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DLG1 (discs, large homolog 1 (Drosophila))

Written2009-05Paola Massimi, Lawrence Banks
International Centre for Genetic Engeneering, Biotechnology (ICGEB), Trieste, Italy
Updated2015-01Paola Massimi, Lawrence Banks
International Centre for Genetic Engeneering, Biotechnology (ICGEB), Trieste, Italy

Abstract The human homologue of Drosophila disc large tumor suppressor protein (hDlg) also known as synapse-associated protein 97, is a scaffold protein, a member of the membrane-associated guanylate kinase family. It is one of the proteins known to act cooperatively in regulating cell polarity and proliferation, suggesting an important connection between epithelial organization and cellular growth control. An abnormal expression of hDlg has been reported in several cancer types.This protein may have a role in cell junction formation, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation.

Keywords Polarity, cell junctions, tumour progression

(Note : for Links provided by Atlas : click)

Identity

Alias_namesdiscs, large homolog 1 (Drosophila)
discs large homolog 1, scribble cell polarity complex component
Alias_symbol (synonym)SAP97
SAP-97
hdlg
DLGH1
dJ1061C18.1.1
Other aliasSynapse-Associated Protein 97
Presynaptic Protein SAP97
DKFZp761P0818
DKFZp781B0426
Hdlg
HGNC (Hugo) DLG1
LocusID (NCBI) 1739
Atlas_Id 40333
Location 3q29  [Link to chromosome band 3q29]
Location_base_pair Starts at 197042560 and ends at 197298576 bp from pter ( according to hg19-Feb_2009)  [Mapping DLG1.png]
Fusion genes
(updated 2016)
DLG1 (3q29) / BDH1 (3q29)DLG1 (3q29) / CRYBG3 (3q11.2)DLG1 (3q29) / DLG1 (3q29)
DLG1 (3q29) / LPP (3q28)DLG1 (3q29) / P2RX5 (17p13.2)PCCB (3q22.3) / DLG1 (3q29)
RBM48 (7q21.2) / DLG1 (3q29)UBXN7 (3q29) / DLG1 (3q29)

DNA/RNA

 
  Diagram of DLG1 gene organization and of the two major encoded transcript variants.
Description The DLG1 gene consists of 250,017 bases on the 3q29 locus of chromosome 3 (Azim et al., 1995).
Transcription The DLG1 gene encodes a 960 amino-acid protein of 100355 Da with several distinct domains. A 1310-bp fragment of the 5' flanking region of the DLG1 gene, corresponding to nucleotide (nt) - 1217/+ 93 contains the promoter sequence plus the consensus-binding sites 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 carboxyl-terminal 179 aa show strong homology (35.5%) to yeast guanylate kinase (GUK) an enzyme that transfers a phosphate group from ATP to GMP, converting it to GDP, although DLG1 has no enzymatic activity.
DLG1 contains also a 59 aa SH3 (Src homolgy 3) domain, which mainly mediates binding to other proteins. The N terminal half of the molecule contains three copies of the 80-90 aa motif called DHR/GLGF/PDZ (PSD-95, Dlg, ZO-1), which mediate the binding of the protein to the plasma membrane and confers binding to proteins that possess a class I PDZ binding motif (Morais Cabral et al., 1996).
There are two major transcripts of DLG1 gene. One is Discs large homolog 1 isoform 1, which contains an additional exon (99 nucleotides) in the 5' part of the Dlg homology repeats (DHR) domain and lacks an exon in the 3' coding region, resulting in a shorter protein (isoform 1), compared to isoform 2. The second is Discs large homolog 1 isoform 2, which represents the longer transcript and encodes the longer isoform. This second transcript is alternatively spliced with an insertion of 34 nucleotides in the region between the SH3 and GUK (isoform 2). Another alternative splice has an insertion of 100 nucleotides and the resulting transcript is called Discs large homolog 1 isoform 3.
In conclusion, the protein is regulated by a several different alternative splicing events (Mori et al., 1998) resulting in a number of different combination of spliced variants (which give raise to at least 7 isoforms such as I1I2, I1I3, etc.) (see table), some of which are transcribed in a tissue-specific manner (Lue et al., 1996; McLaughlin et al., 2002).
Pseudogene None.

