Grb2 binding induces phosphorylation-independent activation of Shp2

• Published in: Communications biology Vol. 4; no. 1; p. 437
• Main Authors: Lin, Chi-Chuan, Wieteska, Lukasz, Suen, Kin Man, Kalverda, Arnout P., Ahmed, Zamal, Ladbury, John E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 14; 14/33; 14/35; 631/45/173; 631/80/86/2368; 82/29; 82/6; 82/80; 9/10; 96/10; 96/106; 96/95; Biology; Biomedical and Life Sciences; Breast cancer; Cancer; Cytoplasm; Enzyme Activation; GRB2 Adaptor Protein - genetics; GRB2 Adaptor Protein - metabolism; Grb2 protein; Hyperactivity; Intracellular signalling; Kinases; Life Sciences; MAP kinase; Phosphatase; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Protein-tyrosine kinase receptors; Protein-tyrosine-phosphatase; Proteins; Signal Transduction
• DOI: 10.1038/s42003-021-01969-7
• ISSN: 2399-3642

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. Lin et al. investigate the interactions between adaptor protein, Grb2, and the ubiquitously expressed protein tyrosine phosphatase, Shp2. They find that monomeric Grb2 can activate Shp2 and its downstream signalling in the absence of up-regulation of receptor tyrosine kinases in response to different cellular conditions. They find that cancer-related signalling in breast cancer cells can be attributed to the binding of Grb2 to Shp2.