Genetic screens in the fruit fly Drosophila melanogaster have identified a class 
of neoplastic tumor suppressor genes (endocytic nTSGs), which encode proteins 
that localize to endosomes and facilitate the trafficking of membrane-bound 
receptors and adhesion molecules into the degradative lysosome. Loss of 
endocytic nTSGs transforms imaginal disc epithelia into highly proliferative, 
invasive tissues that fail to differentiate and display defects in cellular 
apicobasal polarity, adhesion and tissue architecture. As vertebrate homologs of 
some Drosophila nTSGs are linked to tumor formation, identifying molecular 
changes in signaling associated with nTSG loss could inform understanding of 
neoplastic transformation in vertebrates. Here we show that mutations in genes 
that act at multiple steps of the endolysosomal pathway lead to autonomous 
activation of the Sav/Wts/Hpo (SWH) transcriptional effector Yki (YAP/TAZ in 
vertebrates) and the Jun N-terminal kinase (JNK), which is known to promote Yki 
activity in cells with disrupted polarity. Yki and JNK activity are elevated by 
mutations at multiple steps in the endolysosomal pathway including mutations in 
the AP-2σ gene, which encodes a component of the AP-2 adaptor complex that 
recruits cargoes into clathrin-coated pits for subsequent internalization. 
Moreover, reduction of JNK activity can decrease elevated Yki-signaling caused 
by altered endocytosis. These studies reveal a broad requirement for components 
of the endocytic pathway in regulating SWH and JNK outputs, and place Drosophila 
endocytic nTSGs into a network that involving two major signaling pathways 
implicated in oncogenesis.