FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway
FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway
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DOI：
10.1038/cr.2009.95
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发表时间：
2009-08
期刊：
影响因子：
44.1
通讯作者：
Wenchao Zhou;Xiujing Feng;Yingjie Wu;Johannes Benge;Zhe Zhang;Zhengjun Chen
中科院分区：
文献类型：
--
作者：
Wenchao Zhou;Xiujing Feng;Yingjie Wu;Johannes Benge;Zhe Zhang;Zhengjun Chen
成纤维细胞生长因子受体底物2α(FRS2α)是成纤维细胞生长因子途径中的主要信号介质。最近的研究表明，丝裂原活化蛋白激酶(MAPK)使FRS2中的丝氨酸和苏氨酸残基磷酸化，从而对成纤维细胞生长因子诱导的FRS2酪氨酸磷酸化(PY)产生负面影响。几种刺激可以诱导FRS2的丝氨酸/苏氨酸磷酸化(PS/T)，提示FRS2可能有助于研究生长因子信号通路之间的串扰。在此，我们报道了在PC12细胞中，EGF共刺激可以减弱成纤维细胞生长因子诱导的FRS2的PY；这种抑制作用可以被MEK的抑制剂U0126完全逆转。我们进一步鉴定了FRS2中的ERK1/2结合基序，并产生了FRS2-3KL，这是一个在成纤维细胞生长因子和/或EGF刺激下缺乏MAPK结合和PT的突变体。与野生型(WT)FRS2不同，成纤维细胞生长因子(FRS2-3KL)诱导的PY不能被EGF共刺激抑制，表达FRS2-3KL的PC12细胞比表达FRS2-WT的PC12细胞具有更强的分化潜能。这些结果表明，FRS2-MAPK负性调控环介导的PS/T可能是一个分子开关，将其他途径的负性调控信号整合到FGFR产生的信号转导中。
Fibroblast growth factor (FGF) receptor substrate 2α (FRS2α) is the main mediator of signaling in the FGF pathway. Recent studies have shown that mitogen-activated protein kinase (MAPK) phosphorylates serine and threonine residues in FRS2, negatively affecting FGF-induced tyrosine phosphorylation (PY) of FRS2. Several kinds of stimuli can induce serine/threonine phosphorylation (PS/T) of FRS2, indicating that FRS2 may be useful for studying crosstalk between growth factor signaling pathways. Here, we report that FGF-induced PY of FRS2 can be attenuated by EGF co-stimulation in PC12 cells; this inhibitory effect could be completely reversed by U0126, an inhibitor of MEK. We further identified the ERK1/2-binding motif in FRS2 and generated FRS2-3KL, a mutant lacking MAPK binding and PT upon FGF and/or EGF stimulation. Unlike wild-type (WT) FRS2, FGF-induced PY of FRS2-3KL could not be inhibited by EGF co-stimulation, and FRS2-3KL-expressing PC12 cells exhibited more differentiating potential than FRS2-WT-expressing cells in response to FGF treatment. These results suggest that PS/T of FRS2 mediated by the FRS2-MAPK negative regulatory loop may function as a molecular switch integrating negative regulatory signals from other pathways into FGFR-generated signal transduction.