RESUMO
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.
Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neoplasias/enzimologia , Neoplasias/patologia , Animais , Polaridade Celular , Proliferação de Células , Sobrevivência Celular , Drosophila melanogaster/citologia , Drosophila melanogaster/ultraestrutura , Complexos Endossomais de Distribuição Requeridos para Transporte , Epitélio/patologia , Deleção de Genes , Integrinas/genética , Integrinas/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Larva/citologia , Larva/ultraestrutura , Sistema de Sinalização das MAP Quinases , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Homologia de Sequência de Aminoácidos , Ubiquitinação , Regulação para Cima/genéticaRESUMO
The ESCRT (endosomal sorting complex required for transport) machinery consists of four protein complexes that mediate sorting of ubiquitinated membrane proteins into the intraluminal vesicles of multivesicular endosomes, thereby targeting them for degradation in lysosomes. In the present paper, we review how ESCRT-mediated receptor down-regulation affects signalling downstream of Notch and growth factor receptors, and how ESCRTs may control cell proliferation, survival and cytoskeletal functions and contribute to tumour suppression.