Alternative titles; symbols
HGNC Approved Gene Symbol: DLG1
Cytogenetic location: 3q29 Genomic coordinates (GRCh38): 3:197,042,560-197,299,321 (from NCBI)
Azim et al. (1995) noted that in Drosophila more than 50 genes have been identified that lead to loss of cell proliferation control, indicating that they are tumor suppressor genes. Many of these genes have been cloned and sequenced, and most have clear mammalian homologs. The Drosophila 'discs large' tumor suppressor protein, Dlg, is the prototype 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. They contain several distinct domains, including a modified guanylate kinase domain, an SH3 motif, and 1 or 3 copies of the DHR (GLGF/PDZ) domain. Recessive lethal mutations in the 'discs large' tumor suppressor gene interfere with the formation of septate junctions (thought to be the arthropod equivalent of tight junctions) between epithelial cells, and they also cause neoplastic overgrowth of imaginal discs, suggesting a role for cell junctions in proliferation control.
A homolog of the Drosophila Dlg protein was isolated from human B lymphocytes (Lue et al., 1994) and shown to bind directly to the membrane cytoskeletal protein 4.1 (130500). The presence of human DLG isoforms with or without the protein 4.1-binding domain suggested that the tissue-specific cytoskeletal interactions of the protein may be regulated by alternative splicing of its transcripts. Mori et al. (1998) identified a number of novel splicing variants, some of which were transcribed in a tissue-specific manner, as well as alteration of splicing patterns in cell lines from neuroblastomas.
Hanada et al. (1997) showed by immunoblot analysis that immunoprecipitates of DLG1 in T lymphocytes contain the Src family tyrosine kinase p56(lck) (LCK; 153390) but not p59(fyn) (FYN; 137025) or PIK3 (see PIK3CA, 171834). Binding analysis demonstrated that LCK interacts with the proline-rich N-terminal domain of DLG1. Additionally, DLG1 interacts with the Kv1.3 channel (see KCNAB1, 601141). Hanada et al. (1997) suggested that DLG1 may function as a coupler of tyrosine kinase and a voltage-gated potassium channel in T lymphocytes.
Ohshiro et al. (2000) demonstrated in Drosophila that lethal giant larvae (Lgl) (LLGL1; 600966) is essential for asymmetric cortical localization of all basal determinants in mitotic neuroblasts, and is therefore indispensable for neural fate decisions. Lgl, which itself is uniformly cortical, interacts with several types of myosin to localize the determinants. Dlg, another tumor suppressor gene, participates in this process by regulating the localization of Lgl. The localization of the apical components is unaffected in Lgl or Dlg mutants. Thus, Lgl and Dlg act in a common process that differentially mediates cortical protein targeting in mitotic neuroblasts, and creates intrinsic differences between daughter cells.
Peng et al. (2000) showed that Drosophila Lgl and Dlg regulate basal protein targeting, but not apical complex formation or spindle orientation, in both embryonic and larval neuroblasts. Dlg protein is apically enriched and is required for maintaining cortical localization of Lgl protein. Basal protein targeting requires microfilament and myosin function, yet the Lgl phenotype is strongly suppressed by reducing levels of myosin II. Peng et al. (2000) concluded that Dlg and Lgl promote, and myosin II inhibits, actomyosin-dependent basal protein targeting in neuroblasts.
Bonilha and Rodriguez-Boulan (2001) identified EBP50 (604990) and SAP97 as binding partners for ezrin (123900), an actin-binding protein crucial for morphogenesis of apical microvilli and basolateral infoldings in retinal pigment epithelial (RPE) cells. Immunofluorescence microscopy detected a polarized distribution of EBP50 at apical microvilli and of SAP97 at the basolateral surface of RPE cells, which overlapped with ezrin.
Willatt et al. (2005) pointed out that the DLG1 and PAK2 (605022) genes are deleted in the 3q29 microdeletion syndrome (609425) 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 (300142) and DLG3 (300189).
Bohl et al. (2007) found that MPP7 (610973) formed a tripartite complex with DLG1 and LIN7A (603380) or LIN7C in vitro and in vivo. 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 localized to epithelial adherens junctions in transfected Madin-Darby canine kidney cells. Expression of an MPP7 construct lacking either the PDZ or SH3 domain redistributed MPP7, DLG1, and LIN7 into the soluble cytoplasmic fraction.
Stucke et al. (2007) showed that the L27N domain of endogenous MPP7 bound DLG1 in human epithelial cells. MPP7 and DLG1 colocalized at the lateral surface of epithelial cells, and they overlapped with markers of adherens junctions and tight junctions. Recruitment of MPP7 to the plasma membrane was dependent on its interaction with DLG1. Loss of either DLG1 or MPP7 from epithelial cells resulted in a significant defect in assembly and maintenance of functional tight junctions. Stucke et al. (2007) concluded that formation of the DLG1-MPP7 complex promotes epithelial cell polarity and tight junction formation.
Cotter et al. (2010) showed that, in Schwann cells, mammalian disks large homolog 1 (Dlg1) interacts with Pten (601728) to inhibit axonal stimulation of myelination. This mechanism limits myelin sheath thickness and prevents overmyelination in mouse sciatic nerves. Removing this brake results in myelin outfoldings and demyelination, characteristics of some peripheral neuropathies. Indeed, the Dlg1 brake is no longer functional in a mouse model of Charcot-Marie-Tooth disease (CMT4B1; 601382). Cotter et al. (2010) concluded that negative regulation of myelination appears to be essential for optimization of nerve conduction velocity and myelin maintenance.
By analysis of human/rodent somatic cell hybrids and by fluorescence in situ hybridization, Azim et al. (1995) mapped the DLG1 gene to 3q29. The authors stated that no tumor suppressor gene had previously been localized to 3q29. By interspecific backcross mapping, Peters et al. (1996) and Burgess et al. (1996) determined that the mouse gene corresponding to human DLG1, Dlgh1, maps to chromosome 16.
Mahoney et al. (2006) stated that mutant mice expressing a truncated Dlgh1 protein retaining the 3 PDZ domains exhibit growth retardation, craniofacial abnormalities, neonatal lethality, increased proliferation in the lens, and small kidneys associated with impaired ureteric bud branching and reduced nephron formation. Mahoney et al. (2006) developed Dlgh1-null mice and found that they were born at the expected mendelian ratio but exhibited respiratory distress and died shortly after birth In addition to the phenotypes described above, all Dlgh1 -/- mice had severely shortened ureters. Unilateral renal agenesis was found in 20% of Dlgh1-null embryos, and unilateral/bilateral perinatal hydronephrosis was found in 35% of Dlgh1-null embryos. Hydronephrosis was associated with a defect in ureteric smooth muscle orientation that dramatically impaired efficient peristalsis.
Azim, A. C., Knoll, J. H. M., Marfatia, S. M., Peel, D. J., Bryant, P. J., Chishti, A. H. DLG1: chromosome location of the closest human homologue of the Drosophila discs large tumor suppressor gene. Genomics 30: 613-616, 1995. [PubMed: 8825652] [Full Text: https://doi.org/10.1006/geno.1995.1286]
Bohl, J., Brimer, N., Lyons, C., Vande Pol, S. B. The Stardust family protein MPP7 forms a tripartite complex with LIN7 and DLG1 that regulates the stability and localization of DLG1 to cell junctions. J. Biol. Chem. 282: 9392-9400, 2007. [PubMed: 17237226] [Full Text: https://doi.org/10.1074/jbc.M610002200]
