Negative regulation of Drosophila JAK-STAT signalling by endocytic trafficking

J Cell Sci. 2010 Oct 15;123(Pt 20):3457-66. doi: 10.1242/jcs.066902. Epub 2010 Sep 14.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex alpha Subunits / genetics
  • Adaptor Protein Complex alpha Subunits / metabolism
  • Animals
  • Cell Line
  • Cell Membrane / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Endocytosis / genetics
  • Endocytosis / physiology*
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Janus Kinases / genetics
  • Janus Kinases / metabolism*
  • Polymerase Chain Reaction
  • Protein Transport / genetics
  • Protein Transport / physiology
  • RNA Interference
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • STAT Transcription Factors / genetics
  • STAT Transcription Factors / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Adaptor Protein Complex alpha Subunits
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Receptors, Cell Surface
  • STAT Transcription Factors
  • Transcription Factors
  • Tsg101 protein
  • Upd2 protein, Drosophila
  • ptc protein, Drosophila
  • Janus Kinases
  • hop protein, Drosophila