A family of Rhomboid intramembrane proteases activates all Drosophila membrane-tethered EGF ligands
A family of Rhomboid intramembrane proteases activates all Drosophila membrane-tethered EGF ligands
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DOI：
10.1093/emboj/cdf434
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发表时间：
2002-08-15
期刊：
影响因子：
11.4
通讯作者：
Freeman, M
中科院分区：
文献类型：
--
作者：
Urban, S;Lee, JR;Freeman, M
果蝇有三种膜拴系的表皮生长因子(EGF)样蛋白：Spitz、Gurken和Keren。Spitz和Gurken已经被基因证实可以激活EGF受体，但Keren的特征尚未确定。Spitz分别通过跨膜蛋白Star和蛋白酶菱形-1调节细胞内转位和切割而激活。菱形体-1是果蝇中七个类似蛋白家族的成员。我们已经分析了其中的四种：它们都是可以裂解Spitz、Gurken和Keren的蛋白酶，并且在体内都只激活EGF受体信号。STAR是这三种物质的内质网(ER)输出因子。当Spitz被内质网中的菱形体切割时，它不能分泌，这一事实突显了这种易位的重要性。Keren在体内激活了EGF受体，提供了强有力的证据，证明它是一个真正的配体。我们的数据表明，果蝇中所有的膜系EGF配体都被菱形体切割的相同策略激活，菱形体是一种古老而广泛的膜内蛋白水解酶。这不同于金属蛋白酶诱导的哺乳动物EGF样配体的激活。
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.