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

Yanhua Zheng; Xinjian Li; Xu Qian; Yugang Wang; Jong-Ho Lee; Yan Xia; David H Hawke; Gang Zhang; Jianxin Lyu; Zhimin Lu

doi:10.1038/ncb3222

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

Nat Cell Biol. 2015 Oct;17(10):1348-55. doi: 10.1038/ncb3222. Epub 2015 Aug 17.

Authors

Yanhua Zheng¹, Xinjian Li¹, Xu Qian¹, Yugang Wang¹, Jong-Ho Lee¹, Yan Xia¹, David H Hawke², Gang Zhang³, Jianxin Lyu⁴, Zhimin Lu^{1

5

6}

Affiliations

¹ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
² Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
³ Department of Surgical Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, China.
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.
⁵ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
⁶ Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.

PMID: 26280537
PMCID: PMC4785887
DOI: 10.1038/ncb3222

Abstract

Activation of epidermal growth factor receptor (EGFR), which occurs in many types of tumour, promotes tumour progression. 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylglucosamine / metabolism*
Animals
Cell Line
Cell Line, Tumor
Cell Proliferation / drug effects
Enzyme Activation / drug effects
Epidermal Growth Factor / metabolism
Epidermal Growth Factor / pharmacology
ErbB Receptors / genetics
ErbB Receptors / metabolism*
Extracellular Signal-Regulated MAP Kinases / metabolism
Glioma / genetics
Glioma / metabolism
Glioma / pathology
Humans
Immunoblotting
JNK Mitogen-Activated Protein Kinases / metabolism
Macrophage Migration-Inhibitory Factors / genetics
Macrophage Migration-Inhibitory Factors / metabolism*
Matrix Metalloproteinase 13 / metabolism
Mice, Nude
Microscopy, Fluorescence
Mutation
Phosphorylation / drug effects
Protein Binding
RNA Interference
Serine / metabolism
Survival Analysis
Threonine / genetics
Threonine / metabolism
Transplantation, Heterologous

Substances

Macrophage Migration-Inhibitory Factors
Threonine
Serine
Epidermal Growth Factor
EGFR protein, human
ErbB Receptors
Extracellular Signal-Regulated MAP Kinases
JNK Mitogen-Activated Protein Kinases
Matrix Metalloproteinase 13
Acetylglucosamine

Abstract

Publication types

MeSH terms

Substances

Grants and funding