IGF2: epigenetic regulation and role in development and disease

Abstract

Insulin-like growth factor II (IGF2) is perhaps the most intricately regulated of all growth factors characterized to date. Its gene is imprinted--only one allele is active, depending on parental origin--and this pattern of expression is maintained epigenetically in almost all tissues. IGF2 activity is further controlled through differential expression of receptors and IGF-binding proteins (IGFBPs) that determine protein availability. This complex and multifaceted regulation emphasizes the importance of accurate IGF2 expression and activity. This review will examine the regulation of the IGF2 gene and what it has revealed about the phenomenon of imprinting, which is frequently disrupted in cancer. IGF2 protein function will be discussed, along with diseases that involve IGF2 overexpression. Roles for IGF2 in sonic hedgehog (Shh) signaling and angiogenesis will also be explored.

Figure 1

(A) Model of imprinted regulation at the Igf2-H19 locus. Adapted from [25]. (B) Model of allele-specific repression in X chromosome inactivation by CTCF. Adapted from [–28]. DMR: differentially methylated region. Lollipops: methylated CpGs. X_i and X_a: inactive and active X chromosomes, respectively.

Figure 2

Overview of the insulin/IGF system. IR exists in two isoforms: IR-A and IR-B. IR-B is responsible for the classic metabolic responses induced by insulin, and also binds IGF1 and IGF2 with low and intermediate affinity, respectively. IR-A has high affinity for insulin and IGF2, and binds IGF1 with low affinity. IGF1R binds the IGFs to stimulate anabolic activity, and also binds insulin at high concentrations. IR-A/IGF1R heterodimers bind insulin and IGFs with similar affinity, whereas IR-B/IGF1R heterodimers bind IGF1 exclusively. IGF2R exclusively binds IGF2 and targets it for degradation. Adapted from [47] and [46].

Figure 3

(A) Normal and (B) BWS gene expression patterns on chromosome 11p15.5. Arrows represent active genes. Lollipops: methylated CpGs. Red octagon: CTCF. Asterisks: point mutations. Filled triangles: translocation breakpoints. Open triangles: deletions. Adapted from [16, 59, 60].

Figure 4

The Shh signaling pathway. A) In the absence of signal, the receptor patched (Ptc) is complexed with smoothened (Smo), and Gli exists in a truncated form that acts as a transcriptional repressor [99, 100]. B) When bound by Shh, Ptc releases Smo, which signals to produce a full-length Gli activator protein. Gli target genes include Gli, Ptc, and genes involved in proliferation and morphogenesis.