Growth Factors Outside of the Platelet-derived Growth Factor (PDGF) Family Employ Reactive Oxygen Species/Src Family Kinases to Activate PDGF Receptor α and Thereby Promote Proliferation and Survival of Cells
Growth Factors Outside of the Platelet-derived Growth Factor (PDGF) Family Employ Reactive Oxygen Species/Src Family Kinases to Activate PDGF Receptor α and Thereby Promote Proliferation and Survival of Cells
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DOI：
10.1074/jbc.m808426200
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发表时间：
2009-03-06
影响因子：
4.8
通讯作者：
Kazlauskas, Andrius
中科院分区：
文献类型：
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作者：
Lei, Hetian;Kazlauskas, Andrius
玻璃体中含有大量的生长因子，这些生长因子与纤维增生性疾病（如增生性玻璃体视网膜病变）的形成密切相关。尽管玻璃体中存在血小板衍生生长因子（PDGF），但在增生性玻璃体视网膜病变兔模型中，PDGF家族外的玻璃体生长因子激活PDGF α受体（PDGFR α）并促进疾病进展（H. Lei， G. Velez， P. Hovland， T. Hirose， D. Gilbertson和a . Kazlauskas（2008）提交发表。）在本报告中，我们研究了非pdgfs激活PDGFR α的机制。我们发现非pdgfs增加了细胞中活性氧（ROS）的水平，这一事件对于PDGFR α的磷酸化是必要和充分的。我们推测其潜在机制是ros介导的磷酸酪氨酸磷酸酶的抑制，该酶可拮抗受体自磷酸化。然而，情况似乎并非如此。非pdgfs促进了催化活性不高的PDGFR α的酪氨酸磷酸化，从而表明至少有一个额外的酪氨酸激酶参与其中。事实上，阻止Src家族激酶的表达或阻断激酶活性会抑制PDGFR α的非pdgf依赖性酪氨酸磷酸化。因此，非pdgfs增加ROS水平，激活Src家族激酶，导致PDGFR α磷酸化。最后，尽管非pdgfs仅诱导PDGFR α适度磷酸化，但PDGFR α的表达显著增强了非pdgfs作用下细胞的增殖和存活。这些研究揭示了PDGFR α激活的新机制，该机制似乎能够增强细胞对PDGF家族外生长因子的反应性。
The vitreous contains a plethora of growth factors that are strongly implicated in the formation of fibroproliferative diseases such as proliferative vitreoretinopathy. Although platelet-derived growth factors (PDGFs) are present in the vitreous, vitreal growth factors outside of the PDGF family activated the PDGF alpha receptor (PDGFR alpha) and promoted disease progression in a rabbit model of proliferative vitreoretinopathy (H. Lei, G. Velez, P. Hovland, T. Hirose, D. Gilbertson, and A. Kazlauskas (2008) submitted for publication.) In this report we investigated the mechanism by which non-PDGFs activated PDGFR alpha. We found that non-PDGFs increased the cellular level of reactive oxygen species (ROS) and that this event was necessary and sufficient for phosphorylation of PDGFR alpha. We speculated that the underlying mechanism was ROS-mediated inhibition of phosphotyrosine phosphatases, which antagonize receptor autophosphorylation. However, this did not appear to be the case. Non-PDGFs promoted tyrosine phosphorylation of catalytically inactive PDGFR alpha, and thereby indicated that at least one additional tyrosine kinase was involved. Indeed, preventing expression or blocking the kinase activity of Src family kinases suppressed non-PDGF-dependent tyrosine phosphorylation of PDGFR alpha. Thus non-PDGFs increased the level of ROS, which activated Src family kinases and resulted in phosphorylation of PDGFR alpha. Finally, although non-PDGFs induced only modest phosphorylation of PDGFR alpha, proliferation and survival of cells in response to non-PDGFs was significantly enhanced by expression of PDGFR alpha. These studies reveal a novel mechanism for activation of PDGFR alpha that appears capable of enhancing the responsiveness of cells to growth factors outside of the PDGF family.