Faletto D L, Kaplan D R, Halverson D O, Rosen E M, Vande Woude G F
ABL-Basic Research Program, NCI-Frederick Cancer Research & Development Center, MD 21702.
EXS. 1993;65:107-30.
We have begun characterizing the signal transduction pathways used by the c-met receptor in cells in which ligand (HGF-SF) stimulates motogenesis in the absence of mitogenesis. Primary targets (within 10-15 minutes) were identified as PI-3 kinase, GAP, PLC gamma, src, and MAP kinase, substrates which are also activated upon growth factor activation of mitogenic receptor systems. Following HGF-SF treatment, the 85 kD subunit of PI-3 kinase is phosphorylated on tyrosine and PI-3 kinase activity rapidly associates with the c-met receptor. A number of these substrates are implicated in cytoskeletal rearrangements and may be important in the motogenic response to the factor. We have also identified a number of colon carcinoma lines which express unamplified levels of constitutively tyrosine phosphorylated c-met protein. In these and other (gastric) cell lines which express amplified levels of activated receptor protein, we have determined that receptor activation is not due to the autocrine production of ligand.
我们已开始对c-met受体在细胞中所使用的信号转导途径进行特性描述，在这些细胞中，配体（肝细胞生长因子-散射因子，HGF-SF）在不引发有丝分裂的情况下刺激细胞运动。主要靶点（在10 - 15分钟内）被确定为PI-3激酶、GAP、磷脂酶Cγ、src和丝裂原活化蛋白激酶，这些底物在有丝分裂受体系统的生长因子激活时也会被激活。在肝细胞生长因子-散射因子（HGF-SF）处理后，PI-3激酶的85 kD亚基在酪氨酸上被磷酸化，并且PI-3激酶活性迅速与c-met受体结合。这些底物中有许多与细胞骨架重排有关，可能在对该因子的运动反应中起重要作用。我们还鉴定出了一些结肠癌细胞系，这些细胞系中组成型酪氨酸磷酸化的c-met蛋白表达水平未扩增。在这些以及其他表达活化受体蛋白扩增水平的（胃）细胞系中，我们已确定受体激活并非由于配体的自分泌产生。
