Drosophila EGFR signalling is modulated by differential compartmentalization of Rhomboid intramembrane proteases.
We explore the role of differential compartmentalization of Rhomboid (Rho) proteases that process the Drosophila EGF receptor ligands, in modulating the amount of secreted ligand and consequently the level of EGF receptor (EGFR) activation. The mSpitz ligand precursor is retained in the ER, and is trafficked by the chaperone Star to a late compartment of the secretory pathway, where Rho-1 resides. This work demonstrates that two other Rho proteins, Rho-2 and Rho-3, which are expressed in the germ line and in the developing eye, respectively, cleave the Spitz precursor and Star already in the ER, in addition to their activity in the late compartment. This property attenuates EGFR activation, primarily by compromising the amount of chaperone that can productively traffic the ligand precursor to the late compartment, where cleavage and subsequent secretion take place. These observations identify changes in intracellular compartment localization of Rho proteins as a basis for signal attenuation, in tissues where EGFR activation must be highly restricted in space and time.
Yogev
Shaul
S
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Schejter
Eyal D
ED
Shilo
Ben-Zion
BZ
D000818:Animals; D002451:Cell Compartmentation / Q000502:physiology*; D002460:Cell Line; D029721:Drosophila Proteins / Q000378:metabolism* / Q000502:physiology*; D004331:Drosophila melanogaster / Q000196:embryology / Q000201:enzymology / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000201:enzymology; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000502:physiology*; D005136:Eye Proteins / Q000378:metabolism / Q000502:physiology; D005854:Germ Cells / Q000378:metabolism; D006868:Hydrolysis; D007425:Intracellular Membranes / Q000201:enzymology*; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology*; D018010:Receptors, Invertebrate Peptide / Q000502:physiology*; D012697:Serine Endopeptidases / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism* / Q000502:physiology
D029721:Drosophila Proteins; D005136:Eye Proteins; D008565:Membrane Proteins; D018010:Receptors, Invertebrate Peptide; C415248:S protein, Drosophila; C472498:Stet protein, Drosophila; C076026:spi protein, Drosophila; D004815:Epidermal Growth Factor; D011494:Protein Kinases; C066532:Egfr protein, Drosophila; D066246:ErbB Receptors; D012697:Serine Endopeptidases; C491029:ru protein, Drosophila; C511153:Rho1 protein, Drosophila; D020741:rho GTP-Binding Proteins