Bonilha, V. L., Rodriguez-Boulan, E. Polarity and developmental regulation of two PDZ proteins in the retinal pigment epithelium. Invest. Ophthal. Vis. Sci. 42: 3274-3282, 2001. [PubMed: 11726633]
Burgess, D. L., Rafael, J. A., Meisler, M. H., Chamberlain, J. S. Dlgh1, a mouse homolog of the Drosophila discs-large gene, is located on chromosome 16. Mammalian Genome 7: 623-624, 1996. [PubMed: 8678991] [Full Text: https://doi.org/10.1007/s003359900187]
Cotter, L., Ozcelik, M., Jacob, C., Pereira, J. A., Locher, V., Baumann, R., Relvas, J. B., Suter, U., Tricaud, N. Dlg1-PTEN interaction regulates myelin thickness to prevent damaging peripheral nerve overmyelination. Science 328: 1415-1418, 2010. [PubMed: 20448149] [Full Text: https://doi.org/10.1126/science.1187735]
Hanada, T., Lin, L., Chandy, K. G., Oh, S. S., Chishti, A. H. Human homologue of the Drosophila discs large tumor suppressor binds to p56lck tyrosine kinase and Shaker type Kv1.3 potassium channel in T lymphocytes. J. Biol. Chem. 272: 26899-26904, 1997. [PubMed: 9341123] [Full Text: https://doi.org/10.1074/jbc.272.43.26899]
Lue, R. A., Marfatia, S. M., Branton, D., Chishti, A. H. Cloning and characterization of hdlg: the human homologue of the Drosophila discs large tumor suppressor binds to protein 4.1. Proc. Nat. Acad. Sci. 91: 9818-9822, 1994. [PubMed: 7937897] [Full Text: https://doi.org/10.1073/pnas.91.21.9818]
Mahoney, Z. X., Sammut, B., Xavier, R. J., Cunninham, J., Go, G., Brim, K. L., Stappenbeck, T. S., Miner, J. H., Swat, W. Discs-large homolog 1 regulates smooth muscle orientation in the mouse ureter. Proc. Nat. Acad. Sci. 103: 19872-19877, 2006. [PubMed: 17172448] [Full Text: https://doi.org/10.1073/pnas.0609326103]
Mori, K., Iwao, K., Miyoshi, Y., Nakagawara, A., Kofu, K., Akiyama, T., Arita, N., Hayakawa, T., Nakamura, Y. Identification of brain-specific splicing variants of the hDLG1 gene and altered splicing in neuroblastoma cell lines. J. Hum. Genet. 43: 123-127, 1998. [PubMed: 9621517] [Full Text: https://doi.org/10.1007/s100380050052]
Ohshiro, T., Yagami, T., Zhang, C., Matsuzaki, F. Role of cortical tumour-suppressor proteins in asymmetric division of Drosophila neuroblast. Nature 408: 593-596, 2000. [PubMed: 11117747] [Full Text: https://doi.org/10.1038/35046087]
Peng, C.-Y., Manning, L., Albertson, R., Doe, C. Q. The tumour-suppressor genes lgl and dlg regulate basal protein targeting in Drosophila neuroblasts. Nature 408: 596-600, 2000. [PubMed: 11117748] [Full Text: https://doi.org/10.1038/35046094]
Peters, L. L., Ciciotte, S. L., Lin, L., Chishti, A. H. The mouse homolog of the Drosophila discs large tumor suppressor gene maps to chromosome 16. Mammalian Genome 7: 619-620, 1996. [PubMed: 8829552] [Full Text: https://doi.org/10.1007/s003359900291]
Stucke, V. M., Timmerman, E., Vandekerckhove, J., Gevaert, K., Hall, A. The MAGUK protein MPP7 binds to the polarity protein hDlg1 and facilitates epithelial tight junction formation. Molec. Biol. Cell 18: 1744-1755, 2007. [PubMed: 17332497] [Full Text: https://doi.org/10.1091/mbc.e06-11-0980]
Willatt, L., Cox, J., Barber, J., Cabanas, E. D., Collins, A., Donnai, D., FitzPatrick, D. R., Maher, E., Martin, H., Parnau, J., Pindar, L., Ramsay, J., Shaw-Smith, C., Sistermans, E. A., Tettenborn, M., Trump, D., de Vries, B. B. A., Walker, K., Raymond, F. L. 3q29 microdeletion syndrome: clinical and molecular characterization of a new syndrome. Am. J. Hum. Genet. 77: 154-160, 2005. [PubMed: 15918153] [Full Text: https://doi.org/10.1086/431653]