Insulin-like Growth Factor 2 (IGF2) is a protein hormone that plays a significant role in various biological processes. As a member of the insulin-like growth factor family, it shares structural similarities with both insulin and IGF1. While IGF1 is predominantly expressed after birth, IGF2 is particularly prominent during early embryonic and fetal development. It is found in a wide array of somatic tissues during these stages, influencing growth and development.
How IGF2 Works in the Body
IGF2 acts primarily as a growth factor, driving cell proliferation, differentiation, migration, and survival. It achieves these effects by interacting with specific receptors on cell surfaces. The main receptor is the Type 1 IGF receptor (IGF1R), a receptor tyrosine kinase. Binding to IGF1R activates a signaling cascade within the cell, which regulates cell growth and metabolism.
Beyond IGF1R, IGF2 can also bind to the insulin receptor (IR), specifically isoform A (IR-A). This interaction stimulates cell proliferation. Its availability for receptor binding is controlled by six insulin-like growth factor binding proteins (IGFBPs), which act as carriers and modulators, influencing its half-life and tissue distribution. IGF2 is present in various tissues, including the heart, placenta, lungs, liver, muscles, and kidneys.
The Genetics of IGF2
The IGF2 gene has a unique characteristic: genomic imprinting, which dictates its expression pattern. Located on chromosome 11 at locus 11p15.5, the IGF2 gene is part of an imprinted gene cluster that also includes the H19 gene. Genomic imprinting means that only one copy of the gene, either from the mother or the father, is expressed, while the other copy is silenced. For IGF2, expression occurs exclusively from the paternal allele in most somatic tissues, while the maternal allele is silenced.
This parent-specific expression is regulated by an imprinting control region (ICR1). The ICR1 contains a differentially methylated region (DMR) where the paternal allele is methylated, allowing IGF2 expression, and the maternal allele is unmethylated, leading to its silencing. Disruptions to this epigenetic balance, such as changes in methylation patterns or small deletions within the ICR1, can lead to abnormal IGF2 expression. This can result in biallelic expression of IGF2, where both parental copies are active, leading to overproduction of the IGF-II peptide.
IGF2 and Human Health
The balanced expression of IGF2 is fundamental for normal health, particularly during prenatal development. Its role as a major fetal growth hormone means that dysregulation can lead to significant growth disorders. For instance, overproduction of IGF2, often due to a loss of imprinting on the maternal allele resulting in biallelic expression, is associated with Beckwith-Wiedemann Syndrome (BWS). This syndrome presents with overgrowth, enlarged organs, and an increased risk of certain pediatric tumors.
Conversely, conditions characterized by undergrowth, such as Silver-Russell Syndrome (SRS), can involve reduced IGF2 expression. In some cases of SRS, a loss of methylation on the paternal IGF2 allele’s imprinting control region leads to its silencing and insufficient IGF2 levels. Beyond developmental disorders, IGF2 has a role in various cancers, including colorectal, lung, and breast cancers, where it can promote tumor growth and survival. Its ability to stimulate cell proliferation and inhibit cell death pathways makes it a factor in tumorigenesis.