HASF (C3orf58) is a novel ligand of the insulin-like growth factor 1 receptor

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cell Signaling

Background:

• Hypoxia and Akt-induced stem cell factor (HASF) demonstrates cardioprotective properties against ischemia and promotes cardiomyocyte proliferation.
• The specific receptor mediating HASF's beneficial effects remained unidentified.

Purpose of the Study:

• To identify the functional receptor responsible for mediating the cardioprotective and proliferative effects of HASF.
• To elucidate the role of the identified receptor in HASF-induced intracellular signaling pathways.

Main Methods:

• Yeast two-hybrid screening to identify potential HASF binding partners.
• Co-immunoprecipitation and binding assays to confirm HASF-IGF1R interaction.
• In vitro studies using neonatal ventricular cardiomyocytes with HASF treatment, IGF1R inhibitors, and siRNAs.
• In vivo studies utilizing an IGF1R knockout mouse model.

Main Results:

• A partial fragment of insulin-like growth factor 1 receptor (IGF1R) was identified as a HASF binding partner.
• HASF demonstrated high-affinity binding to full-length IGF1R, leading to IGF1R phosphorylation and downstream signaling (e.g., ERK activation).
• IGF1R inhibition or knockdown abrogated HASF-mediated ERK activation and cardiomyocyte proliferation, while IGF2R or insulin receptor knockdown had no effect.
• In vivo deletion of IGF1R completely abolished HASF's ability to promote cardiomyocyte proliferation.

Conclusions:

• The insulin-like growth factor 1 receptor (IGF1R) is the functional receptor for hypoxia and Akt-induced stem cell factor (HASF).
• IGF1R mediates HASF's protective effects on the heart, including the promotion of cardiomyocyte proliferation, via specific intracellular signaling pathways.
• Targeting the HASF-IGF1R axis represents a potential therapeutic strategy for cardiac protection and regeneration.