Insulin-Like Growth Factor Biology and Applications

The insulin-like growth factor (IGF) system comprises two ligands (IGF-I and IGF-II), their cell-surface receptor (IGF1R) and a family of six high-affinity IGF-binding proteins (IGFBP-1 to ‑6), together with specialised proteases that regulate ligand availability. IGFs act as both endocrine hormones and autocrine/paracrine growth factors, controlling processes such as cell proliferation, differentiation, survival and metabolism. Under physiological conditions, most circulating IGFs are sequestered by IGFBPs in binary or ternary complexes, which prolong IGF half-life and restrict receptor access. Proteolytic cleavage of IGFBPs by metalloproteinases such as pregnancy-associated plasma protein-A (PAPP-A) and PAPP-A2 liberates free IGF, enabling receptor engagement. Beyond classical growth roles, IGFs and IGFBPs have been implicated in tissue repair, metabolic regulation and immune function. Dysregulation of the IGF axis contributes to human pathologies including growth disorders, cancer and metabolic disease, making components of this system attractive therapeutic targets. Advances in structural biology, protease biology and binding-protein biochemistry now offer routes to modulate IGF action precisely, with potential applications ranging from recombinant IGF therapies and protease inhibitors to IGFBP mimetics and receptor antagonists.

Research from Nature Portfolio

Recent studies have elucidated the structural basis of IGF axis regulation by metalloproteinases. High-resolution cryo-electron microscopy has defined the architecture of human PAPP-A2 in complex with its substrate IGFBP5, revealing how distinct domains govern substrate recognition and cleavage efficiency. Comparative analyses with PAPP-A highlight key differences that underlie the lower catalytic rate of PAPP-A2, providing mechanistic insight into patient mutations that abolish proteolytic activity. These findings establish a foundation for the rational design of modulators that restore or inhibit IGF release in growth failure syndromes and other disorders of IGF bioavailability.

Insulin-Like Growth Factor Biology and Applications publication trend

The graph below shows the total number of articles in insulin-like growth factor biology and applications across all publications each year (not limited to Nature Index journals).

Technical terms

Insulin-like growth factor (IGF): Peptide hormones (IGF-I and IGF-II) that regulate growth, development and metabolism via activation of the IGF1 receptor.

IGF-binding protein (IGFBP): A family of six homologous proteins that bind IGFs with high affinity, extending their half-life and modulating receptor access and independent signalling.

Pregnancy-associated plasma protein-A (PAPP-A): A metalloprotease that cleaves IGFBP-4 (and other IGFBPs) to release free IGFs and enhance IGF receptor activation.

PAPP-A2: A paralogous metalloprotease that selectively cleaves IGFBP5; mutations in PAPP-A2 can lead to growth failure by limiting IGF-I bioavailability.

Cryo-electron microscopy (cryo-EM): A structural technique that images vitrified biomolecules at near-atomic resolution to elucidate protein assemblies and interactions.

References

1. The role of pregnancy associated plasma protein-A in triple negative breast cancer: a promising target for achieving clinical benefits. Journal of Biomedical Science (2024).
2. Cryo-EM structure of human PAPP-A2 and mechanism of substrate recognition. Communications Chemistry (2023).
3. IGF-Binding Proteins: Why Do They Exist and Why Are There So Many?. Frontiers in Endocrinology (2018).
4. Mutations in pregnancy‐associated plasma protein A2 cause short stature due to low IGF‐I availability. EMBO Molecular Medicine (2016).