Ren Yongming, Cheng Long, Rong Zhili, Li Zhiyong, Li Yinghua, Zhang Xinjun, Xiong Shiqin, Hu Jim, Fu Xin-Yuan, Chang Zhijie
School of Medicine, Department of Biological Sciences and Biotechnology, State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University, Beijing, China.
Cell Signal. 2008 Mar;20(3):518-33. doi: 10.1016/j.cellsig.2007.11.010. Epub 2007 Nov 28.
Sef (similar expression to fgf genes) was identified as an effective antagonist of fibroblast growth factor (FGF) in vertebrates. Previous reports have demonstrated that Sef interacts with FGF receptors (FGFRs) and inhibits FGF signaling, however, its role in regulating epidermal growth factor receptor (EGFR) signaling remains unclear. In this report, we found that hSef localizes to the plasma membrane (PM) and is subjected to rapid internalization and well localizes in early/recycling endosomes while poorly in late endosomes/lysosomes. We observed that hSef interacts and functionally colocalizes with EGFR in early endosomes in response to EGF stimulation. Importantly, we demonstrated that overexpression of hSef attenuates EGFR degradation and potentiates EGF-mediated mitogen-activated protein kinase (MAPK) signaling by interfering EGFR trafficking. Finally, our data showed that, with overexpression of hSef, elevated levels of Erk phosphorylation and differentiation of rat pheochromocytoma (PC12) cells occur in response to EGF stimulation. Taken together, these data suggest that hSef plays a positive role in the EGFR-mediated MAPK signaling pathway. This report, for the first time, reveals opposite roles for Sef in EGF and FGF signalings.
Sef（与成纤维细胞生长因子基因相似的表达产物）被鉴定为脊椎动物中成纤维细胞生长因子（FGF）的有效拮抗剂。先前的报道表明，Sef与FGF受体（FGFRs）相互作用并抑制FGF信号传导，然而，其在调节表皮生长因子受体（EGFR）信号传导中的作用仍不清楚。在本报告中，我们发现人源Sef（hSef）定位于质膜（PM），并经历快速内化，且很好地定位于早期/再循环内体，而在晚期内体/溶酶体中定位较差。我们观察到，在表皮生长因子（EGF）刺激下，hSef在早期内体中与EGFR相互作用并在功能上共定位。重要的是，我们证明hSef的过表达通过干扰EGFR的运输来减弱EGFR的降解并增强EGF介导的丝裂原活化蛋白激酶（MAPK）信号传导。最后，我们的数据表明，随着hSef的过表达，在EGF刺激下，大鼠嗜铬细胞瘤（PC12）细胞中细胞外信号调节激酶（Erk）磷酸化水平升高且细胞发生分化。综上所述，这些数据表明hSef在EGFR介导的MAPK信号通路中发挥积极作用。本报告首次揭示了Sef在EGF和FGF信号传导中相反的作用。
