Department of Biochemistry and Molecular Biology and Center for Biomolecular Structure and Function, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell. 2012 Jun 22;149(7):1514-24. doi: 10.1016/j.cell.2012.04.033.
Receptor tyrosine kinase activity is known to occur in the absence of extracellular stimuli. Importantly, this "background" level of receptor phosphorylation is insufficient to effect a downstream response, suggesting that strict controls are present and prohibit full activation. Here a mechanism is described in which control of FGFR2 activation is provided by the adaptor protein Grb2. Dimeric Grb2 binds to the C termini of two FGFR2 molecules. This heterotetramer is capable of a low-level receptor transphosphorylation, but C-terminal phosphorylation and recruitment of signaling proteins are sterically hindered. Upon stimulation, FGFR2 phosphorylates tyrosine residues on Grb2, promoting dissociation from the receptor and allowing full activation of downstream signaling. These observations establish a role for Grb2 as an active regulator of RTK signaling.
受体酪氨酸激酶活性已知会在没有细胞外刺激的情况下发生。重要的是，这种“背景”水平的受体磷酸化不足以产生下游反应，这表明存在严格的控制，以防止完全激活。在这里，描述了一种机制，其中 FGFR2 激活的控制是由衔接蛋白 Grb2 提供的。二聚体 Grb2 与两个 FGFR2 分子的 C 末端结合。这种异四聚体能够进行低水平的受体转磷酸化，但 C 末端磷酸化和信号蛋白的募集受到空间位阻的阻碍。受到刺激后，FGFR2 磷酸化 Grb2 的酪氨酸残基，促进其从受体解离，从而使下游信号的充分激活。这些观察结果确立了 Grb2 作为 RTK 信号的活性调节剂的作用。
