Disease relevance of DLG1

• As one-third retained the normal brain-splicing pattern, the loss of normal splicing of hDLG1 may not in itself cause formation of tumors, but it might reflect the biological character of individual neuroblastomas [1].
• The human homologue of Drosophila tumor suppressor dlg, hDLG1, is one of the proteins known to interact with APC, a tumor suppressor for colorectal cancer [1].
• Our results suggest that (i) besides its well documented role in regulating epithelial polarity, Dlgh1 also regulates smooth muscle orientation, and (ii) human DLG1 mutations may contribute to hereditary forms of hydronephrosis [2].
• Somatic mutations and altered expression of the candidate tumor suppressors CSNK1 epsilon, DLG1, and EDD/hHYD in mammary ductal carcinoma [3].
• The fact that several different human virus oncoproteins, including adenovirus type 9 E4-ORF1, evolved to target the Dlg1 mammalian homolog of the membrane-associated Drosophila discs-large tumor suppressor has implicated this cellular factor in human cancer [4].

High impact information on DLG1

• A human Dlg homolog, hDlg, has been implicated in tumorigenic processes via its association with the product of the Adenomatous Polyposis Coli (APC) gene [5].
• A Dlgh1 mutant incapable of binding p38 failed to activate NFAT [6].
• Scaffold protein Dlgh1 coordinates alternative p38 kinase activation, directing T cell receptor signals toward NFAT but not NF-kappaB transcription factors [6].
• Loss of potentiation was correlated with faster turnover of monomeric SAP97 mutants in dendritic spines [7].
• We also suggest how recently discovered binding interactions could provide a structural readout mechanism: the autophosphorylated state of CaMKII binds tightly to the NMDAR and forms, through CaMKII-actinin-actin-(4.1/SAP97) linkages, additional sites for anchoring AMPARs at synapses [8].

Chemical compound and disease context of DLG1

• Using a yeast two-hybrid screen, we identified hDlg as a cellular binding partner of a viral membrane integral protein, the envelope glycoprotein (Env) of human T-cell leukemia virus type 1 (HTLV-1) [9].

Biological context of DLG1

• DLG1: chromosome location of the closest human homologue of the Drosophila discs large tumor suppressor gene [10].
• 1. Here, we report that the gene for lymphocyte Hdlg, named DLG1, is located at chromosome band 3q29 [10].
• PBK and hDlg are phosphorylated at mitosis in HeLa cells, and the mitotic phosphorylation of PBK is required for its kinase activity [11].
• This evidence shows how PBK could link hDlg or other PDZ-containing proteins to signal transduction pathways regulating the cell cycle or cellular proliferation [11].
• hDlg, a human homologue of the Drosophila Dig tumor suppressor, contains two binding sites for protein 4.1, one within a domain containing three PSD-95/Dlg/ZO-1 (PDZ) repeats and another within the alternatively spliced I3 domain [12].

Anatomical context of DLG1

• In contrast, in stably transfected confluent MDCK cells, both hDlg-I2 and -I3 isoforms localized efficiently to the lateral membrane, consistent with the previous notion that the N-terminal domain of hDlg mediates its membrane targeting in polarized epithelial cells [13].
• 1. Furthermore, we found that Kir4.1 as well as SAP97 distributed not diffusely but clustered in retinal glial cells [14].
• In epithelial cells, hDlg localizes at the basolateral plasma membrane, but its localization mechanism is unknown [15].
• These results suggest that hDlg localizes at the plasma membrane through TEM5 and TEM5-like and furthermore scaffolds these GPCRs in endothelial cells during tumor angiogenesis and neoangiogenesis [15].
• Selective reduction of a PDZ protein, SAP-97, in the prefrontal cortex of patients with chronic schizophrenia [16].

