The human Sef-a isoform utilizes different mechanisms to regulate receptor tyrosine kinase signaling pathways and subsequent cell fate
The human Sef-a isoform utilizes different mechanisms to regulate receptor tyrosine kinase signaling pathways and subsequent cell fate
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DOI：
10.1074/jbc.m607327200
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发表时间：
2006-12-22
影响因子：
4.8
通讯作者：
Ron, Dina
中科院分区：
文献类型：
--
作者：
Ziv, Inbal;Fuchs, Yaron;Ron, Dina
负反馈是调节受体酪氨酸激酶(RTK)信号的关键机制之一。人类Sef是新近发现的RTK信号转导抑制因子，编码不同的亚型，包括跨膜亚型(hSef-a)和胞质亚型(hSef-b)。以前，我们报道了hSef-b抑制成纤维细胞的增殖，阻止丝裂原活化蛋白激酶(MAPK)的激活，而不影响蛋白激酶B/Akt或p38 MAPK。关于hSef-a抑制MAPK激活的结果相互矛盾，而hSef-a对RTK诱导的其他信号通路的影响尚不清楚。在这里，我们发现，在成纤维细胞中，与hSef-b类似，hSef-a的异位表达抑制了成纤维细胞生长因子诱导的细胞增殖。然而，与hSef-b不同的是，生长抑制是通过MAPK非依赖性机制介导的，并伴随着p38MAPK磷酸化水平的升高和蛋白激酶B/Akt的抑制。此外，hSef-a，而不是hSef-b，介导了成纤维细胞生长因子刺激的细胞的凋亡。P38MAPK的化学抑制剂可阻断hSef-a对细胞凋亡的影响。在上皮细胞中，hSef-a的异位表达抑制了MAPK的激活，而内源性hSef-a的下调显著增加了MAPK的激活，并加速了生长因子依赖的细胞的增殖。这些结果表明，hSef-a是RTK信号的多功能负调制子，并清楚地表明hSef-a可以抑制MAPK的激活，尽管是以细胞类型特异性的方式。此外，hSef-a和hSef-b活性的差异表明，hSef亚型通过利用不同的机制来调节RTK信号，从而控制信号的特异性和随后的细胞命运。
Negative feedback is among the key mechanisms for regulating receptor tyrosine kinase (RTK) signaling. Human Sef, a recently identified inhibitor of RTK signaling, encodes different isoforms, including a membrane spanning (hSef-a) and a cytosolic (hSef-b) isoform. Previously, we reported that hSef-b inhibited fibroblast proliferation and prevented the activation of mitogen-activated protein kinase ( MAPK), without affecting protein kinase B/Akt or p38 MAPK. Conflicting results were reported concerning hSef-a inhibition of MAPK activation, and the effect of hSef-a on other RTK-induced signaling pathways is unknown. Here we show that, in fibroblasts, similar to hSef-b, ectopic expression of hSef-a inhibited fibroblast growth factor-induced cell proliferation. Unlike hSef-b, however, the growth arrest was mediated via a MAPK-independent mechanism, and was accompanied by elevated p38 MAPK phosphorylation and inhibition of protein kinase B/Akt. In addition, hSef-a, but not hSef-b, mediated apoptosis in fibroblast growth factor-stimulated cells. Chemical inhibitor of p38 MAPK abrogated the effect of hSef-a on apoptosis. In epithelial cells, ectopic expression of hSef-a inhibited the activation of MAPK, whereas down-regulation of endogenous hSef-a significantly increased MAPK activation and accelerated growth factor-dependent cell proliferation. These results indicate that hSef-a is a multifunctional negative modulator of RTK signaling and clearly demonstrate that hSef-a can inhibit the activation of MAPK, although in a cell type-specific manner. Moreover, the differences between the activities of hSef-a and hSef-b suggest that hSef isoforms can control signal specificity and subsequent cell fate by utilizing different mechanisms to modulate RTK signaling.