Lee J, Dull T J, Lax I, Schlessinger J, Ullrich A
Department of Developmental Biology, Genentech, Inc., South San Francisco, CA 94080.
EMBO J. 1989 Jan;8(1):167-73. doi: 10.1002/j.1460-2075.1989.tb03361.x.
We have investigated the biological function of an unidentified human growth factor, the ligand of the putative HER2 receptor, by characterizing the signalling properties of its receptor. HER2 (or c-erbB-2), the human homolog of the rat neu proto-oncogene, encodes a transmembrane glycoprotein of the tyrosine kinase family that appears to play an important role in human breast carcinoma. Since a potential ligand for HER2 has not yet been identified, it has been difficult to analyze the biochemical properties and biological function of this cell surface protein. For this reason, we replaced the HER2 extracellular domain with the closely related ligand binding domain sequences of the epidermal growth factor (EGF) receptor, and examined the ligand-induced biological signalling potential of this chimeric HER1-2 protein. This HER1-2 receptor is targetted to the cell surface of transfected NIH 3T3 cells, forms high and low affinity binding sites, and generates normal mitogenic and cell transforming signals upon interaction with EGF or TGF alpha. The constitutive activation of wild-type HER2 in transfected NIH 3T3 cells suggests the possibility that these cells synthesize the as yet unidentified HER2 ligand and activate HER2 by an autocrine mechanism.
我们通过表征一种尚未鉴定的人类生长因子（假定的HER2受体的配体）受体的信号特性，研究了该生长因子的生物学功能。HER2（或c-erbB-2）是大鼠neu原癌基因的人类同源物，编码一种酪氨酸激酶家族的跨膜糖蛋白，它似乎在人类乳腺癌中起重要作用。由于尚未鉴定出HER2的潜在配体，因此难以分析这种细胞表面蛋白的生化特性和生物学功能。出于这个原因，我们用表皮生长因子（EGF）受体的密切相关的配体结合域序列替换了HER2的胞外域，并检测了这种嵌合HER1-2蛋白的配体诱导的生物学信号传导潜能。这种HER1-2受体定位于转染的NIH 3T3细胞的细胞表面，形成高亲和力和低亲和力结合位点，并在与EGF或TGFα相互作用时产生正常的促有丝分裂和细胞转化信号。转染的NIH 3T3细胞中野生型HER2的组成性激活提示了这些细胞合成尚未鉴定的HER2配体并通过自分泌机制激活HER2的可能性。
