The protein encoded by the Drosophila gene dlg1 is a component of the Scribble polarity complex, which plays a key role in determining cell polarity and cell proliferation in epithelial cells. Drosophila models of epithelial cancer initiation and progression have been developed using Scribble polarity complex genes in combination with an activated form of the Ras85D gene. See also the human disease model reports 'cancer, multiple, RAS-related' (FBhh0000474), 'cancer, epithelial, Scribble-complex-related' (FBhh0000586), and 'cancer, epithelial, DLG1-related' (FBhh0000678).
In human, there are four genes orthologous to Dmel\dlg1, DLG1 (a component of the Scribble polarity complex), DLG2, DLG3, and DLG4. Although the human Hsap\DLG4 gene has been introduced into flies, DLG1 has not. Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\dlg1.
Expression of dlg1 loss-of-function alleles in combination with the Ras85DV12 activated mutation results in tumors phenotypes more extreme than either genetic alteration alone. Metastatic phenotypes are observed, including basement membrane degradation, loss of E-cadherin expression, migration, invasion, and secondary tumor formation. RAS-DLG1 tumors induced in the larval eye disc have been used to study cachexia.
Animals homozygous for loss-of-function mutations of Dmel\dlg1 typically die during the larval stage; tumors of the brain and imaginal discs are observed; defects associated with neuromuscular junctions are observed.
Animals homozygous for loss-of-function alleles of Dmel\Ras85D die during the larval stage. The constitutively active Ras85D mutation, Ras85DV12, is analogous to oncogenic mutations found in human RAS proteins. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G12V in the fly Ras85D gene (corresponds to G12V in the human KRAS and HRAS genes).This allele is usually lethal during the pupal stage, with larvae showing tumorous growths; somatic clones of Ras85DV12 exhibit an overgrowth phenotype in multiple different tissues tested.
[updated Oct. 2021 by FlyBase; FBrf0222196]
DLG1 encodes an essential multidomain scaffolding protein with multiple roles in normal development. It recruits channels, receptors and signaling molecules to discrete plasma membrane domains in polarized cells, and may play roles in adherens junction assembly, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation. [from Gene Cards, DLG1; 2017.08.01]
DLG1 is a membrane-associated guanylate kinase (MAGUK). [from NCBI Gene, DLG1; 2017.08.01]
The RAS proteins are members of a large superfamily of low-molecular-weight GTP-binding proteins. The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. Three members of the RAS family, HRAS, KRAS and NRAS, are found to be activated by mutation in human tumors. These three members are very closely related, having 85% amino acid sequence identity (Downward, 2003; pubmed:12509763).
Many to many: multiple paralogs and orthologs in both species.
Many to one (4 human to 1 Drosophila); the other human genes are DLG4, DLG2, and DLG3.
Many to many: multiple paralogs and orthologs in both species.
Many to many: multiple paralogs and orthologs in both species.
Moderate- to high-scoring ortholog of human DLG1, DLG4, DLG2, and DLG3 (1 Drosophila to 4 human). Dmel\dlg1 shares 40-49% identity and 55-63% similarity with the human genes.