Protein

 
  Diagram of the DLG1 protein with its characteristic domains and the main protein-protein interactions at the cell-cell junctions
Description The 'discs large' protein, Dlg1, is part of a family of proteins termed MAGUKs (membrane-associated guanylate kinase homologs). MAGUKs are localized at the membrane-cytoskeleton interface, usually at cell-cell junctions, where they appear to have both structural and signaling roles. DLG1 probably exists as an homotetramer. Ultrastructural analysis of hDlg by low angle rotary shadow electron microscopy revealed that the full-length hDlg protein as well as its amino-terminal domain exhibits a highly flexible irregular shape. Further evaluation of the self-association state of hDlg using sedimentation equilibrium centrifugation, matrix-assisted laser desorption/ionization mass spectrometry, and chemical cross-linking techniques confirmed that the oligomerization site of hDlg is contained within its amino-terminal domain. This is mediated by a unique L27 domain which regulates multimerization of hDlg into dimeric and tetrameric species in solution, and sedimentation velocity experiments demonstrated that the oligomerization domain exists as an elongated tetramer in solution (Marfatia et al., 2000). Thus, the L27 domain regulate DLG1 self-association. The N-terminal alternatively spliced region is capable of binding several SH3 domains and also moderates the level of protein oligomerization.
Specific binding partners are known for each domain of DLG1, and different modes of intramolecular interactions have been proposed that particularly involve the SH3 and GUK domains and the so-called HOOK region located between these two domains.
DLG1 binds to the membrane cytoskeletal 4.1 protein through its C-terminal region (Hanada et al., 2003), via a motif encoded by the alternatively spliced exon located between the SH3 and the C-terminal guanylate kinase-like domains (Isoform I3). The PDZ1-2 modules and the I3 domain associate with the 30-kD NH2-terminal domain of protein 4.1 that is conserved in ezrin/radixin/moesin (ERM) proteins module (Lue et al., 1996; Bonilha and Rodriguez-Boulan, 2001). Indeed SAP97 also interacts with ezrin, an actin-binding protein crucial for morphogenesis of apical microvilli and basolateral infoldings in retinal pigment epithelial (RPE) cells.
Through the PDZ2 domain the protein also interacts with the carboxyl-terminal S/TXV motif of the APC (Adenomatous polyposis coli) tumour suppressor protein and plays an important role in transducing the APC cell cycle blocking signal (Makino et al., 1997; Ishidate et al., 2000; Mimori-Kiyosue et al., 2007). Recent studies report that APC can bind to all the three PDZ domains from hDlg, whereas PTEN mainly binds to PDZ-2/hDlg. This indicates the existence of overlapping, but distinct PDZ-domain recognition patterns by APC and PTEN. Furthermore, a ternary complex formed by APC, PTEN, and hDlg has been detected, suggesting that hDlg may serve as a platform to bring in proximity APC and PTEN tumor suppressor activities, which may be relevant in oncogenesis (Sotelo et al. 2012). In addition, APC appears to mediate the interaction between DLG1, beta-catenin and the actin cytoskeleton. Beta-catenin is complexed with gamma-catenin and alpha-catenin, through which DLG1 binds to E-cadherin (Reuver et al., 1998). .
Moreover, the Src homology domain 2 of the p85/PI3K and hDlg are associated with E-cadherin in a common macromolecular complex in differentiating intestinal cells, and in this way hDlg may be a determinant in E-cadherin-mediated adhesion and signaling in mammalian epithelial cells (Laprise et al., 2004).
DLG1 was demonstrated also to bind with voltage-gated or Kv K(+) channels through its PDZ domains (Hanada et al., 1997; Tiffany et al., 2000; Eldstrom et al., 2003). The complex formation involves the association of Cav-3 with a segment of SAP97 localized between its PDZ2 and PDZ3 domains. This scaffolding complex can recruit Kv1.5 to form a tripartite complex in which each of the three components interacts with the other two. These interactions between Kv1.5, Cav3 and SAP97 may constitute the nucleation site for the assembly of macromolecular containing potassium channels and thereby regulates cellular potential currents (Folco et al., 2004).
Hanada showed by immunoblot analysis that immunoprecipitates of DLG1 in T lymphocytes contain the Src family tyrosine kinase p56 (lck). Binding analysis demonstrated that LCK interacts with the proline-rich N-terminal domain of DLG1, suggesting that DLG1 may function as a coupler of tyrosine kinase and a voltage-gated potassium channel in T lymphocytes.
The HOOK region of DLG1 is also a specific site for calmodulin binding and interaction of SAP97 to immobilized calmodulin is strictly calcium-dependent (Paarmann et al., 2002). The calmodulin seems to regulate the intramolecular interaction between the SH3, HOOK, and GK domains of the protein.
DLG1 also forms multiprotein complexes with CASK, LIN7A, LIN7B, LIN7C, APBA1, and KCNJ12 (Nix et al., 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 LIN7 proteins through its L27C domain. The LIN7/MPP7 dimer then linked to DLG1 though the L27N domain of MPP7. This complex localizes to epithelial adherens junctions in transfected Madin-Darby Canine Kidney cells (MDCK). MPP7 constructs lacking either the PDZ or SH3 domain redistributed MPP7, DLG1, and LIN7 into the soluble cytoplasmic fraction. MPP7 and DLG1 colocalized at the lateral surface of epithelial cells, and they overlapped with markers of adherens junctions and tight junctions. Loss of either DLG1 or MPP7 from epithelial cells resulted in a significant defect in assembly and maintenance of functional tight junctions. The formation of the DLG1-MPP7 complex promotes also epithelial cell polarity.

