Grb2 monomer–dimer equilibrium determines normal versus oncogenic function

Zamal Ahmed, Zahra Timsah, Kin M. Suen, Nathan P. Cook, Gilbert R. Lee, Chi-Chuan Lin, Mihai Gagea, Angel A. Marti and John E. Ladbury ()
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Zamal Ahmed: University of Texas, M.D. Anderson Cancer Center
Zahra Timsah: University of Texas, M.D. Anderson Cancer Center
Kin M. Suen: University of Texas, M.D. Anderson Cancer Center
Nathan P. Cook: Rice University
Gilbert R. Lee: Center for Biomolecular Structure and Function, University of Texas, M.D. Anderson Cancer Center
Chi-Chuan Lin: University of Texas, M.D. Anderson Cancer Center
Mihai Gagea: University of Texas, M.D. Anderson Cancer Center
Angel A. Marti: Rice University
John E. Ladbury: University of Texas, M.D. Anderson Cancer Center

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms8354

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