Grb2 monomer–dimer equilibrium determines normal versus oncogenic function

• Published in: Nature communications Vol. 6; no. 1; p. 7354
• Main Authors: Ahmed, Zamal, Timsah, Zahra, Suen, Kin M., Cook, Nathan P., Lee, Gilbert R., Lin, Chi-Chuan, Gagea, Mihai, Marti, Angel A., Ladbury, John E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.06.2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 13; 14; 14/33; 631/67; 631/80/458/1733; 631/80/86; 692/420/755; Breast Neoplasms - metabolism; Colonic Neoplasms - metabolism; Female; GRB2 Adaptor Protein - chemistry; GRB2 Adaptor Protein - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Male; MAP Kinase Signaling System; multidisciplinary; Phosphorylation; Prostatic Neoplasms - metabolism; Protein Multimerization; Science; Science (multidisciplinary); Signal Transduction; Son of Sevenless Proteins - metabolism; src Homology Domains; Tissue Array Analysis; Tyrosine - metabolism
• DOI: 10.1038/ncomms8354
• ISSN: 2041-1723

The adaptor protein growth factor receptor-bound protein 2 (Grb2) is ubiquitously expressed in eukaryotic cells and involved in a multitude of intracellular protein interactions. Grb2 plays a pivotal role in tyrosine kinase-mediated signal transduction including linking receptor tyrosine kinases to the Ras/mitogen-activated protein (MAP) kinase pathway, which is implicated in oncogenic outcome. Grb2 exists in a constitutive equilibrium between monomeric and dimeric states. Here we show that only monomeric Grb2 is capable of binding to SOS and upregulating MAP kinase signalling and that the dimeric state is inhibitory to this process. Phosphorylation of tyrosine 160 (Y160) on Grb2, or binding of a tyrosylphosphate-containing ligand to the SH2 domain of Grb2, results in dimer dissociation. Phosphorylation of Y160 on Grb2 is readily detectable in the malignant forms of human prostate, colon and breast cancers. The self-association/dissociation of Grb2 represents a switch that regulates MAP kinase activity and hence controls cancer progression. Grb2 is an adaptor protein that can exist as a dimer that dissociates on phosphorylation of Y160. Here, the authors show that only the monomeric protein is capable of activating mitogen-activated protein kinase signal transduction and hence control oncogenic outcome.