OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section
Atlas of Genetics and Cytogeneticsin Oncology and HaematologyOPEN ACCESS JOURNAL AT INIST-CNRSGene SectionReviewDLG1 (discs, large homolog 1 (Drosophila))Paola Massimi, Lawrence BanksInternational Centre for Genetic Engeneering and Biotechnology (ICGEB), Trieste, Italy (PM, LB)Published in Atlas Database: May 2009Online updated version: ch3q29.htmlDOI: 10.4267/2042/44730This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematologypossess a class I PDZ binding motif (Morais Cabral etal., 1996).There are two major transcripts of DLG1 gene. One isDiscs large homolog 1 isoform 1, which contains anadditional exon (99 nucleotides) in the 5' part of theDlg homology repeats (DHR) domain and lacks anexon in the 3' coding region, resulting in a shorterprotein (isoform 1), compared to isoform 2. The secondis Discs large homolog 1 isoform 2, which representsthe longer transcript and encodes the longer isoform.This second transcript is alternatively spliced with aninsertion of 34 nucleo-tides in the region between theSH3 and GUK (isoform 2). Another alternative splicehas an inser-tion of 100 nucleotides and the resultingtranscript is called Discs large homolog 1 isoform 3.In conclusion, the protein is regulated by a severaldifferent alternative splicing events (Mori et al., 1998)resulting in a number of different combination ofspliced variants (which give raise to at least 7 isoformssuch as I1I2, I1I3, etc.) (see table), some of which aretranscribed in a tissue-specific manner (Lue et al.,1996; McLaughlin et al., 2002).IdentityOther names: DKFZp761P0818; DKFZp781B0426;DLGH1; SAP-97; SAP97; dJ1061C18.1.1; HdlgHGNC (Hugo): DLG1Location: 3q29DNA/RNADescriptionThe DLG1 gene consists of 250,017 bases on the 3q29locus of chromosome 3 (Azim et al., 1995).TranscriptionThe DLG1 gene encodes a 960 amino-acid protein of100355 Da with several distinct domains. A 1310-bpfragment of the 5' flanking region of the DLG1 gene,corresponding to nucleotide (nt) - 1217/ 93 containsthe promoter sequence plus the consensus-binding sitesfor the Snail family of transcription factors that repressthe expression of some epithelial markers and are upregulated in a variety of tumours. Snail transcriptionfactors repress the transcriptional activity of the DLG1promoter (Cavatorta et al., 2008). The carboxylterminal 179 aa show strong homology (35.5%) toyeast guanylate kinase (GUK) an enzyme that transfersa phosphate group from ATP to GMP, converting it toGDP, although DLG1 has no enzymatic activity.DLG1 contains also a 59 aa SH3 (Src homolgy 3)domain, which mainly mediates binding to otherproteins. The N terminal half of the molecule containsthree copies of the 80-90 aa motif calledDHR/GLGF/PDZ (PSD-95, Dlg, ZO-1), which mediatethe binding of the protein to the plasma membrane andconfers binding to proteins thatAtlas Genet Cytogenet Oncol Haematol. 2010; 14(4)PseudogeneNone.ProteinDescriptionThe 'discs large' protein, Dlg1, is part of a family ofproteins termed MAGUKs (membrane-associatedguanylate kinase homologs). MAGUKs are loca-lizedat the membrane-cytoskeleton interface, usually at cellcell junctions, where they appear to have bothstructural and signaling roles. DLG1 probably exists asan homotetramer.368
DLG1 (discs, large homolog 1 (Drosophila))Massimi P, Banks LDiagram of DLG1 gene organization and of the two major encoded transcript variants.Atlas Genet Cytogenet Oncol Haematol. 2010; 14(4)369
