Schlesinger Ayelet, Kiger Amy, Perrimon Norbert, Shilo Ben-Zion
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Dev Cell. 2004 Oct;7(4):535-45. doi: 10.1016/j.devcel.2004.09.001.
The Drosophila EGF receptor ligand Spitz is cleaved by Rhomboid to generate an active secreted molecule. Surprisingly, when a cleaved variant of Spitz (cSpi) was expressed, it accumulated in the ER, both in embryos and in cell culture. A cell-based RNAi screen for loss-of-function phenotypes that alleviate ER accumulation of cSpi identified several genes, including the small wing (sl) gene encoding a PLCgamma. sl mutants compromised ER accumulation of cSpi in embryos, yet they exhibit EGFR hyperactivation phenotypes predominantly in the eye. Spi processing in the eye is carried out primarily by Rhomboid-3/Roughoid, which cleaves Spi in the ER, en route to the Golgi. The sl mutant phenotype is consistent with decreased cSpi retention in the R8 cells. Retention of cSpi in the ER provides a novel mechanism for restricting active ligand levels and hence the range of EGFR activation in the developing eye.
果蝇表皮生长因子受体配体“斯皮茨”（Spitz）被类菱形蛋白酶切割后生成一种活性分泌分子。令人惊讶的是，当表达“斯皮茨”的一种切割变体（cSpi）时，它在胚胎和细胞培养物中均在内质网中积累。一项基于细胞的RNA干扰筛选，旨在寻找能减轻cSpi在内质网中积累的功能丧失型表型，结果鉴定出了几个基因，包括编码磷脂酶Cγ（PLCγ）的小翅（sl）基因。sl突变体在胚胎中损害了cSpi在内质网中的积累，但它们主要在眼睛中表现出表皮生长因子受体（EGFR）过度激活的表型。眼睛中的“斯皮茨”加工主要由类菱形蛋白酶-3/粗糙蛋白酶（Rhomboid-3/Roughoid）进行，该酶在内质网中、在前往高尔基体的途中切割“斯皮茨”。sl突变体表型与cSpi在R8细胞中的保留减少一致。cSpi在内质网中的保留为限制活性配体水平以及由此限制发育中眼睛里表皮生长因子受体激活范围提供了一种新机制。
