The Hrs/Stam complex acts as a positive and negative regulator of RTK signaling during Drosophila development.
BACKGROUND
Endocytosis is a key regulatory step of diverse signalling pathways, including receptor tyrosine kinase (RTK) signalling. Hrs and Stam constitute the ESCRT-0 complex that controls the initial selection of ubiquitinated proteins, which will subsequently be degraded in lysosomes. It has been well established ex vivo and during Drosophila embryogenesis that Hrs promotes EGFR down regulation. We have recently isolated the first mutations of stam in flies and shown that Stam is required for air sac morphogenesis, a larval respiratory structure whose formation critically depends on finely tuned levels of FGFR activity. This suggest that Stam, putatively within the ESCRT-0 complex, modulates FGF signalling, a possibility that has not been examined in Drosophila yet.


RESULTS
Here, we assessed the role of the Hrs/Stam complex in the regulation of signalling activity during Drosophila development. We show that stam and hrs are required for efficient FGFR signalling in the tracheal system, both during cell migration in the air sac primordium and during the formation of fine cytoplasmic extensions in terminal cells. We find that stam and hrs mutant cells display altered FGFR/Btl localisation, likely contributing to impaired signalling levels. Electron microscopy analyses indicate that endosome maturation is impaired at distinct steps by hrs and stam mutations. These somewhat unexpected results prompted us to further explore the function of stam and hrs in EGFR signalling. We show that while stam and hrs together downregulate EGFR signalling in the embryo, they are required for full activation of EGFR signalling during wing development.


CONCLUSIONS
Our study shows that the ESCRT-0 complex differentially regulates RTK signalling, either positively or negatively depending on tissues and developmental stages, further highlighting the importance of endocytosis in modulating signalling pathways during development.
Chanut-Delalande
Hélène
H
Biozentrum der Universität Basel, Abteilung Zellbiologie, Basel, Switzerland. chanut@cict.fr
Jung
Alain C
AC
Baer
Magdalena M
MM
Lin
Li
L
Payre
François
F
Affolter
Markus
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015536:Down-Regulation; D004330:Drosophila / Q000254:growth & development; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D047108:Embryonic Development; D004705:Endocytosis; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000502:physiology*; D011992:Endosomes; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D010750:Phosphoproteins; D017468:Receptors, Fibroblast Growth Factor; C524045:STAM protein, Drosophila; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D020794:Receptor Protein-Tyrosine Kinases