SAP97 binds two other mLIN-7 binding MAGUK proteins. One of these MAGUK proteins, DLG3, coimmunoprecipitates with SAP97 in lysates from rat brain and transfected MDCK cells. This interaction requires the MRE (MAGUK recruitment) domain of SAP97 and surprisingly, both the L27N and L27 carboxyl-terminal (L27C) domains of DLG3. SAP97 can interact with the MAGUK protein, DLG2, but not the highly related protein, PALS2. The ability of SAP97 to interact with multiple MAGUK proteins is likely to be important for the targeting of specific protein complexes in polarized cells (Karnak et al., 2002).
The kinesin-3 motor protein, GAKIN, is regulated by the direct binding of its protein cargo hDlg. Direct binding of the SH3-I3-GUK module of hDlg to the MAGUK Binding Stalk domain of GAKIN activates the 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 protein from a human cDNA library was isolated as a binding partner of DLG1. This protein is a component of TJs rather than AJs (where DLG1 is normally found), even if it is incorporated into TJs after TJ strands are formed, and therefore it is named Pilt (protein incorporated later into TJs) (Kawabe et al., 2001).
DLG1 is known to interact also with several human virus oncoproteins : HPV E6 (Lee et al., 1997; Kiyono et al.,1997, Gardiol et al., 1999) through its C-terminus and DLG1 PDZ2 domain and as result is subjected to proteasome mediated degradation; HTLV-1 TAX (Suzuki et al., 1999), via the C-terminus of Tax and the PDZ domain of hDLG. Tax prevents the binding of hDLG to APC tumor suppressor gene product, suggesting the mechanism for inhibition of hDLG function; Adenovirus type 9 E4-ORF1 specifically requires endogenous DLG1 to provoke oncogenic activation of phosphatidylinositol 3-kinase (PI3K) in cells. E4-ORF1 binding to Dlg1 on ts PDZ domain triggers the resulting complex to translocate to the plasma membrane and, at this site, to promote Ras-mediated PI3K activation, suggesting a surprising oncogenic function for DLG1 in virus-mediated cellular transformation (Frese et al., 2006; Chung et al., 2007). Moreover, phosphatidylinositol 3-kinases are one class of signaling molecules reported to regulate adherens junction and to be activated by adherens junction assembly . While the exact molecular mechanisms involved are not clear, data indicate that one of the earliest events likely involves c-Src which is rapidly activated by E-cadherin-mediated cellular aggregation and may facilitate the recruitment and activation of PI3K to E-cadherin-containing complexes. Beta-catenin, gamma-catenin and hDlg which are present at cell-cell adhesions can act as docking proteins for PI3K (Rivard N. 2009).
hDlg also binds the tumor endothelial marker 5 (TEM5), a seven-pass transmembrane protein that is homologous to the B family of G-protein-coupled receptors (GPCRs). The PDZ domains of hDlg bound the C-terminal PDZ-binding motif of TEM5. DLG1 is furthermore able to interact with a novel seven-pass transmembrane protein, which was homologous to TEM5, and was named here a TEM5-like protein (TEM5-like) (Yamamoto et al., 2004).
SAP97/hDlg as a scaffold protein is also targeted to the cytoskeleton by its association with the protein guanylate kinase-associated protein (GKAP), which is part of the postsynaptic scaffold in neuronal cells (Sabio et al., 2005). Moreover, hDlg is believed to associate with AMPA receptors (AMPARs) containing the GluR1 subunit, but the functional significance of these interactions is partially unclear, even if this interaction seems to be occur early in the secretory pathway, while the receptors are in the endoplasmic reticulum or cis-Golgi (Sans et al., 2001). In light membrane fractions prepared from rat brain, myosin VI and SAP97 form a trimeric complex with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit, GluR1. It is possible that SAP97 may serve as a molecular link between GluR1 and the actin-dependent motor protein myosin VI during the dynamic translocation of AMPA receptors to and from the postsynaptic plasma membrane (Wu et al., 2002).
DLG1 is also able to translocate to the immune synapse and lipid rafts in response to T cell receptor (TCR)/CD28 engagement and LckSH3-mediated interactions with DLG1 control its membrane targeting. TCR/CD28 engagement induces the formation of endogenous Lck-DLG1-Zap70-Wiskott-Aldrich syndrome protein (WASp) complexes in which DLG1 acts to facilitate interactions of Lck with Zap70 and WASp (Round et al., 2005).
Delta 1 acts as a membrane-bound ligand that interacts with the Notch receptor and plays a critical role in cell fate specification. DLG1 binds the Delta 1 C-terminal region, in a PDZ dependent manner. Delta 4 also interacts with DLG1, whereas Jagged1, another Notch ligand, does not (Six et al., 2004).
MARCH 2, which is part of the MARCH family ubiquitin ligases and is implicated in the endosomal trafficking interacts with full-length DLG1 in a PDZ domain dependent manner. Furthermore, MARCH2 co-localized with DLG1 at sites of cell-cell contact (Cao et al., 2008).
SAP97 is a binding partner of the cytoplasmic domain of TACE, which is the Tumour necrosis factor alpha converting enzyme and is the metalloprotease-disintegrin responsible for the ectodomain shedding of several proteins, including tumour necrosis factor alpha. The interaction involved the PDZ3 domain of SAP97 and the extreme C-terminal amino-acid sequence of TACE (Peiretti et al., 2003).
DLG1 is able to interact also with Net 1 which is a nuclear RhoA-specific guanine nucleotide exchange factor. The binding is through the PDZ-binding motif. The ability of oncogenic Net1 to transform cells may be in part related to its ability to sequester tumour suppressor proteins like DLG1 in the cytosol, thereby interfering with their normal cellular function (Garcia-Mata et al., 2007).
DLG1 interacts with the tSNARE syntaxin 4 which is involved in vesicle transport, and this binding may contribute to the correct colocaliation of the other proteins of the Scrib complex: hScribble and Hugl-1 (Massimi et al., 2008).
Osmotic stress triggers hDlg degradation through a mechanism different from the one mediated by proteasomes, and hDlg is also a caspase substrate during the apoptotic process, although its proteolysis may not be implicated in the progression of early apoptosis (Inesta-Vaquera FA et al. 2009).
In response to hyperosmotic stress, p38? also regulates formation of complexes between hDlg and the nuclear protein polypyrimidine tract-binding protein-associated-splicing factor (PSF). Following osmotic shock, p38? in the cell nucleus increases its association with nuclear hDlg, thereby causing dissociation of hDlg-PSF complexes. Moreover, hDlg and PSF bind different RNAs; in response to osmotic shock, p38? causes hDlg-PSF and hDlg-RNA dissociation independently of its kinase activity, affecting mRNA processing and/or gene transcription (Sabio et al. 2010). Moreover, the exposure of cells to osmotic shock induces the hyperphosphorylation of Dlg and its concomitant accumulation within the cell membrane at sites of cell contact, a process that requires an intact actin filament network. In addition, hyperphosphorylation of Dlg also renders it more susceptible to degradation induced by the HPV-18 E6 oncoprotein (Massimi et al.2006).
Also the ERK5 pathway is reported to mediate hDlg cell cycle dependent phosphorylation. This is likely to have important implications in the correct timely mitotic entry and mitosis progression ( Inesta- Vaquera et al. 2010).
Using the yeast two-hybrid system to screen a human aorta cDNA library, mitogen-activated protein/extracellular signal-responsive kinase (ERK) kinase (MEK)2, a member of the ERK cascade it was identified as an hDlg binding partner. Site-directed mutagenesis showed a major involvement of the PSD-95, disc-large, ZO-1 domain-2 of hDlg and the C-terminal sequence RTAV of MEK2 in this interaction. hDlg acts as a MEK2-specific scaffold protein for the ERK signaling pathway differentially tuning MEK1/MEK2 signaling and cell responses ( Maiga et al. 2011). Both proteins localize also to a sub-structure of the midbody, the midbody ring (Massimi et al. 2003; Gaudet et al. 2011).
Using a proteomic approach it has been shown that a strong interacting partner of hDlg is the RhoG-specific guanine nucleotide exchange factor SGEF. The interaction between hDlg1 and SGEF involves both PDZ and SH3 domain recognition, and directly contributes to the regulation of SGEF's cellular localization and activity. Consistent with this, hDlg is a strong enhancer of RhoG activity, which occurs in an SGEF-dependent manner and directly contributes to the invasive capacity of HPV-16 and HPV-18 transformed tumour cells displaying a distinct oncogenic function in the context of HPV induced malignancy (Krishna Subbaiah et al. 2012).
Loss of gap junctional communication correlatedswith relocalization of Cx43 to the cytoplasm late in tumorigenesis. A similar pattern of altered expression for the hDlg was found in cervical tumour cells, with partial co-localization of Cx43 and hDlg in an endosomal/lysosomal compartment. Relocalization of these proteins is not due to a general disruption of cell membrane integrity or Cx targeting. Cx43 (via its C-terminus) and hDlg interact directly in vitro and can form a complex in cells. This novel interaction requires the N- and C-termini of hDlg (Macdonald et al. 2012).
The components of the Scrib/Dlg tumour suppressor complex have complementary roles in Drosophila and loss of both proteins is a common event in many different human tumours. In human keratinocytes the removal of hScrib greatly reduces cell-cell contact and cell-matrix interactions, and promotes an invasive phenotype. Conversely, in cells lacking hDlg1 cell-cell contacts are maintained and there are decreases in both cell growth and invasion (Massimi et al. 2012).

