Intracellular Proteolysis

Abstract

Some secreted growth factors originate as membrane-bound precursor proteins, and upon cleavage, they are released to act on their cognate receptors at the cell surface. Ligands for the epidermal growth factor (EGF) receptors are synthesized as such, but the mechanism and regulation of their cleavage have not been fully elucidated. Genetic evidence in Drosophila indicates that the fly EGF receptor is activated by a ligand called Spitz, which is synthesized as a membrane-bound precursor. Spitz action is somehow supported by the actions of two other membrane proteins, Star and Rhomboid, a type-2 transmembrane and seven-transmembrane domain protein, respectively. Lee et al. report that in Drosophila embryos and in transfected mammalian cells, Star chaperones Spitz from the endoplasmic reticulum to the Golgi, where Rhomboid then cleaves Spitz to the mature form. Hence, the EGF receptor ligand is proteolytically processed intracellularly, before secretion. Furthermore, Urban et al. deduced that Rhomboid is a serine protease whose active site lies within its transmembrane domains. Both studies demonstrate that Rhomboid cleaves Spitz within its transmembrane domain as well. Rhomboids are conserved across numerous species and may represent a widespread mechanism of signal regulation. J. R. Lee, S. Urban, C. F. Garvey, M. Freeman, Regulated intracellular ligand transport and proteolysis control EGF signal activation in Drosophila . Cell 107 , 161-171 (2001). [Online Journal] S. Urban, J. R. Lee, M. Freeman, Drosophila Rhomboid-1 defines a family of putative intramembrane serine proteases, Cell 107 , 173-182 (2001). [Online Journal]