Schweitzer R, Howes R, Smith R, Shilo B Z, Freeman M
Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel.
Nature. 1995 Aug 24;376(6542):699-702. doi: 10.1038/376699a0.
The Drosophila homologue of the mammalian epidermal growth factor (EGF) receptor (DER) is a receptor tyrosine kinase involved in many stages of fly development, including photoreceptor determination, and wing-vein formation. Its primary activating ligand is the Spitz protein, which is similar to mammalian TGF-alpha. Argos is a secreted protein that, like Spitz, contains a single EGF motif. It is a repressor of cell determination in the eye, and acts in other tissues, including the wing. Because Argos has the opposite effects to DER in the eye (the former blocks photoreceptor determination, the latter promotes it) we have tested whether it acts by blocking the DER pathway. We show that Argos does indeed repress this pathway in vivo and find that, in vitro, Argos protein can inhibit the activation of DER by Spitz. Thus the determination of cells by the DER pathway is regulated by a balance between extracellular activating and inhibiting signals. This is the first in vivo example of an extracellular inhibitor of a receptor tyrosine kinase.
哺乳动物表皮生长因子（EGF）受体（DER）在果蝇中的同源物是一种受体酪氨酸激酶，参与果蝇发育的许多阶段，包括光感受器的确定和翅脉形成。其主要激活配体是Spitz蛋白，它类似于哺乳动物的转化生长因子α（TGF-α）。Argos是一种分泌蛋白，与Spitz一样，含有一个单一的EGF基序。它是眼睛中细胞确定的抑制因子，并在包括翅膀在内的其他组织中发挥作用。由于Argos在眼睛中的作用与DER相反（前者阻止光感受器的确定，后者促进光感受器的确定），我们测试了它是否通过阻断DER途径发挥作用。我们表明，Argos在体内确实抑制了该途径，并发现，在体外，Argos蛋白可以抑制Spitz对DER的激活。因此，DER途径对细胞的确定是由细胞外激活信号和抑制信号之间的平衡调节的。这是受体酪氨酸激酶细胞外抑制剂的第一个体内实例。