Expression DLG1 is widely expressed, with different isoforms displaying different expression profiles (McLaughlin et al., 2002). DLG1 is expressed mainly in epithelial cells and 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).
Localisation DLG1 is localised at the plasma membrane (Hanada et al., 2000), cell-cell junctions (Lue et al., 1994), at the basolateral plasma membrane (Lue et al., 1996; Mimori et al., 2007). It is also found at the immunological synapse, endoplasmic reticulum, endoplasmic reticulum membrane, postsynaptic density, lateral plasma membrane, neuromuscular junction membrane, raft synapse and the postsynaptic membrane. . In human vascular tissues, hDlg is highly expressed in smooth muscle cells (VSMCs) and in these cells associates with the endoplasmic reticulum and microtubules ( Maiga et al 2011). There is equal expression of the two spliced variants in most human tissues; however, in skeletal muscle the transcript with the 99-bp insertion is predominant, whilst in the brain, the isoform lacking the 99-bp insertion is predominant. In brain there are six different, alternatively spliced transcripts, two of which included a novel, 36-bp, brain-specific exon encoding a peptide bearing significant homology to a portion of rat synapse-associated proteins, SAP97 and PSD95.
Again, the different isoforms of the protein seem to have diverse localisation in the cell. I2 and I3 variants have distinct distributions in epidermal and cervical epithelia. In skin and cervix, I3 variants are found in the cytoplasm. Cytoplasmic localization of I3 variants decreases as cervical keratinocytes differentiate, concomitant with relocalization to the cell periphery. I2 variants are found at the cell periphery of differentiated epidermal and cervical keratinocytes. Nuclear localization of I2 variants is evident in both tissues, with a concentration of nuclear I2 variants in basal and parabasal cervical keratinocytes (Roberts et al., 2007), underlining that different hDlg isoforms play distinct roles at various stages of epithelial differentiation. Moreover, upon transient transfection into subconfluent (MDCK) epithelial cells, hDlg-I3 accumulated predominantly at the plasma membrane of cell-cell contact sites, whereas hDlg-I2 distributed in the cytoplasm. The hDlg-I3 but not the hDlg-I2 isoform binds to the FERM (Four.1-Ezrin-Radixin-Moesin) domain of protein 4.1, playing a critical role in recruiting DLG1 to the lateral membrane in epithelial cells (Bonhila et al., 2001; Hanada et al., 2003; Massimi et al., 2003; Wu et al., 2002).
Several different domains of DLG1 contribute to its localisation. Mutation of the SH3 or GUK domain, but not the PDZ domain, results in a re-localization of hDLG to the nucleus and, moreover, DLG1 possess a potential nuclear localization signal in the HOOK domain (Kohu et al., 2002).
It has been reported that the localisation of DLG1 is also dependent on the post-translational modification of the protein, by phosphorylation occurring post-osmotic shock (Massimi et al., 2006; Remy et al. 2010) and also during the cell cycle following CDK phosphorylation (Narayan et al., 2009). Nuclear forms of Dlg phosphorylated on its CDK phospho-acceptor sites (S158 and S442) has enhanced susceptibility to E6-induced degradation (Narayan et al. 2009; Nagasaka et al. 2013). Moreover, DLG1 localises dependently from the other proteins involved in the complex at the adherens junctions: hScribble and Hugl-1 (Massimi et al., 2008).
In addition, CaMKII (calcium/calmodulin-dependent protein kinase II) activation led to increased targeting of SAP97 into dendritic spines, whereas CaMKII inhibition was responsible for SAP97 colocalization in the cell soma with the endoplasmic reticulum protein disulfide-isomerase (Mauceri et al., 2004).
Regarding the localisation of the different isoforms, the two main cardiac SAP97 isoforms contains both I3 and I1B inserts and differs by the I1A insert. Both isoforms co-precipitate with hKv1.5 channels, and have different effects on the hKv1.5 current, depending on their capacity to form clusters (Godreau et al., 2003).
In the case of endothelial cells of embryonic liver the expression of TEM5 colocalises with DLG1. This suggest that hDlg localizes at the plasma membrane through TEM5 and TEM5-like proteins and furthermore scaffolds these GPCRs in endothelial cells during tumour angiogenesis and neoangiogenesis (Yamamoto et al., 2004).
Function DLG1 is an essential multidomain scaffolding protein required for normal development.
It is able to recruits channels (Hanada et al., 1997; Tiffany et al., 2000; Abi-Char et al., 2008), receptors and signaling molecules (Sans et al., 2001; Wuh et al., 2002; Six et al., 2004) to discrete plasma membrane domains in polarized cells. Its main role is played in adherens junctions assembly (Laprise et al., 2004; Bohl et al., 2007; Stucke et al., 2007; Massimi et al., 2008). However DLG1 with the establishment of a multiprotein complexes at cell-cell contacts is also involved in signal transduction (Massimi et al., 2006), cell proliferation (Suzuki et al., 1999; Ishidate et al., 2000; Massimi et al., 2003; Thomas et al., 2005; Frese et al., 2006; Garcia-Mata et al., 2007; Unno et al., 2008), synaptogenesis (Mori et al., 1998; Sans et al., 2001; Mauceri et al., 2004), lymphocyte activation (Hanada et al., 1997; Hanada et al., 2000; Round et al., 2005), cell differentiation (Laprise et al., 2004; Roberts et al., 2007), cell migration (Six et al., 2004) and cellular apical-basal polarity control (Bonilha et al., 2001).
Homology The four best-characterised mammalian Dlg family members are Dlg1 (hDlg/SAP97), Dlg2 (PSD-93/Chapsyn-110), Dlg3 (NE-Dlg/SAP102) and Dlg4 (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 the characteristic MAGUK structural domains found in Drosophila Dlg including the three PDZ domains, a Src homology domain-3 (SH3) and a guanylate kinase-like (GUK) domain. Although most mammalian Dlg homologues were first identified in neuronal tissues, all of these proteins are expressed in a variety of non-neuronal tissues including epithelial and lymphoid cells. Strikingly, localisation studies in all of these tissues are suggestive of a role for mammalian Dlg homologues in polarisation.

Mutations

Note See paragraphs below.

Implicated in

Note
  
Entity Epithelial-derived cancers
Note The mis-localisation of DLG1 is linked to the development of epithelial-derived cancers (Gardiol et al., 2006). In uterine cervical squamous epithelia, prominent localization of hDlg at sites of intercellular contact occurs in cells that have left the proliferating basal cell layers and begun maturation. The presence of hDlg at sites of cell:cell contact diminishes, whilst intracellular cytoplasmic levels increase significantly in high-grade, but not low-grade, cervical neoplasias. In invasive squamous cell carcinomas, total cellular hDlg levels are greatly reduced (Watson et al., 2002; Vazquez-Ulloa et al. 2011).
  
  
Entity Mammary ductal carcinoma
Note In humans there is only one report of mutations occuring in Dlg in cancer. In this study somatic mutations were found in three genes (CSNK1 epsilon, encoding the Ser/Thr kinase casein kinase I epsilon, DLG1, and EDD/hHYD, encoding a progestin induced putative ubiquitin-protein ligase) in mammary ductal carcinoma. For CSNK1 epsilon and DLG1, most of the mutations affected highly conserved residues, some were found repetitively in different patients, and no synonymous mutations were found, indicating that the observed mutations were selected in tumours and may be functionally significant (Fuja et al., 2004).
  
