IGF2

IGF2, or insulin-like growth factor 2, is a peptide growth factor in the IGF family. It is a secreted protein similar to insulin, involved in fetal and postnatal growth.

The IGF2 gene is located on chromosome 11p15.5 in humans; it encodes multiple transcripts from several promoters (P0, P1, P2, P3, P4) with tissue- and stage-specific expression.

Expression is tightly regulated by genomic imprinting: IGF2 is paternally expressed while the maternal allele is typically silenced. The imprinting control region (ICR) near the neighboring H19 gene is differentially methylated: the maternal ICR is unmethylated and bound by CTCF, which insulates IGF2 from enhancers and allows H19 transcription; the paternal ICR is methylated, preventing CTCF binding and enabling IGF2 expression.

IGF2 signals primarily through the IGF1 receptor (IGF1R) and the insulin receptor isoform A (IR-A), and can also bind the IGF2 receptor (IGF2R), which primarily clears IGF2 rather than signaling. Through IGF1R and IR-A, IGF2 activates MAPK and PI3K/AKT pathways, promoting cell proliferation, survival, and growth, especially during fetal development. IGF2 expression declines after birth and is governed by growth factors and imprinting status.

Clinical significance: Regulation of IGF2, particularly imprinting defects at 11p15, contributes to growth disorders such as Beckwith-Wiedemann syndrome (IGF2 overexpression) and Silver-Russell syndrome (IGF2 underexpression). Aberrant IGF2 expression and loss of imprinting are also observed in various cancers.