Zheng Yanhua, Li Xinjian, Qian Xu, Wang Yugang, Lee Jong-Ho, Xia Yan, Hawke David H, Zhang Gang, Lyu Jianxin, Lu Zhimin
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Nat Cell Biol. 2015 Oct;17(10):1348-55. doi: 10.1038/ncb3222. Epub 2015 Aug 17.
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.
表皮生长因子受体（EGFR）的激活存在于多种类型的肿瘤中，会促进肿瘤进展。然而，尚未发现人EGFR的细胞外拮抗剂。我们发现人巨噬细胞迁移抑制因子（MIF）在其羧基末端的Ser 112/Thr 113位点发生O-连接的N-乙酰葡糖胺糖基化修饰。天然分泌且发生O-连接的N-乙酰葡糖胺糖基化修饰的MIF与EGFR结合，从而抑制EGF与EGFR的结合以及EGF诱导的EGFR激活、ERK和c-Jun的磷酸化、细胞侵袭、增殖和脑肿瘤形成。通过突变或其配体结合激活EGFR会增强MMP13的分泌，MMP13会降解细胞外的MIF，并导致MIF对EGFR的负调控作用丧失。EGFR激活会下调肿瘤微环境中的拮抗剂这一发现，代表了人类肿瘤细胞增强EGFR信号传导并促进肿瘤发生的一种重要的前馈机制。