DLG1 (discs, large homolog 1 (Drosophila))Massimi P, Banks LDiagram of the DLG1 protein with its characteristic domains and the main protein-protein interactions at the cell-cell junctions.Ultrastructural analysis of hDlg by low angle rotaryshadow electron microscopy revealed that the fulllength hDlg protein as well as its amino-terminaldomain exhibits a highly flexible irregular shape.Further evaluation of the self-association state of hDlgusing sedimentation equilibrium centrifugation, matrixassisted laser desorption/ionization mass spectrometryand chemical cross-linking techniques confirmed thatthe oligomerization site of hDlg is contained within itsamino-terminal domain. This is mediated by a uniqueL27 domain which regulates multimerization of hDlginto dimeric and tetrameric species in solution, andsedimentation velocity experiments demonstrated thatthe oligomerization domain exists as an elongatedtetramer in solution (Marfatia et al., 2000). Thus, theL27 domain regulate DLG1 self-association. The Nterminal alternatively spliced region is capable ofbinding several SH3 domains and also moderates thelevel of protein oligomerization.Specific binding partners are known for each domain ofDLG1, and different modes of intramolecularinteractions have been proposed that particularlyinvolve the SH3 and GUK domains and the so-calledHOOK region located between these two domains.Atlas Genet Cytogenet Oncol Haematol. 2010; 14(4)DLG1 binds to the membrane cytoskeletal 4.1 proteinthrough its C-terminal region (Hanada et al., 2003), viaa motif encoded by the alternatively spliced exonlocated between the SH3 and the C-terminal guanylatekinase-like domains (Isoform I3). The PDZ1-2 modulesand the I3 domain associate with the 30-kD NH2terminal domain of protein 4.1 that is conserved inezrin/radixin/moesin (ERM) proteins module (Lue etal., 1996; Bonilha and Rodriguez-Boulan, 2001).Indeed SAP97 also interacts with ezrin, an actinbinding protein crucial for morphogenesis of apicalmicrovilli and basolateral infoldings in retinal pigmentepithelial (RPE) cells.Through the PDZ2 domain the protein also interactswith the carboxyl-terminal S/TXV motif of the APC(Adenomatous polyposis coli) tumour suppressorprotein and plays an important role in transducing theAPC cell cycle blocking signal (Makino et al., 1997;Ishidate et al., 2000; Mimori-Kiyosue et al., 2007). Inaddition, APC appears to mediate the interactionbetween DLG1, beta-catenin and the actincytoskeleton. Beta-catenin is complexed with gammacatenin and alpha-catenin, through which DLG1 bindsto E-cadherin (Reuver et al., 1998). Moreover, the Src370
DLG1 (discs, large homolog 1 (Drosophila))Massimi P, Banks Lbrain and transfected MDCK cells. This interactionrequires the MRE (MAGUK recruitment) domain ofSAP97 and surprisingly, both the L27N and L27carboxyl-terminal (L27C) domains of DLG3. SAP97can interact with the MAGUK protein, DLG2, but notthe highly related protein, PALS2. The ability ofSAP97 to interact with multiple MAGUK proteins islikely to be important for the targeting of specificprotein complexes in polarized cells (Karnak et al.,2002).The kinesin-3 motor protein, GAKIN, is regulated bythe direct binding of its protein cargo hDlg. Directbinding of the SH3-I3-GUK module of hDlg to theMAGUK Binding Stalk domain of GAKIN activatesthe microtubule-stimulated ATPase activity of GAKIN(Hanada et al., 2000; Yamada et al., 2007; Unno et al.,2008).Using the yeast two-hybrid screening a novel proteinfrom a human cDNA library was isolated as a bindingpartner of DLG1. This protein is a component of TJsrather than AJs (where DLG1 is normally found), evenif it is incorporated into TJs after TJ strands are formed,and therefore it is named Pilt (protein incorporated laterinto TJs) (Kawabe et al., 2001).DLG1 is known to interact also with several humanvirus oncoproteins : HPV E6 (Lee et al., 1997; Kiyonoet al.,1997, Gardiol et al., 1999) through its C-terminusand DLG1 PDZ2 domain and as result is subjected toproteasome