Secreted and O-GlcNAcylated MIF binds to the human EGF receptor and inhibits its activation.
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.
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Yanhua
Y
Zheng
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Xinjian
X
Li
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Xu
X
Qian
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Yugang
Y
Wang
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Jong-Ho
JH
Lee
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Yan
Y
Xia
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
David H
DH
Hawke
Department of Surgical Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, China.
Gang
G
Zhang
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
J
Lyu
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.
Zhimin
Z
Lu
D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D034622:RNA Interference; D012694:Serine / Q000378:metabolism; D016019:Survival Analysis; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
D008263:Macrophage Migration-Inhibitory Factors; D013912:Threonine; D012694:Serine; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D053509:Matrix Metalloproteinase 13; D000117:Acetylglucosamine