Lu X, Qu C K, Shi Z Q, Feng G S
Department of Biochemistry and Molecular Biology, and Walther Oncology Center, Indiana University School of Medicine, Indianapolis 46202-5121, USA.
Oncogene. 1998 Jul 30;17(4):441-8. doi: 10.1038/sj.onc.1201988.
The SH2-containing tyrosine phosphatase Shp-2 appears to function downstream of a variety of growth factor receptors and might play a positive role in cell proliferation. Here we report that expression of the beta subunit of platelet-derived growth factor receptor (PDGFR-beta) was specifically downregulated in mutant fibroblasts lacking a functional Shp-2, while the levels of PDGFR-alpha EGFR and IGFIR were not changed. PDGF-stimulated DNA synthesis and extracellular signal regulated kinase (Erk) activation was severely suppressed in mutant cells. RasGAP, that responds to activation of PDGFR-beta but not PDGFR-alpha, was not phosphorylated on tyrosine in mutant cells upon PDGF-treatment. Northern blot analysis failed to detect PDGFR-beta mRNA in mutant cells. The transcription initiation from the PDGFR-beta gene promoter was not significantly changed, but the half-life of its mRNA was shortened in Shp-2 mutant cells. These observations indicate that Shp-2 not only participates in transmission of signals from growth factor receptors but also plays a specific role in the control of the PDGFR-beta expression. We propose that this is an important mechanism for the positive control of cell proliferation by Shp-2.
含SH2结构域的酪氨酸磷酸酶Shp-2似乎在多种生长因子受体的下游发挥作用，可能在细胞增殖中起积极作用。在此我们报告，在缺乏功能性Shp-2的突变成纤维细胞中，血小板衍生生长因子受体（PDGFR-β）的β亚基表达特异性下调，而PDGFR-α、表皮生长因子受体（EGFR）和胰岛素样生长因子受体1（IGFIR）的水平未发生变化。在突变细胞中，血小板衍生生长因子（PDGF）刺激的DNA合成和细胞外信号调节激酶（Erk）激活受到严重抑制。RasGAP对PDGFR-β而非PDGFR-α的激活作出反应，在PDGF处理后，突变细胞中的RasGAP酪氨酸未被磷酸化。Northern印迹分析未能在突变细胞中检测到PDGFR-β mRNA。PDGFR-β基因启动子的转录起始没有显著变化，但其mRNA的半衰期在Shp-2突变细胞中缩短。这些观察结果表明，Shp-2不仅参与生长因子受体信号的传递，而且在控制PDGFR-β表达中发挥特定作用。我们认为，这是Shp-2对细胞增殖进行正向调控的重要机制。