mediated degradation; HTLV-1 TAX(Suzuki et al., 1999), via the C-terminus of Tax and thePDZ domain of hDLG. Tax prevents the binding ofhDLG to APC tumor suppressor gene product,suggesting the mechanism for inhibition of hDLGfunction; Adenovirus type 9 E4-ORF1 specificallyrequires endogenous DLG1 to provoke oncogenicactivation of phosphatidyl-inositol 3-kinase (PI3K) incells. E4-ORF1 binding to Dlg1 on ts PDZ domaintriggers the resulting complex to translocate to theplasma membrane and, at this site, to promote Rasmediated PI3K activation, suggesting a surprisingoncogenic function for DLG1 in virus-mediatedcellular transformation (Frese et al., 2006; Chung et al.,2007).hDlg also binds the tumor endothelial marker 5(TEM5), a seven-pass transmembrane protein that ishomologous to the B family of G-protein-coupledreceptors (GPCRs). The PDZ domains of hDlg boundthe C-terminal PDZ-binding motif of TEM5. DLG1 isfurthermore able to interact with a novel seven-passtransmembrane protein, which was homologous toTEM5, and was named here a TEM5-like protein(TEM5-like) (Yamamoto et al., 2004).SAP97/hDlg as a scaffold protein is also targeted to thecytoskeleton by its association with the proteinguanylate kinase-associated protein (GKAP), which ispart of the postsynaptic scaffold in neuronal cells(Sabio et al., 2005). Moreover, hDlg is believed tohomology domain 2 of the p85/PI3K and hDlg areassociatedwith E-cadherin in a commonmacromolecular complex in differentiating intestinalcells, and in this way hDlg may be a determinant in Ecadherin-mediated adhesion and signaling inmammalian epithelial cells (Laprise et al., 2004).DLG1 was demonstrated also to bind with voltagegated or Kv K( ) channels through its PDZ domains(Hanada et al., 1997; Tiffany et al., 2000; Eldstrom etal., 2003). The complex formation involves theassociation of Cav-3 with a segment of SAP97localized between its PDZ2 and PDZ3 domains. Thisscaffolding complex can recruit Kv1.5 to form atripartite complex in which each of the threecomponents interacts with the other two. Theseinteractions between Kv1.5, Cav3 and SAP97 mayconstitute the nucleation site for the assembly ofmacromolecular containing potassium channels andthereby regulates cellular potential currents (Folco etal., 2004).Hanada showed by immunoblot analysis thatimmunoprecipitates of DLG1 in T lymphocytes containthe Src family tyrosine kinase p56 (lck). Bindinganalysis demonstrated that LCK interacts with theproline-rich N-terminal domain of DLG1, suggestingthat DLG1 may function as a coupler of tyrosine kinaseand a voltage-gated potassium channel in Tlymphocytes.The HOOK region of DLG1 is also a specific site forcalmodulin binding and interaction of SAP97 toimmobilized calmodulin is strictly calcium-depen-dent(Paarmann et al., 2002). The calmodulin seems toregulate the intramolecular interaction between theSH3, HOOK, and GK domains of the protein.DLG1 also forms multiprotein complexes with CASK,LIN7A, LIN7B, LIN7C, APBA1, and KCNJ12 (Nix etal., 2000; Lee et al., 2002; Leonoudakis et al., 2004)and exists as a tripartite complex composed of DLG1,MPP7 and LIN7 (LIN7A or LIN7C) (Bohl et al., 2007;Stucke et al., 2007). MPP7 dimerized with the LIN7proteins through its L27C domain. The LIN7/MPP7dimer then linked to DLG1 though the L27N domain ofMPP7. This complex localizes to epithelial adherensjunctions in transfected Madin-Darby Canine Kidneycells (MDCK). MPP7 constructs lacking either the PDZor SH3 domain redistributed MPP7, DLG1, and LIN7into the soluble cytoplasmic fraction. MPP7 and DLG1colocalized at the lateral surface of epithelial cells, andthey overlapped with markers of adherens junctionsand tight junctions. Loss of either DLG1 or MPP7 fromepithelial cells resulted in a significant defect inassembly and maintenance of functional tight junctions.The formation of the DLG1-MPP7 complex promotesalso epithelial cell polarity.SAP97 binds two other mLIN-7 binding MAGUKproteins. One of these MAGUK proteins, DLG3,coimmunoprecipitates with SAP97 in lysates from ratAtlas Genet Cytogenet Oncol Haematol. 2010; 14(4)371
