The Drosophila Tumor Suppressor vps25 Prevents Nonautonomous Overproliferation by Regulating Notch Trafficking

Abstract

Cell-cell signaling coordinates proliferation of metazoan tissues during development, and its alteration can induce malignant transformation. Endocytosis regulates signaling by controlling the levels and activity of transmembrane receptors, both prior to and following ligand engagement. Here, we identify Vps25, a component of the ESCRT machinery that regulates endocytic sorting of signaling receptors, as an unconventional type of Drosophila tumor suppressor. vps25 mutant cells undergo autonomous neoplastic-like transformation, but they also stimulate nonautonomous cell proliferation. Endocytic trafficking defects in vps25 cells cause endosomal accumulation of the signaling receptor Notch and enhanced Notch signaling. Increased Notch activity leads to ectopic production of the mitogenic JAK-STAT pathway ligand Unpaired, which is secreted from mutant cells to induce overproliferation of the surrounding epithelium. Our data show that defects in endocytic sorting can both transform cells and, through heterotypic signaling, alter the behavior of neighboring wild-type tissue.

ESCRTing Cell Proliferation Off the Beaten Path: Unexpected Lessons from the Drosophila Eye

“…Recently published work continues this trend by establishing an unexpected link between defects in endocytic trafficking and tissue overgrowth in Drosophila. [1][2][3][4] Three of these studies focus on the proliferative effects of mutations in the vps25 (vacuolar protein sorting) and erupted (ept; the fruit fly vps23 homolog) genes, each of which encode ESCRT (Endosomal Sorting Complex Required for Transport) components. Homozygosity for mutations in vps25 or erupted is sufficient to trigger excess growth of the developing eye imaginal disc, an organ composed primarily of polarized epithelial cells.…”

“…[1][2][3] This phenotype is observed in eye-specific genetic mosaics, in which the developing eye is composed of a mixture of wild type cells and mutant cells. The adult eye structures that develop from this mixed-genotype tissue are dramatically enlarged (the eye tissue appears to 'erupt' out of the head, hence the name erupted) yet composed of mostly wild type cells, indicating that mutant cells induce surrounding wild type tissue to overgrow.…”

“…[1][2][3] Ectopic endosomal accumulation of Notch in the cytoplasm of endocytic TSG mutant cells activates Notch signaling and results in ectopic expression of Notch target genes in the eye. The Crb protein also mislocalizes to a sub-apical, cytoplasmic domain of mutant cells, and this is proposed to alter its ability to participate in pathways that define the apical and basolateral membrane domains.…”

“…These 'tumors' exhibit molecular features of defective epithelial polarity and tissue architecture, including the redistribution of proteins that mark the apical, lateral and junctional domains of polarized epithelia. [1][2][3] Within erupted neoplastic masses, cells fail to express differentiation markers, continue to divide long after normal cells have terminally exited the cell cycle, and appear to continue to proliferate for as long as the animals bearing them survive (MMG and KHM, unpublished). vps25 mutant cells expressing p35 have also been shown to metastasize to distant sites within the organism.…”

The reverse logic of multivesicular endosomes

“…propagation (Vaccari & Bilder, 2005). However, before becoming fully committed to ILV production, nascent MVBs sort transmembrane proteins and lipids within emanating tubules to other intracellular destinations, such as the trans-Golgi network, recycling endosomes, or back to the plasma membrane (Fig 1).…”