Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs): post-transcriptional drivers of cancer progression?

Jessica L Bell,Marcell Lederer,Stefan Hüttelmaier,Marcel Köhn,Kristin Wächter,Britta Mühleck,Nikolaos Pazaitis

doi:10.1007/s00018-012-1186-z

Abstract

The insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (IGF2BP1, IGF2BP2, IGF2BP3) belong to a conserved family of RNA-binding, oncofetal proteins. Several studies have shown that these proteins act in various important aspects of cell function, such as cell polarization, migration, morphology, metabolism, proliferation and differentiation. In this review, we discuss the IGF2BP family’s role in cancer biology and how this correlates with their proposed functions during embryogenesis. IGF2BPs are mainly expressed in the embryo, in contrast with comparatively lower or negotiable levels in adult tissues. IGF2BP1 and IGF2BP3 have been found to be re-expressed in several aggressive cancer types. Control of IGF2BPs’ expression is not well understood; however, let-7 microRNAs, β-catenin (CTNNB1) and MYC have been proposed to be involved in their regulation. In contrast to many other RNA-binding proteins, IGF2BPs are almost exclusively observed in the cytoplasm where they associate with target mRNAs in cytoplasmic ribonucleoprotein complexes (mRNPs). During development, IGF2BPs are required for proper nerve cell migration and morphological development, presumably involving the control of cytoskeletal remodeling and dynamics, respectively. Likewise, IGF2BPs modulate cell polarization, adhesion and migration in tumor-derived cells. Moreover, they are highly associated with cancer metastasis and the expression of oncogenic factors (KRAS, MYC and MDR1). However, a pro-metastatic role of IGF2BPs remains controversial due to the lack of ‘classical’ in vivo studies. Nonetheless, IGF2BPs could provide valuable targets in cancer treatment with many of their in vivo roles to be fully elucidated.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-012-1186-z) contains supplementary material, which is available to authorized users.

Highlights

The insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 belong to a highly conserved protein family, which as their name suggests can bind RNA and influence their transcript target’s fate
In contrast to many other RNA-binding proteins, IGF2BPs are almost exclusively observed in the cytoplasm where they associate with target mRNAs in cytoplasmic ribonucleoprotein complexes
These synonyms may reflect the evolution of the various fields of IGF2BP family research which suggest that these RNA-binding proteins (RBPs) modulate important aspects of cell function during development and in cancer

Summary

Introduction

The insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (gene symbols: IGF2BP1, IGF2BP2, IGF2BP3) belong to a highly conserved protein family, which as their. We observed that the KH1/2 domain modulates binding of IGF2BP1 to cis-determinants in the ACTB 30UTR and, more strikingly, the MYC-CRD (coding region stability determinant) RNA in vitro (Fig. S2). This could indicate that KH1/2 are important for the stabilization of IGF2BPRNA complexes. The stability of IGF2BP–RNA complexes was found to increase with the length of probed RNA baits in vitro whereas KD-values were decreased [3] It appears as if the identification of physiological relevant target mRNAs of IGF2BPs cannot be based solely on studying protein–RNA association, but presumably. Proposed regulation of target RNA mRNA localization mRNA localization, IGF2 expression Control of mRNA translation Inhibition of mRNA decay Inhibition of mRNA decay mRNA localization mRNA translation mRNA increase (undefined) Inhibition of mRNA decay RO60 protein localization

Method Incidence

Findings

Current limitations and concluding remarks