Epithelial cancer has been modeled in flies using the Drosophila Vha44 gene in combination with an activated mutation of the Drosophila Ras85D gene. Dmel\Vha44 is orthologous to two human genes, ATP6V1C1 and ATP6V1C2, which encode cytosolic (V1) subunits of a V-type ATPase proton pump (ATP6V). RNAi targeting constructs and many alleles caused by insertional mutagenesis have been generated for Vha44.
Overexpression of Vha44 in a region of the Drosophila wing disc results in epithelial cell overgrowth and a mild invasive phenotype. Overexpression of Vha44 in combination with an activated mutation of Ras85D results in significantly stronger cell migration phenotypes. The role of apoptosis in this system and dependence on TNF-JNK signaling have been investigated.
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. The constitutively active Dmel\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). The Ras85DV12 activated mutation produces overproliferation phenotypes, but typically does not result in phenotypes indicative of metastasis (or results in a low frequency of these phenotypes). For additional information and external links relevant to the role of RAS in human cancers see the human disease model report 'cancer, multiple, RAS-related' (FBhh0000474).
[updated Jun. 2019 by FlyBase; FBrf0222196]
The V-ATPase is a complex enzyme that is composed of several subunits that are assembled into two domains: a transmembrane V0 domain and a cytosolic V1 domain. The V1 domain (ATP6V1) is formed by eight subunits (Breton and Brown, 2013; pubmed:23997191).
V-type ATPases (ATP6V) couple the energy of ATP hydrolysis to proton transport across intracellular and plasma membranes of eukaryotic cells. (HGNC Gene group: V-type ATPases (ATP6V), https://www.genenames.org/data/genegroup/#!/group/415)
Many to one: 2 human genes to 1 Drosophila gene.
Many to one: 2 human genes to 1 Drosophila gene.
High-scoring ortholog of human ATP6V1C1; moderate-scoring ortholog of human ATP6V1C2 (1 Drosophila to 2 human). Dmel\Vha44 shares 26-30% identity and 34-38% similarity with the human genes.