Abstract 3338: IGFBP2 promotes EGFR/STAT3 nuclear crosstalk in glioma

Abstract

Abstract Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic secreted protein that is overexpressed in various cancers including glioma. Extracellular IGFBP2 binds and modulates the activity of insulin growth factors I and II (IGFI and IGFII) while cytoplasmic IGFBP2 interacts with signaling pathways essential for cell proliferation and survival. The versatility of IGFBP2 as a secreted or cytoplasmic signaling effector is widely characterized; however, the functions of nuclear IGFBP2 remain largely unknown. Through genomic and functional analyses of glioma, we mechanistically elucidated the role of nuclear IGFBP2 and discovered a functional interaction of IGFBP2 with epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3) proteins. Our findings established a signaling hierarchy of IGFBP2-EGFR-STAT3; IGFBP2 not only upregulates EGFR/STAT3 signaling activity, but also facilitates EGFR nuclear translocation and subsequent nuclear EGFR/STAT3 activity. Furthermore, mutation of the nuclear localization signal of IGFBP2 demonstrated that nuclear translocation of IGFBP2 is critical to promote the nuclear activity of EGFR. By identifying the role of IGFBP2 in perpetuating nuclear crosstalk between EGFR/STAT3, our study further reveals the importance of exploiting IGFBP2 as a target for glioma therapy. Citation Format: YingXuan Chua, Yuexin Liu, Limei Hu, Kirsi Granberg, Maartje Verploegen, Wei Zhang. IGFBP2 promotes EGFR/STAT3 nuclear crosstalk in glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3338. doi:10.1158/1538-7445.AM2014-3338