Negative regulation of Drosophila JAK-STAT signalling by endocytic trafficking.
Appropriate regulation of signal transduction pathways is essential for normal development and is often disrupted in disease. Therefore, many regulatory mechanisms and feedback loops have evolved to ensure appropriate signalling. One mechanism previously suggested to modulate a range of signal transduction pathways involves the internalisation and destruction of transmembrane receptors by the endocytic trafficking machinery. Strikingly, a recent report has suggested that the endocytic trafficking of the Drosophila JAK-STAT pathway receptor Domeless (Dome) does not act to downregulate pathway activity, but rather is necessary for in vivo signalling. Here, we examine this relationship to address the interaction of Drosophila JAK-STAT pathway signalling and endocytic trafficking. We show that Dome is trafficked through clathrin-mediated endocytosis and a directed RNAi screen identified several components of the endocytic machinery as negative regulators of pathway signalling. We demonstrate that Dome signals both from the plasma membrane and internalised vesicles and show, using knockdown experiments, that endocytic components negatively regulate JAK-STAT signalling in vivo. As such, disruption in endocytic trafficking represents a potent negative regulator of the disease relevant JAK-STAT signalling cascade.
Vidal
Oscar Marino
OM
MRC Centre for Developmental and Biomedical Genetics, The University of Sheffield, Firth Court, Sheffield S102TN, UK.
Stec
Wojciech
W
Bausek
Nina
N
Smythe
Elizabeth
E
Zeidler
Martin P
MP
D033965:Adaptor Protein Complex alpha Subunits / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000235:genetics / Q000502:physiology*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099177:Tsg101 Protein
D033965:Adaptor Protein Complex alpha Subunits; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D053612:Janus Kinases; D011956:Receptors, Cell Surface; D050791:STAT Transcription Factors; D014157:Transcription Factors; D000099177:Tsg101 Protein; C508880:Upd2 protein, Drosophila; C070844:ptc protein, Drosophila; C085845:hop protein, Drosophila