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

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.

Fig. 1

The IGF2BP protein family. a Domain structure of humanIGF2BPs and additionally, the IMP ortholog (dIMP, isoform K) of Drosophila melanogaster. RNA-binding domains comprising RNA recognition motifs (RRMs, blue) and hnRNP-K homology domains (KH, red). The following proteins are shown: IGF2BP1 (Acc. no.: NM006546), the longest IGF2BP1 protein isoform; IGF2BP2-a (Acc. no.: NM006548), the longest IGF2BP2 protein isoform; IGF2BP2-a* (no Acc. no. available), truncated IGF2BP2-a resulting from leaky scanning during translation initiation [58]; IGF2BP2-b (Acc. no.: NM001007225.1), spliced IGF2BP-a lacking exon 10; IGF2BP3 (Acc. no.: NM006547), the only reported variant of this paralogue; dIMP (Acc. no.: NM001042803), variant K of the Drosophila melanogaster ortholog of IGF2BPs. b Phylogentic tree indicating amino acid substitutions of distinct IGF2BP paralogues from different species (hu human, mu murine, ch chicken, xo Xenopus, d Drosophila). The accession number for each ortholog is indicated

Fig. 2

Regulation of cytoplasmic mRNA fate by IGF2BPs. IGF2BPs associate with specific target mRNAs and other RNA-binding proteins (RBPs) in cytoplasmic mRNPs. The release of associated mRNAs from these mRNPs results in either their decay (mRNA degradation) of or protein synthesis (mRNA translation). The formation of ‘stable’ mRNPs is presumed to allow the directed transport of specific mRNAs along the microtubule and/or actin cytoskeleton (mRNA transport). To prevent promiscuous translation of sorted mRNAs, localized transcripts are likely to be translationally silenced during transport

Fig. 3

IGF2BP expression in adult mice and tumor-derived cells. a Semi-quantitative RT-PCR analysis of IGF2BP expression (40 PCR cycles) in adult mouse tissues. Total RNA was analyzed from tissues isolated from either a 16- or 80-week-old male mouse. 28S RNA served as a loading control (20 PCR cycles). Total RNA isolated from E17 mouse embryonic fibroblasts (MEF) was used as positive control. Total lung RNA without reverse transcription (−RT) and water served as negative controls. b IGF2BP protein expression in indicated tumor-derived cells was analyzed by western blotting using mouse monoclonal antibodies directed against each of the three paralogues. Recombinant IGF2BP proteins (20 ng; including IGF2BP2-a and IGF2BP2-b) served as controls. Note, the IGF2BP3-directed antibody shows a significant cross-reactivity with IGF2BP1 (see also supplemental Fig. S4), presumably reflecting the high sequence similarity of both proteins. The cross-reactivity of both anti-IGF2BP1 (6A9) and anti-IGF2BP3 (6G8) with IGF2BP2 is low and presumably negligible for most studies (see also supplemental Fig. S4). Notably, one or two IGF2BP paralogues are expressed at very low levels in some tumor-derived cells, whereas all three paralogues are expressed in other cancer-derived cells. Additional controls for paralogue specificity of used monoclonal antibodies are shown in Fig. S4