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An Integrin Binding-defective Mutant of Insulin-like Growth Factor-1 (R36E/R37E IGF1) Acts as a Dominant-negative Antagonist of the IGF1 Receptor (IGF1R) and Suppresses Tumorigenesis but Still Binds to IGF1R*
- Publication Year :
- 2013
- Publisher :
- American Society for Biochemistry and Molecular Biology, 2013.
-
Abstract
- Insulin-like growth factor-1 (IGF1) is a major therapeutic target for cancer. We recently reported that IGF1 directly binds to integrins (αvβ3 and α6β4) and induces ternary complex formation (integrin-IGF1-IGF1 receptor (IGF1R)) and that the integrin binding-defective mutant of IGF1 (R36E/R37E) is defective in signaling and ternary complex formation. These findings predict that R36E/R37E competes with WT IGF1 for binding to IGF1R and inhibits IGF signaling. Here, we described that excess R36E/R37E suppressed cell viability increased by WT IGF1 in vitro in non-transformed cells. We studied the effect of R36E/R37E on viability and tumorigenesis in cancer cell lines. We did not detect an effect of WT IGF1 or R36E/R37E in cancer cells under anchorage-dependent conditions. However, under anchorage-independent conditions, WT IGF1 enhanced cell viability and induced signals, whereas R36E/R37E did not. Notably, excess R36E/R37E suppressed cell viability and signaling induced by WT IGF1 under anchorage-independent conditions. Using cancer cells stably expressing WT IGF1 or R36E/R37E, we determined that R36E/R37E suppressed tumorigenesis in vivo, whereas WT IGF1 markedly enhanced it. R36E/R37E suppressed the binding of WT IGF1 to the cell surface and the subsequent ternary complex formation induced by WT IGF1. R36E/R37E suppressed activation of IGF1R by insulin. WT IGF1, but not R36E/R37E, induced ternary complex formation with the IGF1R/insulin receptor hybrid. These findings suggest that 1) IGF1 induces signals under anchorage-independent conditions and that 2) R36E/R37E acts as a dominant-negative inhibitor of IGF1R (IGF1 decoy). Our results are consistent with a model in which ternary complex formation is critical for IGF signaling. Background: The integrin binding-defective mutant of IGF1 (R36E/R37E) is functionally defective and does not induce ternary complex formation (integrin-IGF1-IGF1R). Results: R36E/R37E suppressed signaling induced by WT IGF1, the binding of WT IGF1 to cells, ternary complex formation, cell viability, and tumorigenesis. Conclusion: R36E/R37E is a dominant-negative antagonist of IGF signaling. Significance: R36E/R37E has potential as a therapeutic agent.
- Subjects :
- endocrine system
Integrins
Cell Survival
medicine.medical_treatment
Mutation, Missense
Biology
Biochemistry
Models, Biological
Receptor, IGF Type 1
Insulin-like growth factor
Mice
Cell Line, Tumor
medicine
Animals
Humans
Insulin
Viability assay
Insulin-Like Growth Factor I
Protein Structure, Quaternary
Molecular Biology
Ternary complex
Integrin binding
Insulin-like growth factor 1 receptor
Cell Biology
Molecular biology
body regions
Insulin receptor
Cell Transformation, Neoplastic
Amino Acid Substitution
Cancer cell
biology.protein
NIH 3T3 Cells
Signal transduction
hormones, hormone substitutes, and hormone antagonists
Signal Transduction
Protein Binding
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....1dbdfde737e717e0b6d3219667d1531d