Intercellular interactions in the context of tumorigenesis, including cell competition and induction of non-autonomous proliferation, have been investigated using mutations of the fly gene Rab5; this gene has been shown to play a key role in endocytosis. In human, there are three orthologous genes, RAB5B, RAB5C, and RAB5A; RAB genes are members of the Ras superfamily of small GTPases. None of the human RAB5 genes has been implicated in cancer. For Dmel\Rab5, loss-of-function mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
UAS constructs of tagged Hsap\RAB5C and Hsap\RAB5A human genes have been introduced into flies, but have not been characterized in the context of this disease model.
Mutations in Dmel\Rab5 were recovered in a genetic screen using Ras85DV12 clones in the adult eye. Such clones exhibit overgrowth and develop into benign tumors; additional mutations within the clone that induce non-autonomous growth of the surrounding tissue were identified. (See also 'cancer, non-autonomous proliferation, RAS-mito' (FBhh0000774). It was determined that loss of Rab5 alone causes non-autonomous tissue overgrowth. Evidence supports the hypothesis that loss of Rab5 results in increased expression of upd1, a secreted growth-promoting ligand, through inactivation of the Hippo pathway, and that deregulated endocytosis may contribute to tumorigenesis.
In experiments in which clones were induced in wing discs, it was found that a compartment entirely made by Rab5 mutant cells can grow indefinitely, but clones of Rab5 cells surrounded by normal cells are eliminated by cell competition. If the clone is sufficiently large, mutant cells in the periphery are eliminated, but those inside survive and continue proliferating. It was determined that this phenomenon is dependent upon apoptosis occurring in the peripheral cells, and it is postulated that this effect may also impact non-tumorous cells at the periphery of the tumor. These results support evidence from Drosophila and other organisms that apoptosis-induced proliferation (AiP) may facilitate tumor growth in some contexts. See the human disease model report 'cancer, multiple, apoptosis-induced proliferation' (FBhh0000931).
Animals homozygous for loss-of-function mutations of Dmel\Rab5 typically die during the larval stage. Phenotypes of somatic clones and of targeted loss of expression via RNAi have been extensively described. Many physical and genetic interactions of Dmel\Rab5 have been described; see below and in the Rab5 gene report.
Other Drosophila genes with roles in endocytosis have been characterized in the context of tumorigenesis (reviewed in Vaccari and Bilder, 2009, FBrf0209113; discussion in Takino et al., 2014, FBrf0226396).
[updated Oct. 2019 by FlyBase; FBrf0222196]
The Rab family of proteins is a member of the Ras superfamily of monomeric G proteins. Rab GTPases regulate many steps of membrane traffic, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane fusion. [https://www.genenames.org/cgi-bin/genefamilies/set/388]
Many to one: 3 human to 1 Drosophila. The human genes are RAB5A, RAB5B, and RAB5C.
Many to one: 3 human to 1 Drosophila. The human genes are RAB5A, RAB5B, and RAB5C.
Many to one: 3 human to 1 Drosophila. The human genes are RAB5A, RAB5B, and RAB5C.
Moderate- to high-scoring ortholog of human RAB5A, RAB5B, and RAB5C (1 Drosophila to 3 human). Dmel\Rab5 shares 73-75% identity and 80-86% similarity with the human genes.
