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Microarray analysis and identification of novel molecules involved in insulin-like growth factor-1 receptor signaling
Joelle Dupont1, Sandra E Dunn, J Carl Barrett
1Physiologie de la Reproduction et des Comportements, Unite Mixte de Recherches 6073, Institut National de la Recherche Agronomique-Centre National de la Recherche Scientifique, Université F. Rabelais, Tours 37380 Nouzilly, France.
Abstract:
The insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF-1R) are members of the same subfamily of receptor tyrosine kinases. The two receptors phosphorylate many of the same substrates and activate the same signaling modules, including the mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3' kinase (PI3K) signaling pathways. Although the IR and IGF-1R share some redundant functions in metabolism, cell growth, differentiation, and apoptosis, they also exhibit distinct physiological roles. Some of these may be due to differences in tissue distribution, receptor structure, formation of hybrid receptors, or mechanisms of ligand binding. However, the divergent effects of insulin and IGF-1 also may be explained by specificity in the intracellular signals generated by insulin and IGF-1. In particular, the IR and IGF-1R are capable of triggering their own biological responses by using specific or preferential substrates, molecular adapters, or signaling pathways. In a recent study, we used cDNA microarray analysis to identify genes differentially regulated by insulin and IGF-1. Mouse NIH-3T3 fibroblasts expressing either the wild-type human IGF-1R or IR were stimulated with either IGF-1 or insulin, respectively. We identified 39 genes differentially regulated by insulin and IGF-1. Most of these genes had not been reported previously to be responsive to insulin or IGF-1. The genes induced by IGF-1 generally were involved in mitogenesis or differentiation, while the genes found to be induced by insulin did not conform to any particular category. In a separate study, immortalized breast epithelial cells were stimulated with IGF-1 and a cDNA microarray analysis was used to generate a profile of IGF-1-regulated genes. A number of genes known to be involved in angiogenesis were found to be regulated by IGF-1. These results strongly suggest that this technology may be extremely useful in identifying groups of genes that are specifically regulated by different ligands and their activated receptors.
Insights
Insulin receptor (IR) and IGF-1 receptor (IGF-1R) signaling pathways diverge, impacting distinct cellular processes. cDNA microarray analysis identified novel genes regulated by insulin and IGF-1, revealing specific biological roles.
Area of Science:
- Cellular and Molecular Biology
- Receptor Tyrosine Kinases
- Signal Transduction
Background:
- Insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) are related receptor tyrosine kinases.
- Both receptors activate shared signaling pathways like MAPK and PI3K.
- Despite functional overlap, IR and IGF-1R have distinct physiological roles.
Purpose of the Study:
- To identify genes differentially regulated by insulin and IGF-1.
- To explore the specificity of intracellular signaling initiated by IR and IGF-1R.
- To investigate novel gene targets of insulin and IGF-1 signaling.
Main Methods:
- cDNA microarray analysis was employed.
- NIH-3T3 fibroblasts expressing wild-type human IGF-1R or IR were stimulated with IGF-1 or insulin.
- Gene expression profiles were generated for insulin and IGF-1 stimulation.
Main Results:
- 39 genes were identified as differentially regulated by insulin and IGF-1.
- Genes induced by IGF-1 were primarily associated with mitogenesis and differentiation.
- Genes induced by insulin did not fall into a specific functional category.
- IGF-1 was found to regulate angiogenesis-related genes in breast epithelial cells.
Conclusions:
- Insulin and IGF-1 signaling pathways regulate distinct sets of genes.
- cDNA microarray analysis is effective for identifying ligand- and receptor-specific gene regulation.
- Novel biological roles for insulin and IGF-1 signaling are suggested by the identified gene sets.