Abstract
Multiple genes involved in endocytosis and endosomal protein trafficking in Drosophila have been shown to function as neoplastic tumor suppressor genes (nTSGs), including Endosomal Sorting Complex Required for Transport-II (ESCRT-II) components vacuolar protein sorting 22 (vps22), vps25, and vps36. However, most studies of endocytic nTSGs have been done in mosaic tissues containing both mutant and non-mutant populations of cells, and interactions among mutant and non-mutant cells greatly influence the final phenotype. Thus, the true autonomous phenotype of tissues mutant for endocytic nTSGs remains unclear. Here, we show that tissues predominantly mutant for ESCRT-II components display characteristics of neoplastic transformation and then undergo apoptosis. These neoplastic tissues show upregulation of c-Jun N-terminal Kinase (JNK), Notch, and Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling. Significantly, while inhibition of JNK signaling in mutant tissues partially inhibits proliferation, inhibition of JAK/STAT signaling rescues other aspects of the neoplastic phenotype. This is the first rigorous study of tissues predominantly mutant for endocytic nTSGs and provides clear evidence for cooperation among de-regulated signaling pathways leading to tumorigenesis.
Highlights
Tumor development involves destabilization of the wellcontrolled processes of cell proliferation, cell polarization, and programmed cell death that are tightly regulated by widely conserved signaling pathways
In Drosophila, as well as in other organisms, genes that control endocytosis and endosomal protein sorting behave as neoplastic tumor suppressor genes (nTSGs). Such endocytic nTSGs include avalanche [1], Rab5 [1], vps45 [2], Rabenosyn (Rbsn) [2], tumor suppressor protein 101 (tsg101 aka erupted or vps23) [3], vps28 [4], vps25 [5,6,7], vps22 (aka larsen) [8], vps20 [4], shrub [4], vps2 [4], and vps4 [9]. These endocytic nTSGs are involved in endocytosis and endosomal protein sorting of cell signaling receptors and other membrane proteins and inhibit tumor formation by ensuring proper trafficking and collection of cargoes that function in growth control, cell survival, and apical-basal polarity in epithelial tissues
ESCRT-II Mutant Tissues Show Neoplastic Characteristics The ey-FLP/cl method generates eye-antennal imaginal discs that are almost entirely composed of mutant tissue in otherwise heterozygous animals [19,28]
Summary
Tumor development involves destabilization of the wellcontrolled processes of cell proliferation, cell polarization, and programmed cell death that are tightly regulated by widely conserved signaling pathways. Such endocytic nTSGs include avalanche (avl) [1], Rab5 [1], vps45 [2], Rabenosyn (Rbsn) [2], tumor suppressor protein 101 (tsg101 aka erupted (ept) or vps23) [3], vps28 [4], vps25 [5,6,7], vps (aka larsen (lsn)) [8], vps20 [4], shrub (shrb) [4], vps2 [4], and vps4 [9] These endocytic nTSGs are involved in endocytosis and endosomal protein sorting of cell signaling receptors and other membrane proteins and inhibit tumor formation by ensuring proper trafficking and collection of cargoes that function in growth control, cell survival, and apical-basal polarity in epithelial tissues. Loss-of-function mutations of these genes block this process, which causes abnormal signaling and triggers a complex phenotype composed of autonomous and non-cell autonomous effects [5,6,7,8]
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