Understanding the Mechanism of Insulin and Insulin-Like Growth Factor (IGF) Receptor Activation by IGF-II
| Autor: | Carlie Delaine, John C. Wallace, Grant W. Booker, Clair L. Alvino, Briony E. Forbes, Kerrie A. McNeil, Shee Chee Ong |
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| Rok vydání: | 2011 |
| Předmět: |
Bacterial Diseases
Anatomy and Physiology Physiology medicine.medical_treatment lcsh:Medicine Biochemistry Receptor IGF Type 1 Mice Estrogen-related receptor alpha Insulin-like growth factor 0302 clinical medicine Insulin receptor substrate Molecular Cell Biology Insulin 5-HT5A receptor Insulin-Like Growth Factor I Phosphorylation Biomacromolecule-Ligand Interactions lcsh:Science Insulin-like Growth Factor 0303 health sciences Multidisciplinary Mycobacterium Avium Complex 3. Good health Cell biology Infectious Diseases 030220 oncology & carcinogenesis Medicine Protein Binding Signal Transduction Research Article Molecular Sequence Data Biophysics Endocrine System Biology Binding Competitive Protein Chemistry Cell Growth 03 medical and health sciences Growth factor receptor Insulin-Like Growth Factor II medicine Enzyme-linked receptor Animals Amino Acid Sequence Molecular Biology Enzyme Assays 030304 developmental biology Insulin-like growth factor 1 receptor Endocrine Physiology lcsh:R Proteins Cell Biology Receptor Insulin Hormones Enzyme Activation Insulin receptor biology.protein Mutant Proteins lcsh:Q Proto-Oncogene Proteins c-akt Sequence Alignment |
| Zdroj: | PLoS ONE, Vol 6, Iss 11, p e27488 (2011) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Background Insulin-like growth factor-II (IGF-II) promotes cell proliferation and survival and plays an important role in normal fetal development and placental function. IGF-II binds both the insulin-like growth factor receptor (IGF-1R) and insulin receptor isoform A (IR-A) with high affinity. Interestingly both IGF-II and the IR-A are often upregulated in cancer and IGF-II acts via both receptors to promote cancer proliferation. There is relatively little known about the mechanism of ligand induced activation of the insulin (IR) and IGF-1R. The recently solved IR structure reveals a folded over dimer with two potential ligand binding pockets arising from residues on each receptor half. Site-directed mutagenesis has mapped receptor residues important for ligand binding to two separate sites within the ligand binding pocket and we have recently shown that the IGFs have two separate binding surfaces which interact with the receptor sites 1 and 2. Methodology/Principal Findings In this study we describe a series of partial IGF-1R and IR agonists generated by mutating Glu12 of IGF-II. By comparing receptor binding affinities, abilities to induce negative cooperativity and potencies in receptor activation, we provide evidence that residue Glu12 bridges the two receptor halves leading to receptor activation. Conclusions/Significance This study provides novel insight into the mechanism of receptor binding and activation by IGF-II, which may be important for the future development of inhibitors of its action for the treatment of cancer. |
| Databáze: | OpenAIRE |
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