Urban S, Lee J R, Freeman M
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom.
Cell. 2001 Oct 19;107(2):173-82. doi: 10.1016/s0092-8674(01)00525-6.
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.
多结构域膜蛋白类菱形蛋白酶-1促进膜锚定的类转化生长因子α（TGFα）——斯皮茨蛋白（Spitz）的裂解，使其能够激活果蝇表皮生长因子受体。到目前为止，这种关键信号调节因子的作用机制一直不明，但我们的分析表明，类菱形蛋白酶-1是一种新型的膜内丝氨酸蛋白酶，可直接裂解斯皮茨蛋白。鉴于推测的类菱形蛋白酶活性位点位于膜双层中，斯皮茨蛋白在其跨膜结构域内被裂解，因此据我们所知，它是通过调节性膜内蛋白水解激活的生长因子的首个实例。类菱形蛋白酶-1在从古细菌到人类的整个进化过程中都保守存在，我们的结果表明，一种人类类菱形蛋白酶通过类似机制促进斯皮茨蛋白的裂解。因此，这种生长因子激活机制可能广泛存在。
