Mutations of several Drosophila genes that encode components of ESCRT-complexes have been observed to produce overproliferation phenotypes. A part of the endosomal-lysosomal network, the ESCRT complexes, acting sequentially at the endosomal membrane, recognize and sort ubiquitinated endosomal proteins for degradation. Two Drosophila ESCRT-complex genes, TSG101 (orthologous to human TSG101) and Vps25 (orthologous to human VPS25) have been investigated in the context of a cancer model. Classical loss-of-functions mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both fly genes.
A UAS construct of the human Hsap\TSG101 has been introduced into flies, but has not been characterized in the context of this disease model.
Animals homozygous for loss-of-function mutations of Dmel\TSG101 typically die during the larval stage. Loss-of-function mutations of the Drosophila TSG101 gene result in overgrowth phenotypes in two different contexts: first, clones of TSG101 cells promote the overgrowth of surrounding wild-type tissue; second, eye discs composed almost entirely of TSG101 mutant tissue continue to grow during an extended larval stage, failing to respond to signals that normally sense and restrict organ size, and becoming tumorous masses.
Animals homozygous for loss-of-function mutations of Dmel\Vps25 typically die in the late embryonic or larval stages. Lack of Vps25 function in somatic clones causes at least phenotypes related to abnormal patterns of growth: non-autonomous proliferation, non-autonomous resistance to cell death, and autonomous apoptosis. As the mutant cells proliferate, they lose their epithelial organization and undergo apoptosis.
See the FlyBase gene group report ENDOSOMAL SORTING COMPLEXES REQUIRED FOR TRANSPORT (FBgg0000215) and the HGNC gene group reports under 'ESCRT complexes' (https://www.genenames.org/data/genegroup/#!/group/1111).
[updated Feb. 2019 by FlyBase; FBrf0222196]
Upon entering the endosomal-lysosomal network, internalized protein cargo has two potential destinies: either it is trafficked and delivered to the late endosomes and terminally, to lysosomes for degradation (via the ESCRT system); or, it is sorted and transported to the trans-Golgi network or the plasma membrane for reuse (via the retromer). At the endosomal membrane, the ESCRT complexes, acting sequentially, recognize and sort ubiquitinated endosomal proteins for degradation. (Hu et al., 2015; pubmed:26448863)
One to one: 1 human to 1 Drosophila.
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human TSG101 (VPS23) (1 Drosophila to 1 human). Dmel\TSG101 shares 50% identity and 66% similarity with the human gene.
High-scoring ortholog of human VPS25 (1 Drosophila to 1 human). Dmel\Vps25 shares 43% identity and 66% similarity with the human gene.
