• carcinoma

The protein encoded by the Drosophila gene l(2)gl 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) and 'cancer, epithelial, Scribble-complex-related' (FBhh0000586).

Expression of l(2)gl loss-of-function alleles in combination with the Ras85D^V12 activated mutation results in tumors exhibiting metastatic phenotypes, including basement membrane degradation, loss of E-cadherin expression, migration, invasion, and secondary tumor formation.

In human, there are two genes orthologous to Dmel\l(2)gl, the cytoskeletal proteins LLGL1 and LLGL2. Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for l(2)gl; an amorphic allele has been created via gene targeting and recombination. 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. Somatic clones that are homozygous for loss-of-function mutations of l(2)gl exhibit a cell polarity defect; the cells are eliminated from mosaic epithelia by cell competition. 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.

The RAS proteins are GDP/GTP-binding proteins that act as intracellular signal transducers and are crucial players in many signaling networks affecting cell cycle progression, growth, migration, cytoskeletal changes, apoptosis, and senescence. Originally defined as oncogenes, the RAS GTPase family includes KRAS (MIM:190070), HRAS (MIM:190020), and NRAS (MIM:164790); mutations in these three genes are among the most common events in human cancers. For KRAS, HRAS and NRAS, there is a single high-scoring ortholog in Drosophila, Ras85D, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. There are multiple other paralogous and orthologous genes in both species. Of the three human RAS GTPase genes, a tagged UAS construct of Hsap\HRAS has been introduced into flies, but has not been characterized.

The constitutively active Ras85D mutation, Ras85D^V12, 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).

Animals homozygous for loss-of-function alleles of Dmel\Ras85D die during the larval stage. Most work relevant to cancer has been done with an activated form of the gene, Ras85D^V12. This allele is usually lethal during the pupal stage, with larvae showing tumorous growths; somatic clones of Ras85D^V12 exhibit an overgrowth phenotype in multiple different tissues tested. Many physical and genetic interactions for Dmel\Ras85D have been described; see below and in the gene report for Ras85D.

[updated Nov. 2018 by FlyBase; FBrf0222196]