  
Entity 3q29 microdeletion syndrome
Note Moreover, another report (Willatt et al., 2005) pointed out that the DLG1 and PAK2 genes are deleted in the 3q29 microdeletion syndrome and raised the possibility that loss of one of these genes may contribute to the phenotype since PAK2 and DLG1 are autosomal homologs of 2 X-linked mental retardation genes, PAK3 and DLG3.
  
  
Entity Schizophrenia
Note In addition, DLG1 gene may be a susceptibility factor in male schizophrenics and the modification of the glutamate receptor signalling pathway could be involved in the disease pathophysiology. DLG1 protein levels were decreased to less than half that of the control levels specifically in the prefrontal cortex of schizophrenic patients. In parallel, its binding partner, GluR1, similarly decreased in the same brain region (Toyooka et al., 2002; Sato et al., 2008).
  
  
Entity Various cancer
Note Generally, loss of expression (through diverse mechanisms) is a common feature in many late stage of cancers.
  
  
Entity malignant fibrous histiocytoma
Note The patients with a weak or negative expression of hDlg had a significantly shorter metastasis-free survival rate and disease-free survival rate in comparison with those with a strong or moderate expression. The patients have a significantly shorter overall survival rate. A reduced expression of hDlg protein is an independent negative prognostic factor for MFH (Niimi et al. 2010).
  

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Folco EJ, Liu GX, Koren G.
Am J Physiol Heart Circ Physiol. 2004 Aug;287(2):H681-90.
PMID 15277200
 
Oncogenic function for the Dlg1 mammalian homolog of the Drosophila discs-large tumor suppressor.
Frese KK, Latorre IJ, Chung SH, Caruana G, Bernstein A, Jones SN, Donehower LA, Justice MJ, Garner CC, Javier RT.
EMBO J. 2006 Mar 22;25(6):1406-17. Epub 2006 Mar 2.
PMID 16511562
 
Somatic mutations and altered expression of the candidate tumor suppressors CSNK1 epsilon, DLG1, and EDD/hHYD in mammary ductal carcinoma.
Fuja TJ, Lin F, Osann KE, Bryant PJ.
Cancer Res. 2004 Feb 1;64(3):942-51.
PMID 14871824
 
The nuclear RhoA exchange factor Net1 interacts with proteins of the Dlg family, affects their localization, and influences their tumor suppressor activity.
Garcia-Mata R, Dubash AD, Sharek L, Carr HS, Frost JA, Burridge K.
Mol Cell Biol. 2007 Dec;27(24):8683-97. Epub 2007 Oct 15.
PMID 17938206
 
Oncogenic human papillomavirus E6 proteins target the discs large tumour suppressor for proteasome-mediated degradation.
Gardiol D, Kuhne C, Glaunsinger B, Lee SS, Javier R, Banks L.
Oncogene. 1999 Sep 30;18(40):5487-96.
PMID 10523825
 
Human discs large and scrib are localized at the same regions in colon mucosa and changes in their expression patterns are correlated with loss of tissue architecture during malignant progression.
Gardiol D, Zacchi A, Petrera F, Stanta G, Banks L.
Int J Cancer. 2006 Sep 15;119(6):1285-90.
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The MEK2-binding tumor suppressor hDlg is recruited by E-cadherin to the midbody ring
Gaudet S, Langlois MJ, Lue RA, Rivard N, Viel A
BMC Cell Biol 2011 Dec 20;12:55
PMID 22185284
 
Different isoforms of synapse-associated protein, SAP97, are expressed in the heart and have distinct effects on the voltage-gated K+ channel Kv1.5.
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J Biol Chem. 2003 Nov 21;278(47):47046-52. Epub 2003 Sep 10.
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GAKIN, a novel kinesin-like protein associates with the human homologue of the Drosophila discs large tumor suppressor in T lymphocytes.
Hanada T, Lin L, Tibaldi EV, Reinherz EL, Chishti AH.
J Biol Chem. 2000 Sep 15;275(37):28774-84.
PMID 10859302
 
Protein 4.1-mediated membrane targeting of human discs large in epithelial cells.
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Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer.
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ERK5 pathway regulates the phosphorylation of tumour suppressor hDlg during mitosis
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Biochem Biophys Res Commun 2010 Aug 13;399(1):84-90
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The APC-hDLG complex negatively regulates cell cycle progression from the G0/G1 to S phase.
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Pilt, a novel peripheral membrane protein at tight junctions in epithelial cells.
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PMID 11602598
 
Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein.
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Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11612-6.
PMID 9326658
 
The SH3, HOOK and guanylate kinase-like domains of hDLG are important for its cytoplasmic localization.
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Genes Cells. 2002 Jul;7(7):707-15.
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The invasive capacity of HPV transformed cells requires the hDlg-dependent enhancement of SGEF/RhoG activity
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PLoS Pathog 2012 Feb;8(2):e1002543
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Human homolog of disc-large is required for adherens junction assembly and differentiation of human intestinal epithelial cells.
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J Biol Chem. 2004 Mar 12;279(11):10157-66. Epub 2003 Dec 29.
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A novel and conserved protein-protein interaction domain of mammalian Lin-2/CASK binds and recruits SAP97 to the lateral surface of epithelia.
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Mol Cell Biol. 2002 Mar;22(6):1778-91.
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A multiprotein trafficking complex composed of SAP97, CASK, Veli, and Mint1 is associated with inward rectifier Kir2 potassium channels.
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FEBS J 2011 Aug;278(15):2655-65
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A functional interaction between the MAGUK protein hDlg and the gap junction protein connexin 43 in cervical tumour cells
Macdonald AI, Sun P, Hernandez-Lopez H, Aasen T, Hodgins MB, Edward M, Roberts S, Massimi P, Thomas M, Banks L, Graham SV
Biochem J 2012 Aug 15;446(1):9-21
 
Cloning and characterization of NE-dlg: a novel human homolog of the Drosophila discs large (dlg) tumor suppressor protein interacts with the APC protein.
Makino K, Kuwahara H, Masuko N, Nishiyama Y, Morisaki T, Sasaki J, Nakao M, Kuwano A, Nakata M, Ushio Y, Saya H.
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J Biol Chem. 2000 May 5;275(18):13759-70.
PMID 10788497
 
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Massimi P, Gardiol D, Roberts S, Banks L.
Exp Cell Res. 2003 Nov 1;290(2):265-74.
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Exp Cell Res. 2008 Nov 1;314(18):3306-17. Epub 2008 Sep 3.
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Differential regulation of cell-cell contact, invasion and anoikis by hScrib and hDlg in keratinocytes
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PLoS One 2012;7(7):e40279
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Calcium/calmodulin-dependent protein kinase II phosphorylation drives synapse-associated protein 97 into spines.
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J Biol Chem. 2002 Feb 22;277(8):6406-12. Epub 2001 Nov 26.
PMID 11723125
 
