Models of epithelial cancer initiation and progression have been developed using the Drosophila scrib gene in combination with the Drosophila Ras85D gene. Investigations using these models include assessment of anti-tumor pharmaceutical candidates, identification of induced transcription factors, and characterization of involvement of the JNK and Hippo signaling pathways. See also the human disease model reports 'cancer, multiple, RAS-related' (FBhh0000474), 'cancer, epithelial, SCRIB-related' (FBhh0000587), and 'cancer, epithelial, Scribble-complex-related' (FBhh0000586).
Expression of scrib loss-of-function alleles in combination with the Ras85DV12 activated mutation results in extensive tumors in larvae; metastatic phenotypes, including basement membrane degradation, loss of E-cadherin expression, migration, invasion, and secondary tumor formation, are observed. Metastatic phenotypes are not observed for either type of mutation alone.
The Scribble polarity complex plays a key role in determining cell polarity and cell proliferation in epithelial cells. The eponymous Drosophila scrib gene is a cell polarity regulator and neoplastic tumor suppressor; there are two orthologous genes in human, SCRIB and LRRC1. The mammalian SCRIB gene has also been characterized as a tumor suppressor. Dmel\scrib is well characterized genetically: classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. A tagged wild-type transgene of human Hsap\SCRIB has been introduced into flies; partial heterologous rescue (functional complementation) of homozygous Dmel\scrib loss-of-function phenotypes is observed.
Animals homozygous for loss-of-function mutations of Dmel\scrib typically die during the larval stage; somatic clones that are homozygous for scrib exhibit overgrowth phenotypes. Many physical and genetic interactions for Dmel\scrib have been described; see below and in the gene report for scrib.
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, 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).
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, Ras85DV12. 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. 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]
The SCRIB gene encodes a scaffold protein involved in cell polarization processes; it is involved in tumor suppression pathways (Gene Cards, SCRIB; 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).
SCRIB is a cytoplasmic multi-modular scaffold protein targeted to epithelial adherens junctions and neuronal presynaptic compartments. SCRIB and its orthologs in vertebrates and invertebrates participate in cell polarization (summary by Nola et al., 2008; pubmed:18716323). [from MIM:607733; 2017.08.01]
Many to many: multiple paralogs and orthologs in both species.
Many to one: 2 human to 1 Drosophila; the second human gene is LRRC1.
Many to many: multiple paralogs and orthologs in both species.
Many to many: multiple paralogs and orthologs in both species.
Ortholog of human SCRIB and LRRC1 (1 Drosophila to 2 human); Dmel\scrib shares 33% identity and 45% similarity with the human SCRIB gene. The human LRRC1 gene encodes a much smaller protein, corresponding to the amino end of SCRIB and Dmel\scrib; it shares 57% identity and 73% similarity with Dmel\scrib within that extent.