GAREM, a Novel Adaptor Protein for Growth Factor Receptor-bound Protein 2, Contributes to Cellular Transformation through the Activation of Extracellular Signal-regulated Kinase Signaling
GAREM, a Novel Adaptor Protein for Growth Factor Receptor-bound Protein 2, Contributes to Cellular Transformation through the Activation of Extracellular Signal-regulated Kinase Signaling
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DOI：
10.1074/jbc.m109.021139
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发表时间：
2009-07-24
影响因子：
4.8
通讯作者：
Konishi, Hiroaki
中科院分区：
文献类型：
--
作者：
Tashiro, Kyoko;Tsunematsu, Takumi;Konishi, Hiroaki
各种生长因子受体的衔接蛋白通过酪氨酸磷酸化在信号转导中起着至关重要的作用。最近的磷酸化蛋白质组学研究已经确定了几种对表皮生长因子（EGF）受体介导的信号通路具有潜在影响的衔接蛋白候选物。在这里，我们专注于一种新的蛋白质，GAREM（Grb 2相关和调节Erk/MAPK）作为EGF受体的下游分子。在EGF刺激后，GAREM在酪氨酸105和453处磷酸化。Grb 2被鉴定为它的结合伴侣，并且GAREM的富含脯氨酸的基序被Grb 2的N端和C端SH 3结构域识别。此外，GAREM的酪氨酸磷酸化是其与Grb 2结合所必需的。由于酪氨酸453周围的氨基酸序列与免疫受体酪氨酸基抑制基序相似，因此Erk的正调节因子Shp 2以这种磷酸化依赖性方式与GAREM结合。因此，响应于EGF刺激的Erk活化通过COS-7和HeLa细胞中GAREM的表达来调节，其发生独立于其它结合蛋白（如Gab 1和SOS）对活化的EGF受体的存在。此外，GAREM的表达对培养细胞的转化活性有影响。总之，这些发现表明GAREM在EGF受体的配体介导的信号传导途径和细胞的肿瘤发生中起关键作用。
Adaptor proteins for the various growth factor receptors play a crucial role in signal transduction through tyrosine phosphorylation. Several candidates for adaptor proteins with potential effects on the epidermal growth factor (EGF) receptor-mediated signaling pathway have been identified by recent phosphoproteomic studies. Here, we focus on a novel protein, GAREM (Grb2-associated and regulator of Erk/MAPK) as a downstream molecule of the EGF receptor. GAREM is phosphorylated at tyrosine 105 and 453 after EGF stimulation. Grb2 was identified as its binding partner, and the proline-rich motifs of GAREM are recognized by the Nand C-terminal SH3 domains of Grb2. In addition, the tyrosine phosphorylations of GAREM are necessary for its binding to Grb2. Because the amino acid sequence surrounding tyrosine 453 is similar to the immunoreceptor tyrosine-based inhibitory motif, Shp2, a positive regulator of Erk, binds to GAREM in this phosphorylation-dependent manner. Consequently, Erk activation in response to EGF stimulation is regulated by the expression of GAREM in COS-7 and HeLa cells, which occurs independent of the presence of other binding proteins, such as Gab1 and SOS, to the activated EGF receptor. Furthermore, the expression of GAREM has an effect on the transformation activity of cultured cells. Together, these findings suggest that GAREM plays a key role in the ligand-mediated signaling pathway of the EGF receptor and the tumorigenesis of cells.