Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases.
The polytopic membrane protein Rhomboid-1 promotes the cleavage of the membrane-anchored TGFalpha-like growth factor Spitz, allowing it to activate the Drosophila EGF receptor. Until now, the mechanism of this key signaling regulator has been obscure, but our analysis suggests that Rhomboid-1 is a novel intramembrane serine protease that directly cleaves Spitz. In accordance with the putative Rhomboid active site being in the membrane bilayer, Spitz is cleaved within its transmembrane domain, and thus is, to our knowledge, the first example of a growth factor activated by regulated intramembrane proteolysis. Rhomboid-1 is conserved throughout evolution from archaea to humans, and our results show that a human Rhomboid promotes Spitz cleavage by a similar mechanism. This growth factor activation mechanism may therefore be widespread.
Urban
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MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom.
Lee
J R
JR
Freeman
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D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D019556:COS Cells; D002384:Catalysis; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D004330:Drosophila / Q000378:metabolism*; D029721:Drosophila Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000378:metabolism*; D014162:Transfection
D029721:Drosophila Proteins; D008565:Membrane Proteins; C081481:Rho protein, Drosophila; C472498:Stet protein, Drosophila; C076026:spi protein, Drosophila; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D012697:Serine Endopeptidases