DLG1 (discs, large homolog 1 (Drosophila))Massimi P, Banks Lassociate with AMPA receptors (AMPARs) containingthe GluR1 subunit, but the functional significance ofthese interactions is partially unclear, even if thisinteraction seems to be occur early in the secretorypathway, while the receptors are in the endoplasmicreticulum or cis-Golgi (Sans et al., 2001). In lightmembrane fractions prepared from rat brain, myosin VIand SAP97 form a trimeric complex with the alphaamino-3-hydroxy-5-methylisoxazole-4-propionic acid(AMPA) receptor subunit, GluR1. It is possible thatSAP97 may serve as a molecular link between GluR1and the actin-dependent motor protein myosin VIduring the dynamic translocation of AMPA receptors toand from the postsynaptic plasma membrane (Wu et al.,2002).DLG1 is also able to translocate to the immune synapseand lipid rafts in response to T cell receptor(TCR)/CD28 engagement and LckSH3-mediatedinteractions with DLG1 control its membrane targeting.TCR/CD28 engagement induces the formation ofendogenousLck-DLG1-Zap70-Wiskott-Aldrichsyndrome protein (WASp) complexes in which DLG1acts to facilitate interactions of Lck with Zap70 andWASp (Round et al., 2005).Delta 1 acts as a membrane-bound ligand that interactswith the Notch receptor and plays a critical role in cellfate specification. DLG1 binds the Delta 1 C-terminalregion, in a PDZ dependent manner. Delta 4 alsointeracts with DLG1, whereas Jagged1, another Notchligand, does not (Six et al., 2004).MARCH 2, which is part of the MARCH familyubiquitin ligases and is implicated in the endosomaltrafficking interacts with full-length DLG1 in a PDZdomain dependent manner. Furthermore, MARCH2 colocalized with DLG1 at sites of cell-cell contact (Cao etal., 2008).SAP97 is a binding partner of the cytoplasmic domainof TACE, which is the Tumour necrosis factor alphaconverting enzyme and is the metalloproteasedisintegrin responsible for the ectodomain shedding ofseveral proteins, including tumour necrosis factoralpha. The interaction involved the PDZ3 domain ofSAP97 and the extreme C-terminal amino-acidsequence of TACE (Peiretti et al., 2003).DLG1 is able to interact also with Net 1 which is anuclear RhoA-specific guanine nucleotide exchangefactor. The binding is through the PDZ-binding motif.The ability of oncogenic Net1 to transform cells maybe in part related to its ability to sequester tumoursuppressor proteins like DLG1 in the cytosol, therebyinterfering with their normal cellular function (GarciaMata et al., 2007).DLG1 interacts with the tSNARE syntaxin 4 which isinvolved in vesicle transport, and this binding maycontribute to the correct colocaliation of the otherproteins of the Scrib complex: hScribble and Hugl-1(Massimi et al., 2008).Atlas Genet Cytogenet Oncol Haematol. 2010; 14(4)ExpressionDLG1 is widely expressed, with different isoformsdisplaying different expression profiles (McLaughlin etal., 2002). DLG1 is expressed mainly in epithelial cellsand in the nervous system, but is also fond in thymus,bone marrow, T cells, spleen, brain, spinal cord, heart,kidney, lung, liver,pancreas, prostate (at the protein level).LocalisationDLG1 is localised at the plasma membrane (Hanada etal., 2000), cell-cell junctions (Lue et al., 1994), at thebasolateral plasma membrane (Lue et al., 1996; Mimoriet al., 2007). It is also found at the micreticulum membrane, postsynaptic density, lateralplasma