Abstract
Several regulators of endocytic trafficking have recently been identified as tumour suppressors in Drosophila. These include components of the endosomal sorting complex required for transport (ESCRT) machinery. Disruption of subunits of ESCRT-I and –II leads to cell-autonomous endosomal accumulation of ubiquitinated receptors, loss of apicobasal polarity and epithelial integrity, and increased cell death. Here we report that disruption of the ATPase dVps4, the most downstream component of the ESCRT machinery, causes the same array of cellular phenotypes. We find that loss of epithelial integrity and increased apoptosis, but not loss of cell polarity, require the activation of JNK signalling. Abrogation of JNK signalling prevents apoptosis in dVps4 deficient cells. Indeed double deficiency in dVps4 and JNK signalling leads to the formation of neoplastic tumours. We conclude that dvps4 is a tumour suppressor in Drosophila and that JNK is central to the cell-autonomous phenotypes of ESCRT-deficient cells.
Highlights
Correct receptor signalling and cell polarisation are required for proper organisation of epithelia
We find that several cell-autonomous effects observed when endosomal sorting complex required for transport (ESCRT) function is disrupted are mediated by c-Jun Nterminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family, which has extensively been implicated in programmed cell death [20] and is misregulated in many types of mammalian cancers [21,22,23,24,25]
An antibody raised against Drosophila Vps4 (dVps4) recognised a protein with the predicted size on Western blots from lysates of wild type L1 control larvae, but not from L1 dvps4D7b larvae, indicating that the antibody is specific and that dVps4 protein is absent in the mutants (Fig. 1D)
Summary
Correct receptor signalling and cell polarisation are required for proper organisation of epithelia. Signalling from ligandbound receptors is modulated by endocytosis [1,2], which mediates spatial restriction or downregulation of signalling [3,4,5] by sorting into intraluminal vesicles of multivesicular endosomes (MVEs) that fuse with lysosomes [6,7,8,9]. Both in the yeast Saccharomyces cerevisiae and in mammalian cells, Class E vacuolar protein sorting (Vps) proteins are important for sorting ubiquitinated receptors into the lumen of the MVEs. The class E vps yeast mutants accumulate vacuolar, endocytic and late-Golgi markers in an aberrant multilamellar endosome, the class E compartment [6,9,10,11,12,13]. We focus on the cell autonomous effects caused by ESCRT deficiency
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
