IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer

Abstract

IMPs, also known as insulin-like growth factor 2 (IGF2) messenger RNA (mRNA)-binding proteins (IGF2BPs), are highly conserved oncofetal RNA-binding proteins (RBPs) that regulate RNA processing at several levels, including localization, translation, and stability. Three mammalian IMP paralogs (IMP1-3) have been identified that are expressed in most organs during embryogenesis, where they are believed to play an important role in cell migration, metabolism, and stem cell renewal. Whereas some IMP2 expression is retained in several adult mouse organs, IMP1 and IMP3 are either absent or expressed at very low levels in most tissues after birth. However, all three paralogs can be re-expressed upon malignant transformation and are found in a broad range of cancer types where their expression often correlates with poor prognosis. IMPs appear to resume their physiological functions in malignant cells, which not only contribute to tumor progression but participate in the establishment and maintenance of tumor cell hierarchies. This review summarizes our current understanding of the functions of IMPs during normal development and focuses on a series of recent observations that have provided new insight into how their physiological functions enable IMPs to play a potentially key role in cancer stem cell maintenance and tumor growth.

Keywords: IGF2BP; IMP; RNA binding proteins; cancer; let-7; stem cells.

Figure 1.

Structure of IMP paralogs. (Top) Amino acid sequence alignment and corresponding domain structure of IMP1, IMP2, and IMP3. Sequence similarity among the paralogs is highlighted in red, and colors indicate the boundaries of the domains shown in B. Numbers represent corresponding base numbers of the respective genes. (Bottom) Schematic representation of IMP domains.

Figure 2.

Mechanisms of mRNA protection from miRNA-mediated silencing by IMPs. Whereas LIN28A/B impair let-7 miRNAs maturation, IMP2 prevents let-7 target gene silencing by direct binding to let-7 MREs on mRNAs. IMP2 is found in P bodies, where it may be in direct competition with AGO2, the catalytic component of the RISC. Although IMP1 and IMP3 may also bind to MREs or in their immediate vicinity, safe-housing transcripts in a RISC-free environment constituted of mRNP granules is currently the best-understood mechanism by which they protect their target mRNAs.

Figure 3.

Schematic representation of the principal known functions of IMPs that may contribute to CSC properties and maintenance. All three IMP paralogs as well as LIN28A/B block let-7 activity, albeit by different mechanisms, and their transcripts are also let-7 targets. Poorly differentiated tumor cells that display self-renewal and tumor-initiating properties express elevated levels of LIN28 paralogs, usually in conjunction with IMP family members, although some such cells express either LIN28 or IMP paralogs. Low let-7 levels facilitate expression of LIN28, IMPs, and HMGA2. In addition, LIN28 and IMPs stabilize each others’ expression as well as that of HMGA2; HMGA2 in turn promotes expression of IMP2. The main functions of IMPs recognized thus far that are associated with their elevated expression in tumor cells include maintenance of stemness or pluripotency; transport of cytoskeletal and adhesion receptor mRNAs to the cell periphery, which promote migration and invasiveness; enhancement of IGF2 translation; and transport of several nuclear-derived mRNAs that encode various components of the respiratory chain to mitochondria, promoting oxidative phosphorylation (OXPHOS).