membrane, neuromuscular junction membrane,raft synapse and the post-synaptic membrane. There isequal expression of the two spliced variants in mosthuman tissues; however, in skeletal muscle thetranscript with the 99-bp insertion is predominant,whilst in the brain, the isoform lacking the 99-bpinsertion is predominant. In brain there are sixdifferent, alternatively spliced transcripts, two of whichincluded a novel, 36-bp, brain-specific exon encoding apeptide bearing significant homology to a portion of ratsynapse-associated proteins, SAP97 and PSD95.Again, the different isoforms of the protein seem tohave diverse localisation in the cell. I2 and I3 variantshave distinct distributions in epidermal and cervicalepithelia. In skin and cervix, I3 variants are found inthe cytoplasm. Cytoplasmic localization of I3 variantsdecreases as cervical keratinocytes differentiate,concomitant with relocalization to the cell periphery. I2variants are found at the cell periphery of differentiatedepidermal and cervical keratinocytes. Nuclearlocalization of I2 variants is evident in both tissues,with a concentration of nuclear I2 variants in basal andparabasal cervical keratinocytes (Roberts et al., 2007),underlining that different hDlg isoforms play distinctroles at various stages of epithelial nintosubconfluent (MDCK) epithelial cells, hDlg-I3accumulated predominantly at the plasma membrane ofcell-cell contact sites, whereas hDlg-I2 distributed inthe cytoplasm. The hDlg-I3 but not the hDlg-I2 isoformbinds to the FERM (Four.1-Ezrin-Radixin-Moesin)domain of protein 4.1, playing a critical role inrecruiting DLG1 to the lateral membrane in epithelialcells (Bonhila et al., 2001; Hanada et al., 2003;Massimi et al., 2003; Wu et al., 2002).Several different domains of DLG1 contribute to itslocalisation. Mutation of the SH3 or GUK domain, butnot the PDZ domain, results in a re-localization ofhDLG to the nucleus and, moreover, DLG1 possess apotential nuclear localization signal in the HOOKdomain (Kohu et al., 2002).372
DLG1 (discs, large homolog 1 (Drosophila))Massimi P, Banks LIt has been reported that the localisation of DLG1 isalso dependent on the post-translational modifica-tionof the protein, by phosphorylation occurring postosmotic shock (Massimi et al., 2006) and also duringthe cell cycle following CDK phosphoryla-tion(Narayan et al., 2009). Moreover, DLG1 localisesdependently from the other proteins involved in thecomplex at the adherens junctions:hScribble and Hugl-1 (Massimi et al., 2008).In addition, CaMKII (calcium/calmodulin-depen-dentprotein kinase II) activation led to increased targetingof SAP97 into dendritic spines, whereas CaMKIIinhibition was responsible for SAP97 colocalization inthe cell soma with the endoplasm-mic reticulum proteindisulfide-isomerase (Mauceri et al., 2004).Regarding the localisation of the different isoforms, thetwo main cardiac SAP97 isoforms contains both I3 andI1B inserts and differs by the I1A insert. Both isoformsco-precipitate with hKv1.5 channels, and have differenteffects on the hKv1.5 current, depending on theircapacity to form clusters (Godreau et al., 2003).In the case of endothelial cells of embryonic liver theexpression of TEM5 colocalises with DLG1. Thissuggest that hDlg localizes at the plasma membranethrough TEM5 and TEM5-like proteins andfurthermore scaffolds these GPCRs in endothelial cellsduring tumour angiogenesis and neoangiogenesis(Yamamoto et al., 2004).