Adenomatous polyposis coli (APC) protein regulates epithelial cell migration and morphogenesis via PDZ domain-based interactions with plasma membranes.
Mimori-Kiyosue Y, Matsui C, Sasaki H, Tsukita S.
Genes Cells. 2007 Feb;12(2):219-33.
PMID 17295841
 
Crystal structure of a PDZ domain.
Morais Cabral JH, Petosa C, Sutcliffe MJ, Raza S, Byron O, Poy F, Marfatia SM, Chishti AH, Liddington RC.
Nature. 1996 Aug 15;382(6592):649-52.
PMID 8757139
 
Identification of brain-specific splicing variants of the hDLG1 gene and altered splicing in neuroblastoma cell lines.
Mori K, Iwao K, Miyoshi Y, Nakagawara A, Kofu K, Akiyama T, Arita N, Hayakawa T, Nakamura Y.
J Hum Genet. 1998;43(2):123-7.
PMID 9621517
 
PDZ domains and viral infection: versatile potentials of HPV-PDZ interactions in relation to malignancy
Nagasaka K, Kawana K, Osuga Y, Fujii T
Biomed Res Int 2013;2013:369712
PMID 24093094
 
CDK phosphorylation of the discs large tumour suppressor controls its localisation and stability.
Narayan N, Massimi P, Banks L.
J Cell Sci. 2009 Jan 1;122(Pt 1):65-74. Epub 2008 Dec 9.
PMID 19066288
 
The high-risk HPV E6 oncoprotein preferentially targets phosphorylated nuclear forms of hDlg
Narayan N, Subbaiah VK, Banks L
Virology 2009 Apr 25;387(1):1-4
PMID 19307009
 
The expression of hDlg as a biomarker of the outcome in malignant fibrous histiocytomas
Niimi R, Matsumine A, Iino T, Murata T, Shintani K, Nakazora S, Nakamura T, Uehara Y, Kusuzaki K, Akiyama T, Uchida A
Oncol Rep 2010 Mar;23(3):631-8
PMID 20127000
 
hCASK and hDlg associate in epithelia, and their src homology 3 and guanylate kinase domains participate in both intramolecular and intermolecular interactions.
Nix SL, Chishti AH, Anderson JM, Walther Z.
J Biol Chem. 2000 Dec 29;275(52):41192-200.
PMID 10993877
 
Formation of complexes between Ca2+.calmodulin and the synapse-associated protein SAP97 requires the SH3 domain-guanylate kinase domain-connecting HOOK region.
Paarmann I, Spangenberg O, Lavie A, Konrad M.
J Biol Chem. 2002 Oct 25;277(43):40832-8. Epub 2002 Aug 19.
PMID 12189141
 
Identification of SAP97 as an intracellular binding partner of TACE.
Peiretti F, Deprez-Beauclair P, Bonardo B, Aubert H, Juhan-Vague I, Nalbone G.
J Cell Sci. 2003 May 15;116(Pt 10):1949-57. Epub 2003 Mar 26.
PMID 12668732
 
Differential activation of p38MAPK isoforms by MKK6 and MKK3
Remy G, Risco AM, Iñesta-Vaquera FA, González-Terá B, Sabio G, Davis RJ, Cuenda A
Cell Signal 2010 Apr;22(4):660-7
PMID 20004242
 
E-cadherin mediated cell adhesion recruits SAP97 into the cortical cytoskeleton.
Reuver SM, Garner CC.
J Cell Sci. 1998 Apr;111 ( Pt 8):1071-80.
PMID 9512503
 
Phosphatidylinositol 3-kinase: a key regulator in adherens junction formation and function
Rivard N
Front Biosci (Landmark Ed) 2009 Jan 1;14:510-22
PMID 19273082
 
Changes in localization of human discs large (hDlg) during keratinocyte differentiation are [corrected] associated with expression of alternatively spliced hDlg variants.
Roberts S, Calautti E, Vanderweil S, Nguyen HO, Foley A, Baden HP, Viel A.
Exp Cell Res. 2007 Jul 15;313(12):2521-30. Epub 2007 May 24.
PMID 17574238
 
Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells.
Round JL, Tomassian T, Zhang M, Patel V, Schoenberger SP, Miceli MC.
J Exp Med. 2005 Feb 7;201(3):419-30.
PMID 15699074
 
p38gamma regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP.
Sabio G, Arthur JS, Kuma Y, Peggie M, Carr J, Murray-Tait V, Centeno F, Goedert M, Morrice NA, Cuenda A.
EMBO J. 2005 Mar 23;24(6):1134-45. Epub 2005 Feb 24.
PMID 15729360
 
p38gamma regulates interaction of nuclear PSF and RNA with the tumour-suppressor hDlg in response to osmotic shock
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J Cell Sci 2010 Aug 1;123(Pt 15):2596-604
PMID 20605917
 
Synapse-associated protein 97 selectively associates with a subset of AMPA receptors early in their biosynthetic pathway.
Sans N, Racca C, Petralia RS, Wang YX, McCallum J, Wenthold RJ.
J Neurosci. 2001 Oct 1;21(19):7506-16.
PMID 11567040
 
An association analysis of synapse-associated protein 97 (SAP97) gene in schizophrenia.
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J Neural Transm. 2008 Sep;115(9):1355-65. Epub 2008 Jul 30.
PMID 18665322
 
The notch ligand Delta1 recruits Dlg1 at cell-cell contacts and regulates cell migration.
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J Biol Chem. 2004 Dec 31;279(53):55818-26. Epub 2004 Oct 14.
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A functional network of the tumor suppressors APC, hDlg, and PTEN, that relies on recognition of specific PDZ-domains
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J Cell Biochem 2012 Aug;113(8):2661-70
PMID 22434720
 
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Mol Biol Cell. 2007 May;18(5):1744-55. Epub 2007 Mar 1.
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Tax oncoprotein of HTLV-1 binds to the human homologue of Drosophila discs large tumor suppressor protein, hDLG, and perturbs its function in cell growth control.
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Citation

This paper should be referenced as such :
Massimi P, Banks L
DLG1 (discs, large homolog 1 (Drosophila));
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/DLG1ID40333ch3q29.html
History of this paper:
Massimi, P ; Banks, L. DLG1 (discs, large homolog 1 (Drosophila)). Atlas Genet Cytogenet Oncol Haematol. 2010;14(4):368-376.
http://documents.irevues.inist.fr/bitstream/handle/2042/44730/05-2009-DLG1ID40333ch3q29.pdf