Associations of DLG1 with chemical compounds

• In a two-hybrid screen, we identified a 322-aa serine/threonine kinase that binds to the PDZ2 domain of hDlg [11].
• Threonine phosphorylation of the MMAC1/ PTEN-PDZBD peptide inhibited both microtiter plate binding to the hDLG and hMAST205 PDZ domains and coprecipitation of the Mr 140,000 and > 200,000 proteins, but promoted coprecipitation of proteins of approximately Mr 90,000 and Mr 120,000 from A431 cell lysate [17].
• Here, green fluorescent protein (GFP)-tagged chimeras and deletion mutants of SAP97 and SAP90 were employed to define the molecular mechanism underlying their differential association with kainate receptors [18].
• Selective binding of synapse-associated protein 97 to GluR-A alpha-amino-5-hydroxy-3-methyl-4-isoxazole propionate receptor subunit is determined by a novel sequence motif [19].
• Surface plasmon resonance experiments revealed that mutation of SAP97 Thr(389) to alanine, as with the other PSD-95-like membrane-associated guanylate kinases, induced binding to megalin [20].

Physical interactions of DLG1

• In vitro, PBK binds specifically to PDZ2 of hDlg through its C-terminal T/SXV motif [11].
• Human discs large (hDlg) protein binds to protein 4.1R via a motif encoded by an alternatively spliced exon located between the SH3 and the C-terminal guanylate kinase-like domains [13].
• The PDZ domains of hDlg bound the C-terminal PDZ-binding motif of TEM5 [15].
• Identification of SAP97 as an intracellular binding partner of TACE [21].
• Here we show that hDLG interacts through its PDZ domains with the carboxy-terminal S/TXV motif of the mitochondrial ribosomal protein S-34 (MRP-S34) [22].

Co-localisations of DLG1

• 1) hDlg co-localizes with E-cadherin, but not with ZO-1, at the sites of cell-cell contact in intestinal epithelial cells [23].

Regulatory relationships of DLG1

• In the present study, we found that overexpression of hDLG suppresses cell proliferation by blocking cell cycle progression from the G0/G1 to S phase [24].
• Using RNA interference, we also demonstrate that endogenous beta-TrCP regulates hDlg protein levels in epithelial cells [25].
• Additionally, phosphorylation of the Kir2.2 C terminus by protein kinase A inhibited the association with SAP97 [26].
• Thus, CaMKII-dependent phosphorylation of SAP97 in different time frames and locations within the neurons controls both NR2A trafficking and insertion [27].

Other interactions of DLG1

• We introduced a double mutation (I38A/I40A) into the N-terminal domain of hDlg, which disrupted its interaction with DLG2, a key event in the membrane targeting of hDlg [13].
• The SAP97 PDZ2 domain differed at four positions from the other members of the PSD-95 subfamily [20].
• Together, our results demonstrate that in addition to the N-terminal targeting domain, the alternatively spliced I3 insertion plays a critical role in recruiting hDlg to the lateral membrane in epithelial cells via its interaction with protein 4.1R [13].
• E6AP was required for the in vivo degradation of DLG1 by both HVP-18 E6 and a chimeric HPV-11E6 [28].
• hDlg, the human homologue of the Drosophila Discs-large (Dlg) tumor suppressor protein, is known to interact with the tumor suppressor protein APC and the human papillomavirus E6 transforming protein [11].

Analytical, diagnostic and therapeutic context of DLG1

• Confocal immunofluorescence microscopy revealed the exclusive presence and colocalization of PMCA4b and SAP97 in the basolateral membrane of polarized Madin-Darby canine kidney epithelial cells [29].
• By deletions and site-directed mutagenesis, we demonstrated that this interaction involved the PDZ3 domain of SAP97 and the extreme C-terminal amino-acid sequence of TACE [21].
• In addition, confocal microscopy showed that endogenous TACE and SAP97 colocalized in some intracellular areas of COS-7 cells and CACO-2 cells [21].
• We analyzed the levels and distribution of hDlg and hScrib by immunohistochemistry, using serial sections of the same sample [30].
• In human T lymphocyte cell lines, binding properties of hDlg were studied by immunoprecipitation, immunoblotting, and immune complex kinase assays [31].

References