School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK.
Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, UK.
Commun Biol. 2021 Apr 1;4(1):437. doi: 10.1038/s42003-021-01969-7.
The regulation of phosphatase activity is fundamental to the control of intracellular signalling and in particular the tyrosine kinase-mediated mitogen-activated protein kinase (MAPK) pathway. Shp2 is a ubiquitously expressed protein tyrosine phosphatase and its kinase-induced hyperactivity is associated with many cancer types. In non-stimulated cells we find that binding of the adaptor protein Grb2, in its monomeric state, initiates Shp2 activity independent of phosphatase phosphorylation. Grb2 forms a bidentate interaction with both the N-terminal SH2 and the catalytic domains of Shp2, releasing the phosphatase from its auto-inhibited conformation. Grb2 typically exists as a dimer in the cytoplasm. However, its monomeric state prevails under basal conditions when it is expressed at low concentration, or when it is constitutively phosphorylated on a specific tyrosine residue (Y160). Thus, Grb2 can activate Shp2 and downstream signal transduction, in the absence of extracellular growth factor stimulation or kinase-activating mutations, in response to defined cellular conditions. Therefore, direct binding of Grb2 activates Shp2 phosphatase in the absence of receptor tyrosine kinase up-regulation.
磷酸酶活性的调节对于细胞内信号转导的控制至关重要，特别是酪氨酸激酶介导的丝裂原活化蛋白激酶（MAPK）途径。Shp2 是一种广泛表达的蛋白酪氨酸磷酸酶，其激酶诱导的过度活跃与许多癌症类型有关。在非刺激细胞中，我们发现衔接蛋白 Grb2 在单体状态下与 Shp2 的 N 端 SH2 和催化结构域结合，从而启动 Shp2 活性，而不依赖于磷酸酶的磷酸化。Grb2 与 Shp2 的 N 端 SH2 和催化结构域形成双齿相互作用，将磷酸酶从其自身抑制构象中释放出来。Grb2 通常在细胞质中以二聚体的形式存在。然而，当它以低浓度表达或在特定酪氨酸残基（Y160）上发生组成性磷酸化时，其单体状态占主导地位。因此，Grb2 可以在没有细胞外生长因子刺激或激酶激活突变的情况下，响应特定的细胞条件，激活 Shp2 和下游信号转导，而不需要受体酪氨酸激酶的上调。因此，Grb2 的直接结合在受体酪氨酸激酶上调缺失的情况下激活了 Shp2 磷酸酶。
