Regulators of endocytosis maintain localized receptor tyrosine kinase signaling in guided migration.
Guidance receptors detect extracellular cues and instruct migrating cells how to orient in space. Border cells perform a directional invasive migration during Drosophila oogenesis and use two receptor tyrosine kinases (RTKs), EGFR and PVR (PDGF/VEGF Receptor), to read guidance cues. We find that spatial localization of RTK signaling within these migrating cells is actively controlled. Border cells lacking Cbl, an RTK-associated E3 ubiquitin ligase, have delocalized guidance signaling, resulting in severe migration defects. Absence of Sprint, a receptor-recruited, Ras-activated Rab5 guanine exchange factor, gives related defects. In contrast, increasing the level of RTK signaling by receptor overexpression or removing Hrs and thereby decreasing RTK degradation does not perturb migration. Cbl and Sprint both regulate early steps of RTK endocytosis. Thus, a physiological role of RTK endocytosis is to ensure localized intracellular response to guidance cues by stimulating spatial restriction of signaling.
Jékely
Gáspár
G
Developmental Biology Program, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Sung
Hsin-Ho
HH
Luque
Carlos M
CM
Rørth
Pernille
P
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology*; D056827:Endosomal Sorting Complexes Required for Transport; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors; D009154:Mutation; D009865:Oocytes / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D050721:Proto-Oncogene Proteins c-cbl; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D018010:Receptors, Invertebrate Peptide / Q000235:genetics / Q000502:physiology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology
D002352:Carrier Proteins; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D020662:Guanine Nucleotide Exchange Factors; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D018010:Receptors, Invertebrate Peptide; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; C429774:spri protein, Drosophila; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C066532:Egfr protein, Drosophila; D066246:ErbB Receptors; C438368:Pvr protein, Drosophila; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor