Sachsenmaier C, Sadowski H B, Cooper J A
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Oncogene. 1999 Jun 17;18(24):3583-92. doi: 10.1038/sj.onc.1202694.
Activation of the platelet-derived growth factor (PDGF) receptor tyrosine kinase induces tyrosine phosphorylation of Signal Transducer and Activator of Transcription (STAT) proteins. Since the PDGF receptor also activates the Src tyrosine kinase, it is possible that Src mediates tyrosine phosphorylation of STATs in PDGF-treated cells. Consistent with a role for Src in STAT activation, we found that a PDGF receptor juxtamembrane tyrosine residue required for Src activation is necessary and sufficient for activation of STATs 1 and 3. To test the Src requirement further, we made other mutations in the PDGF receptor juxtamembrane region that increased or decreased Src binding. In epithelial and fibroblast cells, PDGF activated STAT1, 3 and 6 in the absence of detectable binding and activation of Src. In addition, PDGF induced c-myc RNA expression and DNA synthesis even though Src was not detectably activated. The activation of MAP kinase and the induction of c-fos gene expression both correlated with STAT but not Src activation by the receptor. We conclude that juxtamembrane tyrosine phosphorylation is necessary for both Src tyrosine kinase and STAT activation by the betaPDGF receptor, but that both processes are regulated independently by this region.
血小板衍生生长因子（PDGF）受体酪氨酸激酶的激活会诱导信号转导及转录激活蛋白（STAT）的酪氨酸磷酸化。由于PDGF受体也会激活Src酪氨酸激酶，因此Src有可能介导了PDGF处理细胞中STAT的酪氨酸磷酸化。与Src在STAT激活中所起的作用一致，我们发现Src激活所需的一个PDGF受体近膜酪氨酸残基对于STAT1和STAT3的激活是必要且充分的。为了进一步测试对Src的需求，我们在PDGF受体近膜区域进行了其他突变，这些突变增加或减少了Src的结合。在上皮细胞和成纤维细胞中，PDGF在未检测到Src结合和激活的情况下激活了STAT1、STAT3和STAT6。此外，即使未检测到Src被激活，PDGF也会诱导c-myc RNA表达和DNA合成。MAP激酶的激活以及c-fos基因表达的诱导均与受体激活STAT而非Src相关。我们得出结论，近膜酪氨酸磷酸化对于βPDGF受体激活Src酪氨酸激酶和STAT都是必要的，但这两个过程均受该区域独立调控。
