Boccaccio C, Andò M, Tamagnone L, Bardelli A, Michieli P, Battistini C, Comoglio P M
Institute for Cancer Research, University of Torino Medical School, Candiolo, Italy.
Nature. 1998 Jan 15;391(6664):285-8. doi: 10.1038/34657.
Hepatocyte growth factor (HGF) induces a three-phase response leading to the formation of branched tubular structures in epithelial cells. The HGF receptor tyrosine kinase works through a Src homology (SH2) docking site that can activate several signalling pathways. The first phase of the response (scattering), which results from cytoskeletal reorganization, loss of intercellular junctions and cell migration, is dependent on phosphatidylinositol-3-OH kinase and Rac activation. The second phase (growth) requires stimulation of the Ras-MAP kinase cascade. Here we show that the third phase (tubulogenesis) is dependent on the STAT pathway. HGF stimulates recruitment of Stat-3 to the receptor, tyrosine phosphorylation, nuclear translocation and binding to the specific promoter element SIE. Electroporation of a tyrosine-phosphorylated peptide, which interferes with both the association of STAT to the receptor and STAT dimerization, inhibits tubule formation in vitro without affecting either HGF-induced 'scattering' or growth. The same result is obtained using a specific 'decoy' oligonucleotide that prevents STAT from binding to DNA and affecting the expression of genes involved in cell-cycle regulation (c-fos and waf-1). Activation of signal transducers that directly control transcription is therefore required for morphogenesis.
肝细胞生长因子（HGF）可诱导上皮细胞产生三相反应，最终形成分支管状结构。HGF受体酪氨酸激酶通过一个能激活多种信号通路的Src同源（SH2）对接位点发挥作用。反应的第一阶段（散射）是由细胞骨架重组、细胞间连接丧失和细胞迁移引起的，这一阶段依赖于磷脂酰肌醇-3-OH激酶和Rac激活。第二阶段（生长）需要刺激Ras-MAP激酶级联反应。我们在此表明，第三阶段（管状结构形成）依赖于STAT途径。HGF刺激Stat-3募集到受体上，使其酪氨酸磷酸化、发生核转位并与特定启动子元件SIE结合。电穿孔导入一种酪氨酸磷酸化肽，该肽可干扰STAT与受体的结合以及STAT二聚化，在不影响HGF诱导的“散射”或生长的情况下，抑制体外管状结构的形成。使用一种特异性“诱饵”寡核苷酸也可得到相同结果，该寡核苷酸可阻止STAT与DNA结合并影响参与细胞周期调控的基因（c-fos和waf-1）的表达。因此，形态发生需要直接控制转录的信号转导子的激活。
