A family of Rhomboid intramembrane proteases activates all Drosophila membrane-tethered EGF ligands.
Drosophila has three membrane-tethered epidermal growth factor (EGF)-like proteins: Spitz, Gurken and Keren. Spitz and Gurken have been genetically confirmed to activate the EGF receptor, but Keren is uncharacterized. Spitz is activated by regulated intracellular translocation and cleavage by the transmembrane proteins Star and the protease Rhomboid-1, respectively. Rhomboid-1 is a member of a family of seven similar proteins in Drosophila. We have analysed four of these: all are proteases that can cleave Spitz, Gurken and Keren, and all activate only EGF receptor signalling in vivo. Star acts as an endoplasmic reticulum (ER) export factor for all three. The importance of this translocation is highlighted by the fact that when Spitz is cleaved by Rhomboids in the ER it cannot be secreted. Keren activates the EGF receptor in vivo, providing strong evidence that it is a true ligand. Our data demonstrate that all membrane-tethered EGF ligands in Drosophila are activated by the same strategy of cleavage by Rhomboids, which are ancient and widespread intramembrane proteases. This is distinct from the metalloprotease-induced activation of mammalian EGF-like ligands.
Urban
Sinisa
S
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
Lee
Jeffrey R
JR
Freeman
Matthew
M
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D004330:Drosophila / Q000201:enzymology* / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism*; D019476:Insect Proteins / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D015398:Signal Transduction / Q000502:physiology; D016211:Transforming Growth Factor alpha; D015291:Transforming Growth Factors / Q000378:metabolism
D029721:Drosophila Proteins; D019476:Insect Proteins; D008024:Ligands; D008565:Membrane Proteins; C081481:Rho protein, Drosophila; C415248:S protein, Drosophila; C472498:Stet protein, Drosophila; D016211:Transforming Growth Factor alpha; C083730:grk protein, Drosophila; C076026:spi protein, Drosophila; D004815:Epidermal Growth Factor; D015291:Transforming Growth Factors; D010450:Endopeptidases