(PSD-95/SAP90) (Lue et al., 1994; Makno et al., 1997;Brenman et al., 1996; Cho et al., 1992; Humbert et al.,2003). Mammalian Dlg family members display thecharacteristic MAGUK structural domains found inDrosophila Dlg including the three PDZ domains, a Srchomology domain-3 (SH3) and a guanylate kinase-like(GUK) domain. Although most mammalian Dlghomologues were first identified in neuronal tissues, allof these proteins are expressed in a variety of nonneuronal tissues including epithelial and lymphoidcells. Strikingly, localisation studies in all of thesetissues are suggestive of a role for mammalian Dlghomologues in polarisation.MutationsNoteSee paragraphs below.GerminalNone.SomaticThere is one report in breast cancer (Fuja et al., 2004).Implicated inEpithelial-derived cancersNoteThe mis-localisation of DLG1 is linked to thedevelopment of epithelial-derived cancers (Gardiol etal., 2006). In uterine cervical squamous epithelia,prominent localization of hDlg at sites of inter-cellularcontact occurs in cells that have left the proliferatingbasal cell layers and begun maturation. The presence ofhDlg at sites of cell-cell contact diminishes, whilstintracellular cytoplasmic levels increase significantly inhigh-grade, but not low-grade, cervical neoplasias. Ininvasive squamous cell carcinomas, total cell
for the Snail family of transcription factors that repress the expression of some epithelial markers and are up-regulated in a variety of tumours. Snail transcription factors repress the transcriptional activity of the DLG1 promoter (Cavatorta et al., 2008). The
COUNTY Archery Season Firearms Season Muzzleloader Season Lands Open Sept. 13 Sept.20 Sept. 27 Oct. 4 Oct. 11 Oct. 18 Oct. 25 Nov. 1 Nov. 8 Nov. 15 Nov. 22 Jan. 3 Jan. 10 Jan. 17 Jan. 24 Nov. 15 (jJr. Hunt) Nov. 29 Dec. 6 Jan. 10 Dec. 20 Dec. 27 ALLEGANY Open Open Open Open Open Open Open Open Open Open Open Open Open Open Open Open Open Open .
Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Scope The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
Keywords: Open access, open educational resources, open education, open and distance learning, open access publishing and licensing, digital scholarship 1. Introducing Open Access and our investigation The movement of Open Access is attempting to reach a global audience of students and staff on campus and in open and distance learning environments.
Network Blue Open Access POS Blue Open Access POS Blue Open Access POS Blue Open Access POS Blue Open Access POS Blue Open Access POS Blue Open Access POS Contract code 3UWH 3UWF 3UWD 3UWB 3UW9 3UW7 3UW5 Deductible1 (individual/family) 1,500/ 3,000 1,750/ 3,500 2,000/ 4,000 2,250/ 4,500 2,500/ 5,000 2,750/ 5,500 3,000/ 6,000
Cystic Fibrosis and CFTR Gene 67 Pascale Fanen, Afia Hasnain Skeletal development in human 76 Jacky Bonaventure . Gene Section Mini Review Atlas Genet Cytogenet Oncol Haematol. 2002; 6(1) 1 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS
Anatomy of a journal 1. Introduction This short activity will walk you through the different elements which form a Journal. Learning outcomes By the end of the activity you will be able to: Understand what an academic journal is Identify a journal article inside a journal Understand what a peer reviewed journal is 2. What is a journal? Firstly, let's look at a description of a .
Journals (DOAJ), Open J-Gate, Genamics JournalSeek, MediaFinder -Standard Periodical Directory, PubsHub, J-Gate. Journal of 9/11 Studies Both the Open Chemical Physics Journal and the Open Civil Engineering Journal are open access, online journals of Bentham Open.3 The Journal of 9/11 Studies is the primary peer-
Part 1 – Day Trading Explained At DayTradeToWin.com, we mainly focus on one type of market: futures. Some people like to trade stocks, but not everyone has 20,000 to do so. Some people like to trade forex (also called currencies), but not everyone likes the lack of regulation and other shady things in that industry. We prefer to trade futures because they are regulated, are much more .
