Loss of apical-basal polarity is an early event in the development of epithelial cancers. This model uses the Drosophila gene l(2)gl, which encodes a component of the Scribble polarity complex; this complex plays a key role in determining cell polarity and cell proliferation in epithelial cells. In human, there are two genes orthologous to Dmel\l(2)gl, the cytoskeletal proteins LLGL1 and LLGL2. Classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\l(2)gl.
See also human diseases model reports 'cancer, epithelial, Scribble-complex-related' (FBhh0000586), 'cancer, epithelial, RAS-LLGL-related' (FBhh0000588), and 'cancer, epithelial, LLGL-YAP1-related' (FBhh0000590).
A tagged wild-type transgene of human Hsap\LLGL1 has been introduced into flies; partial heterologous rescue (functional complementation) of the homozygous Dmel\l(2)gl lethal phenotype is observed.
Animals homozygous for loss-of-function mutations of Dmel\l(2)gl typically die during the larval stage and exhibit abnormal overproliferation of tissues, including in the brain, imaginal discs, and hematopoietic organs; cell-polarity defects are observed. Somatic clones in different regions of the wing disc differ in susceptibility to development of l(2)gl-induced overproliferation: in some regions mutant cells are eliminated from mosaic epithelia by cell competition, in other regions clones produce tumor-like overgrowths. Observing that a number of microRNAs are dysregulated in l(2)gl tumors, a specific microRNA (mir-9a) was tested phenotypically; overexpression of mir-9a was found to reduce the overgrowth phenotype caused by loss of l(2)gl function in the wing epithelium. Multiple physical and many genetic interactions for Dmel\l(2)gl have been described; see below and in the gene report for l(2)gl.
[updated Jan. 2019 by FlyBase; FBrf0222196]
LLGL1 and LLGL2 encode cortical cytoskeleton proteins found in a complex involved in maintaining cell polarity and epithelial integrity, the Scribble Cell Polarity Complex. This complex plays a role in the initial phase of the establishment of epithelial cell polarity; it is involved in the regulation of mitotic spindle orientation, proliferation, differentiation, and tissue organization of neuroepithelial cells. [Gene Cards, LLGL1, LLGL2; 2017.08.01]
Many to one: 2 human to 1 Drosophila; the second human gene is LLGL1.
Many to one: 2 human to 1 Drosophila; the second human gene is LLGL2.
Moderate- to high-scoring ortholog of human LLGL1 and LLGL2 (1 Drosophila to 2 human). Dmel\l(2)gl shares 34-36% identity and 51-54% similarity with the human genes.
