Competition between Grb2 and Plcγ1 for FGFR2 regulates basal phospholipase activity and invasion
Competition between Grb2 and Plcγ1 for FGFR2 regulates basal phospholipase activity and invasion
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DOI：
10.1038/nsmb.2752
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发表时间：
2014-02-01
影响因子：
16.8
通讯作者：
Ladbury, John E.
中科院分区：
文献类型：
--
作者：
Timsah, Zahra;Ahmed, Zamal;Ladbury, John E.
具有低浓度接头蛋白 Grb2 的表达 FGFR2 的人类癌细胞显示出高转移结果的发生率。在未刺激的细胞中，Plc gamma 1 的 SH3 结构域（而不是 SH2 结构域）直接与 Grb2 的 C 端 SH3 结构域竞争 FGFR2 C 末端的结合位点。 Grb2 浓度的降低允许 Plc gamma 1 接近受体。以这种方式募集 Plc gamma 1 足以上调磷脂酶活性。这导致磷脂酰肌醇 4,5-二磷酸周转率和细胞内钙水平升高，从而在没有细胞外受体刺激的情况下增加细胞运动性并促进细胞侵袭行为。因此，转移结果可以通过 Grb2 和 Plc gamma 1 之间对 FGFR2 上不依赖于磷酸化的结合位点的组成型竞争来决定。
FGFR2-expressing human cancer cells with low concentrations of the adaptor protein Grb2 show high prevalence for metastatic outcome. In nonstimulated cells, the SH3 domain (and not the SH2 domains) of Plc gamma 1 directly competes for a binding site at the very C terminus of FGFR2 with the C-terminal SH3 domain of Grb2. Reduction of Grb2 concentration permits Plc gamma 1 access to the receptor. Recruitment of Plc gamma 1 in this way is sufficient to upregulate phospholipase activity. This results in elevated phosphatidylinositol 4,5-bisphosphate turnover and intracellular calcium levels, thus leading to increased cell motility and promotion of cell-invasive behavior in the absence of extracellular receptor stimulation. Therefore, metastatic outcome can be dictated by the constitutive competition between Grb2 and Plc gamma 1 for the phosphorylation-independent binding site on FGFR2.