External links

Nomenclature
HGNC (Hugo)DLG1   2900
Cards
AtlasDLG1ID40333ch3q29
Entrez_Gene (NCBI)DLG1  1739  discs large MAGUK scaffold protein 1
AliasesDLGH1; SAP-97; SAP97; dJ1061C18.1.1; 
hdlg
GeneCards (Weizmann)DLG1
Ensembl hg19 (Hinxton)ENSG00000075711 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000075711 [Gene_View]  chr3:197042560-197298576 [Contig_View]  DLG1 [Vega]
ICGC DataPortalENSG00000075711
TCGA cBioPortalDLG1
AceView (NCBI)DLG1
Genatlas (Paris)DLG1
WikiGenes1739
SOURCE (Princeton)DLG1
Genetics Home Reference (NIH)DLG1
Genomic and cartography
GoldenPath hg38 (UCSC)DLG1  -     chr3:197042560-197298576 -  3q29   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)DLG1  -     3q29   [Description]    (hg19-Feb_2009)
EnsemblDLG1 - 3q29 [CytoView hg19]  DLG1 - 3q29 [CytoView hg38]
Mapping of homologs : NCBIDLG1 [Mapview hg19]  DLG1 [Mapview hg38]
OMIM601014   
Gene and transcription
Genbank (Entrez)AA837080 AB209536 AB855790 AB855791 AI223994
RefSeq transcript (Entrez)NM_001098424 NM_001204386 NM_001204387 NM_001204388 NM_001290983 NM_004087
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)DLG1
Cluster EST : UnigeneHs.292549 [ NCBI ]
CGAP (NCI)Hs.292549
Alternative Splicing GalleryENSG00000075711
Gene ExpressionDLG1 [ NCBI-GEO ]   DLG1 [ EBI - ARRAY_EXPRESS ]   DLG1 [ SEEK ]   DLG1 [ MEM ]
Gene Expression Viewer (FireBrowse)DLG1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1739
GTEX Portal (Tissue expression)DLG1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ12959   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ12959  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ12959
Splice isoforms : SwissVarQ12959
PhosPhoSitePlusQ12959
Domaine pattern : Prosite (Expaxy)GUANYLATE_KINASE_1 (PS00856)    GUANYLATE_KINASE_2 (PS50052)    L27 (PS51022)    PDZ (PS50106)    SH3 (PS50002)   
Domains : Interpro (EBI)DLG1    DLG1_PEST_dom    GK/Ca_channel_bsu    Guanylate_kin-like_dom    Guanylate_kinase_CS    L27_1    L27_dom    P-loop_NTPase    PDZ    PDZ_assoc    SH3_2    SH3_domain   
Domain families : Pfam (Sanger)Guanylate_kin (PF00625)    L27_1 (PF09058)    MAGUK_N_PEST (PF10608)    PDZ (PF00595)    PDZ_assoc (PF10600)    SH3_2 (PF07653)   
Domain families : Pfam (NCBI)pfam00625    pfam09058    pfam10608    pfam00595    pfam10600    pfam07653   
Domain families : Smart (EMBL)GuKc (SM00072)  L27 (SM00569)  MAGUK_N_PEST (SM01277)  PDZ (SM00228)  SH3 (SM00326)  
Conserved Domain (NCBI)DLG1
DMDM Disease mutations1739
Blocks (Seattle)DLG1
PDB (SRS)1PDR    2M3M    2OQS    2X7Z    3LRA    3RL7    3RL8    3W9Y    4AMH    4G69   
PDB (PDBSum)1PDR    2M3M    2OQS    2X7Z    3LRA    3RL7    3RL8    3W9Y    4AMH    4G69   
PDB (IMB)1PDR    2M3M    2OQS    2X7Z    3LRA    3RL7    3RL8    3W9Y    4AMH    4G69   
PDB (RSDB)1PDR    2M3M    2OQS    2X7Z    3LRA    3RL7    3RL8    3W9Y    4AMH    4G69   
Structural Biology KnowledgeBase1PDR    2M3M    2OQS    2X7Z    3LRA    3RL7    3RL8    3W9Y    4AMH    4G69   
SCOP (Structural Classification of Proteins)1PDR    2M3M    2OQS    2X7Z    3LRA    3RL7    3RL8    3W9Y    4AMH    4G69   
CATH (Classification of proteins structures)1PDR    2M3M    2OQS    2X7Z    3LRA    3RL7    3RL8    3W9Y    4AMH    4G69   
SuperfamilyQ12959
Human Protein AtlasENSG00000075711
Peptide AtlasQ12959
HPRD03007
IPIIPI00030351   IPI00218729   IPI00553029   IPI00552511   IPI00552682   IPI00552213   IPI00552376   IPI00975721   IPI00794349   IPI00830135   IPI00798030   IPI00796899   IPI00790354   IPI00789849   IPI00926279   IPI00927298   IPI00927236   IPI00927003   
Protein Interaction databases
DIP (DOE-UCLA)Q12959
IntAct (EBI)Q12959
FunCoupENSG00000075711
BioGRIDDLG1
STRING (EMBL)DLG1
ZODIACDLG1
Ontologies - Pathways
QuickGOQ12959
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  branching involved in ureteric bud morphogenesis  immunological synapse formation  immunological synapse  immunological synapse  endothelial cell proliferation  lens development in camera-type eye  T cell cytokine production  guanylate kinase activity  phosphoprotein phosphatase activity  protein binding  basal lamina  nucleus  cytoplasm  endoplasmic reticulum  endoplasmic reticulum membrane  Golgi apparatus  cytosol  microtubule  plasma membrane  cell-cell junction  bicellular tight junction  protein dephosphorylation  actin filament organization  mitotic cell cycle checkpoint  establishment or maintenance of cell polarity  chemical synaptic transmission  nervous system development  protein C-terminus binding  cytoskeletal protein binding  positive regulation of cell proliferation  ionotropic glutamate receptor complex  regulation of cell shape  cytoplasmic side of plasma membrane  postsynaptic density  intercalated disc  ligand-gated ion channel activity  potassium channel regulator activity  potassium channel regulator activity  potassium channel regulator activity  viral process  basolateral plasma membrane  lateral plasma membrane  single organismal cell-cell adhesion  protein kinase binding  phosphatase binding  cell junction  peristalsis  positive regulation of actin filament polymerization  cortical actin cytoskeleton organization  astral microtubule organization  cell projection membrane  mitogen-activated protein kinase kinase binding  membrane raft organization  neuromuscular junction  regulation of myelination  activation of protein kinase activity  protein complex scaffold  node of Ranvier  ion transmembrane transport  cellular protein complex localization  ionotropic glutamate receptor binding  myelin sheath abaxonal region  T cell activation  negative regulation of T cell proliferation  sarcolemma  regulation of membrane potential  amyloid precursor protein metabolic process  receptor clustering  lateral loop  positive regulation of potassium ion transport  cortical microtubule organization  ion channel binding  membrane raft  establishment or maintenance of epithelial cell apical/basal polarity  postsynaptic membrane  cadherin binding  negative regulation of mitotic cell cycle  GMP metabolic process  GDP metabolic process  perinuclear region of cytoplasm  reproductive structure development  embryonic skeletal system morphogenesis  smooth muscle tissue development  negative regulation of epithelial cell proliferation  establishment of centrosome localization  negative regulation of protein kinase B signaling  hard palate development  extracellular exosome  