. Parsing the polarity code.Nat Rev Mol Cell Biol. 2004; 5: 220-231Crossref PubMed Scopus (233) Google Scholar PAR3 and PAR6, two scaffolding proteins as well as atypical PKC constitute the apical polarity PAR complex. PAR3, PAR6, and aPKC physically interact in a complex fashion (see Figure 1). The aPKC-binding domain of PAR3 directly binds to the kinase domain of aPKC,45.Tabuse Y. Izumi Y. Piano F. et al.Atypical protein kinase C cooperates with PAR-3 to establish embryonic polarity in Caenorhabditis elegans.Development. 1998; 125: 3607-3614Crossref PubMed Google Scholar the PAR3–PAR6 interaction is between the PDZ domain of PAR6 and one of the three PDZ domains of PAR3, and the PB1 domain dimerization mediates the PAR6–aPKC interaction.46.Qiu R.G. Abo A. Steven Martin G. A human homolog of the C. elegans polarity determinant Par-6 links Rac and Cdc42 to PKCzeta signaling and cell transformation.Curr Biol. 2000; 10: 697-707Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar,47.Noda Y. Kohjima M. Izaki T. et al.Molecular recognition in dimerization between PB1 domains.J Biol Chem. 2003; 278: 43516-43524Crossref PubMed Scopus (58) Google Scholar PAR3 can also oligomerize through its N terminus.48.Benton R. St Johnston D. A conserved oligomerization domain in Drosophila Bazooka/PAR-3 is important for apical localization and epithelial polarity.Curr Biol. 2003; 13: 1330-1334Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar,49.Mizuno K. Suzuki A. Hirose T. et al.Self-association of PAR-3-mediated by the conserved N-terminal domain contributes to the development of epithelial tight junctions.J Biol Chem. 2003; 278: 31240-31250Crossref PubMed Scopus (69) Google Scholar In mammals, there are at least three splice variants of PAR3, four isoforms of PAR6, and two isoforms of aPKC, adding to the complexity.50.Gao L. Macara I.G. Joberty G. Multiple splice variants of Par3 and of a novel related gene, Par3L, produce proteins with different binding properties.Gene. 2002; 294: 99-107Crossref PubMed Scopus (42) Google Scholar, 51.Gao L. Macara I.G. Isoforms of the polarity protein par6 have distinct functions.J Biol Chem. 2004; 279: 41557-41562Crossref PubMed Scopus (42) Google Scholar, 52.Yoshii T. Mizuno K. Hirose T. et al.sPAR-3, a splicing variant of PAR-3, shows cellular localization and an expression pattern different from that of PAR-3 during enterocyte polarization.Am J Physiol Gastrointest Liver Physiol. 2005; 288: G564-G570Crossref PubMed Scopus (4) Google Scholar The Drosophila ortholog of PAR3 is Bazooka (Baz), which directly binds Drosophila aPKC and PAR6.53.Wodarz A. Ramrath A. Grimm A. Knust E. Drosophila atypical protein kinase C associates with Bazooka and controls polarity of epithelia and neuroblasts.J Cell Biol. 2000; 150: 1361-1374Crossref PubMed Scopus (285) Google Scholar,54.Rolls M.M. Albertson R. Shih H.P. et al.Drosophila aPKC regulates cell polarity and cell proliferation in neuroblasts and epithelia.J Cell Biol. 2003; 163: 1089-1098Crossref PubMed Scopus (165) Google Scholar The small GTPase Cdc42 has been known to be a central cell polarity regulator in many contexts, and the discovery of PAR6 as its effector largely explains this role. PAR6 binds Cdc42-GTP through its semi-Cdc42/Rac interacting binding domain in concert with a part of the PDZ domain.46.Qiu R.G. Abo A. Steven Martin G. A human homolog of the C. elegans polarity determinant Par-6 links Rac and Cdc42 to PKCzeta signaling and cell transformation.Curr Biol. 2000; 10: 697-707Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 55.Joberty G. Petersen C. Gao L. Macara I.G. The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42.Nat Cell Biol. 2000; 2: 531-539Crossref PubMed Scopus (583) Google Scholar, 56.Johansson A. Driessens M. Aspenstrom P. The mammalian homologue of the Caenorhabditis elegans polarity protein PAR-6 is a binding partner for the Rho GTPases Cdc42 and Rac1.J Cell Sci. 2000; 113: 3267-3275PubMed Google Scholar, 57.Lin D. Edwards A.S. Fawcett J.P. et al.A mammalian PAR-3–PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity.Nat Cell Biol. 2000; 2: 540-547Crossref PubMed Scopus (44) Google Scholar The involvement of the PDZ domain was elucidated by the crystal structure of PAR6 bound to Cdc42-GTP, which showed that the semi-Cdc42/Rac interacting binding domain and the adjacent PDZ domain form a continuous eight-stranded sheet that binds Cdc42.58.Garrard S.M" @default.
• W2044486518 created "2016-06-24" @default.
• W2044486518 creator A5068110148 @default.
• W2044486518 creator A5078091189 @default.
• W2044486518 date "2007-12-01" @default.
• W2044486518 modified "2023-10-15" @default.
• W2044486518 title "Apical junctional complexes and cell polarity" @default.
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