Ekman S, Thuresson E R, Heldin C H, Rönnstrand L
Ludwig Institute for Cancer Research, Biomedical Center, Uppsala, Sweden.
Oncogene. 1999 Apr 15;18(15):2481-8. doi: 10.1038/sj.onc.1202606.
The different platelet-derived growth factor (PDGF) isoforms cause activation of their alpha and beta protein tyrosine kinase receptors through dimerization. Homodimerization as well as heterodimerization of receptors occur. It has been shown previously that the heterodimeric receptor complex mediates a stronger mitogenic response than either of the homodimeric complexes. In this report, we show that in cells expressing both PDGF alpha- and beta-receptors, stimulation with PDGF-AB, which leads to preferential heterodimer formation, leads to a very low degree of phosphorylation of Tyr771 in the beta-receptor. In contrast, Tyr771 is phosphorylated in a homodimeric complex of beta-receptors. Phosphorylated Tyr771 is a binding site for RasGAP; an analogous site is not present in the alpha-receptor, which lacks the ability to associate with RasGAP. The lowered phosphorylation of Tyr771 in the heterodimeric receptor complex correlates with lowered association with RasGAP, as well as with a more efficient activation of Ras and MAP kinase, which is consistent with the increased mitogenicity elicited by PDGF-AB, compared to PDGF-AA or PDGF-BB.
不同的血小板衍生生长因子（PDGF）亚型通过二聚化激活其α和β蛋白酪氨酸激酶受体。受体的同型二聚化以及异型二聚化均会发生。先前已表明，异型二聚体受体复合物介导的促有丝分裂反应比任何一种同型二聚体复合物都更强。在本报告中，我们表明，在同时表达PDGFα受体和β受体的细胞中，用PDGF-AB刺激（其导致优先形成异型二聚体）会导致β受体中Tyr771的磷酸化程度非常低。相比之下，Tyr771在β受体的同型二聚体复合物中被磷酸化。磷酸化的Tyr771是RasGAP的结合位点；α受体中不存在类似位点，其缺乏与RasGAP结合的能力。异型二聚体受体复合物中Tyr771磷酸化程度的降低与与RasGAP结合的减少相关，也与Ras和MAP激酶更有效的激活相关，这与PDGF-AB与PDGF-AA或PDGF-BB相比所引发的更强的促有丝分裂活性一致。