negative regulation of ERK1 and ERK2 cascade  bicellular tight junction assembly  protein localization to plasma membrane  protein localization to plasma membrane  positive regulation of establishment of protein localization to plasma membrane  L27 domain binding  MPP7-DLG1-LIN7 complex  receptor localization to synapse  regulation of ventricular cardiac muscle cell action potential  regulation of NIK/NF-kappaB signaling  regulation of sodium ion transmembrane transport  regulation of potassium ion import  negative regulation of p38MAPK cascade  regulation of voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization  regulation of potassium ion export across plasma membrane  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  branching involved in ureteric bud morphogenesis  immunological synapse formation  immunological synapse  immunological synapse  endothelial cell proliferation  lens development in camera-type eye  T cell cytokine production  guanylate kinase activity  phosphoprotein phosphatase activity  protein binding  basal lamina  nucleus  cytoplasm  endoplasmic reticulum  endoplasmic reticulum membrane  Golgi apparatus  cytosol  microtubule  plasma membrane  cell-cell junction  bicellular tight junction  protein dephosphorylation  actin filament organization  mitotic cell cycle checkpoint  establishment or maintenance of cell polarity  chemical synaptic transmission  nervous system development  protein C-terminus binding  cytoskeletal protein binding  positive regulation of cell proliferation  ionotropic glutamate receptor complex  regulation of cell shape  cytoplasmic side of plasma membrane  postsynaptic density  intercalated disc  ligand-gated ion channel activity  potassium channel regulator activity  potassium channel regulator activity  potassium channel regulator activity  viral process  basolateral plasma membrane  lateral plasma membrane  single organismal cell-cell adhesion  protein kinase binding  phosphatase binding  cell junction  peristalsis  positive regulation of actin filament polymerization  cortical actin cytoskeleton organization  astral microtubule organization  cell projection membrane  mitogen-activated protein kinase kinase binding  membrane raft organization  neuromuscular junction  regulation of myelination  activation of protein kinase activity  protein complex scaffold  node of Ranvier  ion transmembrane transport  cellular protein complex localization  ionotropic glutamate receptor binding  myelin sheath abaxonal region  T cell activation  negative regulation of T cell proliferation  sarcolemma  regulation of membrane potential  amyloid precursor protein metabolic process  receptor clustering  lateral loop  positive regulation of potassium ion transport  cortical microtubule organization  ion channel binding  membrane raft  establishment or maintenance of epithelial cell apical/basal polarity  postsynaptic membrane  cadherin binding  negative regulation of mitotic cell cycle  GMP metabolic process  GDP metabolic process  perinuclear region of cytoplasm  reproductive structure development  embryonic skeletal system morphogenesis  smooth muscle tissue development  negative regulation of epithelial cell proliferation  establishment of centrosome localization  negative regulation of protein kinase B signaling  hard palate development  extracellular exosome  negative regulation of ERK1 and ERK2 cascade  bicellular tight junction assembly  protein localization to plasma membrane  protein localization to plasma membrane  positive regulation of establishment of protein localization to plasma membrane  L27 domain binding  MPP7-DLG1-LIN7 complex  receptor localization to synapse  regulation of ventricular cardiac muscle cell action potential  regulation of NIK/NF-kappaB signaling  regulation of sodium ion transmembrane transport  regulation of potassium ion import  negative regulation of p38MAPK cascade  regulation of voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization  regulation of potassium ion export across plasma membrane  
Pathways : BIOCARTASynaptic Proteins at the Synaptic Junction [Genes]   
Pathways : KEGGHippo signaling pathway    T cell receptor signaling pathway    HTLV-I infection    Viral carcinogenesis   
REACTOMEQ12959 [protein]
REACTOME PathwaysR-HSA-8849932 [pathway]   
NDEx NetworkDLG1
Atlas of Cancer Signalling NetworkDLG1
Wikipedia pathwaysDLG1
Orthology - Evolution
OrthoDB1739
GeneTree (enSembl)ENSG00000075711
Phylogenetic Trees/Animal Genes : TreeFamDLG1
HOVERGENQ12959
HOGENOMQ12959
Homologs : HomoloGeneDLG1
Homology/Alignments : Family Browser (UCSC)DLG1
Gene fusions - Rearrangements
Fusion : MitelmanDLG1/CRYBG3 [3q29/3q11.2]  
Fusion : MitelmanPCCB/DLG1 [3q22.3/3q29]  [t(3;3)(q22;q29)]  
Fusion: TCGADLG1 3q29 BDH1 3q29 LUSC
Fusion: TCGADLG1 3q29 CRYBG3 3q11.2 PRAD
Fusion: TCGAPCCB 3q22.3 DLG1 3q29 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerDLG1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)DLG1
dbVarDLG1
ClinVarDLG1
1000_GenomesDLG1 
Exome Variant ServerDLG1
ExAC (Exome Aggregation Consortium)DLG1 (select the gene name)
Genetic variants : HAPMAP1739
Genomic Variants (DGV)DLG1 [DGVbeta]
DECIPHERDLG1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisDLG1 
Mutations
ICGC Data PortalDLG1 
TCGA Data PortalDLG1 
Broad Tumor PortalDLG1
OASIS PortalDLG1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICDLG1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDDLG1
intOGen PortalDLG1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch DLG1
DgiDB (Drug Gene Interaction Database)DLG1
DoCM (Curated mutations)DLG1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)DLG1 (select a term)
intoGenDLG1
NCG5 (London)DLG1
Cancer3DDLG1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601014   
Orphanet
MedgenDLG1
Genetic Testing Registry DLG1
NextProtQ12959 [Medical]
TSGene1739
GENETestsDLG1
Target ValidationDLG1
Huge Navigator DLG1 [HugePedia]
snp3D : Map Gene to Disease1739
BioCentury BCIQDLG1
ClinGenDLG1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD1739
Chemical/Pharm GKB GenePA27356
Clinical trialDLG1
Miscellaneous
canSAR (ICR)DLG1 (select the gene name)
Probes
Litterature
PubMed186 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineDLG1
EVEXDLG1
GoPubMedDLG1
iHOPDLG1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Jun 7 12:00:49 CEST 2017

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