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Grb2 monomer–dimer equilibrium determines normal versus oncogenic function

Author

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  • Zamal Ahmed

    (University of Texas, M.D. Anderson Cancer Center
    Center for Biomolecular Structure and Function, University of Texas, M.D. Anderson Cancer Center)

  • Zahra Timsah

    (University of Texas, M.D. Anderson Cancer Center
    School of Molecular and Cellular Biology, University of Leeds)

  • Kin M. Suen

    (University of Texas, M.D. Anderson Cancer Center
    School of Molecular and Cellular Biology, University of Leeds)

  • Nathan P. Cook

    (Rice University
    Present address: Laboratory of Cellular Dynamics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.)

  • 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
    School of Molecular and Cellular Biology, University of Leeds)

  • 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
    Center for Biomolecular Structure and Function, University of Texas, M.D. Anderson Cancer Center
    School of Molecular and Cellular Biology, University of Leeds)

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.

Suggested Citation

  • Zamal Ahmed & Zahra Timsah & Kin M. Suen & Nathan P. Cook & Gilbert R. Lee & Chi-Chuan Lin & Mihai Gagea & Angel A. Marti & John E. Ladbury, 2015. "Grb2 monomer–dimer equilibrium determines normal versus oncogenic function," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8354
    DOI: 10.1038/ncomms8354
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    Cited by:

    1. Zu Ye & Shengfeng Xu & Yin Shi & Xueqian Cheng & Yuan Zhang & Sunetra Roy & Sarita Namjoshi & Michael A. Longo & Todd M. Link & Katharina Schlacher & Guang Peng & Dihua Yu & Bin Wang & John A. Tainer , 2024. "GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Michael J. Roy & Minglyanna G. Surudoi & Ashleigh Kropp & Jianmei Hou & Weiwen Dai & Joshua M. Hardy & Lung-Yu Liang & Thomas R. Cotton & Bernhard C. Lechtenberg & Toby A. Dite & Xiuquan Ma & Roger J., 2023. "Structural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3 signaling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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