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Updated: Aug 26, 2025

Coculture Analysis of Extracellular Protein Interactions Affecting Insulin Secretion by Pancreatic Beta Cells
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Glycan Modulation of Insulin-like Growth Factor-1 Receptor

Rio S Boothello1, Nehru Viji Sankaranarayanan2,3, Jyothi C Sistla2,3

  • 1Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249, USA.

Angewandte Chemie (International Ed. in English)
|October 7, 2022
PubMed

Insights

Shorter heparan sulfate (HS) sequences preferentially inhibit insulin-like growth factor-1 receptor (IGF-1R) activation, unlike longer chains. This discovery offers new avenues for anti-cancer drug development targeting IGF-1R signaling.

Area of Science:

  • Glycobiology
  • Cancer Biology
  • Molecular Pharmacology

Background:

  • The insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) crucial in cancer development and progression.
  • Heparan sulfates (HS) are complex carbohydrates typically known to modulate growth factor signaling, including IGF-1R activation.

Purpose of the Study:

  • To investigate the differential effects of heparan sulfate (HS) chain length on IGF-1R activation.
  • To elucidate the mechanism by which HS sequences interact with and modulate IGF-1R activity.

Main Methods:

  • Utilized microarray, computational modeling, thermodynamic analyses, and cellular imaging techniques.
  • Examined the binding interactions between various lengths of HS sequences and the IGF-1R ectodomain.
  • Assessed the impact of HS binding on IGF-1R activation by its ligand, IGF1.

Main Results:

  • Shorter, soluble HS sequences (e.g., HS06) were found to inhibit IGF-1R activation by IGF1.
  • Longer, polymeric HS chains did not exhibit this inhibitory effect, contrary to established GAG-protein interactions.
  • Inhibition by short HS sequences is attributed to binding within a specific pocket on the IGF-1R ectodomain, competing with IGF1 binding.

Conclusions:

  • This study reveals a novel, size-dependent inhibitory mechanism of HS on IGF-1R signaling.
  • Preferential inhibition by smaller HS oligosaccharides presents a unique therapeutic target for modulating IGF-1R in cancer.
  • Findings provide valuable insights for glycobiologists and the development of novel anti-cancer therapeutics targeting RTKs.
Keywords:
Drug DiscoveryGlycosaminoglycansGrowth FactorsHeparan SulfateReceptor Tyrosine Kinases

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