Mechanism of β-catenin regulation by IGFBP2: Role in Glioblastoma progression

Abstract

Insulin-like growth factor binding proteins (IGFBPs) were initially identified as high affinity binders of Insulin-like growth factors (IGFs). There are six IGFBPs which regulate the bioavailability and functions of IGFs by increasing the half-life in circulation. IGFBPs are known to play important roles in embryonic development, postnatal growth, and diseases including cancer. The physiological roles of IGFBPs are not limited to IGF regulation. In cancer, these molecules can work as tumor suppressors or promoters in a context dependent manner. Also, IGFBP1 and IGFBP2 have Arg-Gly-Asp (RGD) motifs in their C-terminal domain and they are known to interact with integrins and activate integrin signalling. IGFBP2 has been shown to have IGF independent functions which include pro-tumorigenic actions. In multiple studies, IGFBP2 has been shown to play a role in cell proliferation, migration, invasion, stem cell maintenance, and chemoresistance in various cancers. Plasma and tissue levels of IGFBP2 have been associated with clinical outcomes including response to therapy, relapse, and overall survival in glioblastoma following objectives for our study. ➢ To understand the mechanism of IGFBP2 induced migration and invasion in glioma cells. ➢ Regulation of β-catenin by IGFBP2 and its cytoplasmic actions in glioma Isolation of human single chain variable fragment (scFv) antibodies against IGFBP2 from yeast surface display library and their characterization In conclusion, this study provides mechanistic insights of IGFBP2 activated FAK/p38/GSK3β/β-catenin/HIF1α and FAK/Src/EGFR/ERK1/2 signalling pathways and their role in IGFBP2 induced glioma cell migration, invasion, and stem cell maintenance. In addition, we have isolated scFvs against IGFBP2 which in principle can be used to mitigate pro-tumorigenic actions of IGFBP2