Letter | Published:

Secreted and O-GlcNAcylated MIF binds to the human EGF receptor and inhibits its activation

Nature Cell Biology volume 17, pages 13481355 (2015) | Download Citation

Abstract

Activation of epidermal growth factor receptor (EGFR), which occurs in many types of tumour, promotes tumour progression1,2. However, no extracellular antagonist of human EGFR has been identified. We found that human macrophage migration inhibitory factor (MIF) is O-GlcNAcylated at Ser 112/Thr 113 at its carboxy terminus. The naturally secreted and O-GlcNAcylated MIF binds to EGFR, thereby inhibiting the binding of EGF to EGFR and EGF-induced EGFR activation, phosphorylation of ERK and c-Jun, cell invasion, proliferation and brain tumour formation. Activation of EGFR through mutation or its ligand binding enhances the secretion of MMP13, which degrades extracellular MIF, and results in abrogation of the negative regulation of MIF on EGFR. The finding that EGFR activation downregulates its antagonist in the tumour microenvironment represents an important feedforward mechanism for human tumour cells to enhance EGFR signalling and promote tumorigenesis.

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Acknowledgements

We thank X. Yu (University of Michigan Medical School) for the pCMV-Myc-OGT plasmid, D. M. F. Van Aalten (University of Dundee, UK) for the pEBG-6P-hOGA plasmid, and M. Wade in the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for critically reading this manuscript. We thank J. Gumin in the Department of Neurosurgery at The University of Texas MD Anderson Cancer Center for her help in mice intracranial injection. This work was supported by National Cancer Institute grants 2R01 CA109035 (Z.L.) and 1R0 CA169603 (Z.L.), National Institute of Neurological Disorders and Stroke grant 1R01 NS089754 (Z.L.), MD Anderson Support Grant CA016672, the James S. McDonnell Foundation 21st Century Science Initiative in Brain Cancer Research Award 220020318 (Z.L.), 2P50 CA127001 (Brain Cancer SPORE), a Sister Institution Network Fund from MD Anderson (Z.L.), National Institutes of Health Grant 1S10 OD012304-01 (D.H.H.), and Cancer Prevention and Research Institute of Texas research grant RP130397 (D.H.H.). Z.L. is a Ruby E. Rutherford Distinguished Professor.

Author information

Affiliations

  1. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Yanhua Zheng
    • , Xinjian Li
    • , Xu Qian
    • , Yugang Wang
    • , Jong-Ho Lee
    • , Yan Xia
    •  & Zhimin Lu
  2. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • David H. Hawke
  3. Department of Surgical Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, China

    • Gang Zhang
  4. Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China

    • Jianxin Lyu
  5. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Zhimin Lu
  6. Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA

    • Zhimin Lu

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Contributions

This study was conceived by Z.L.; Y.Z. and Z.L. designed research, Y.Z., X.L., X.Q., Y.W., J.-H.L., Y.X., D.H.H., G.Z. and J.L. performed experiments; Z.L. wrote the paper with comments from all authors.

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Zhimin Lu.

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DOI

https://doi.org/10.1038/ncb3222

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