Microarray Analysis and Identification of Novel Molecules Involved in Insulin-like Growth Factor-1 Receptor Signaling and Gene Expression

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 3Ј 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.

Gene expression profiling of ErbB receptor and ligand-dependent transcription

“…Table 1 in bold) and PPAP2A, which were preferentially up-and downregulated by ErbB2Ab, respectively, were also confirmed by QRT-PCR as being specific to ErbB2 activation ( Figure 3 Fambrough et al (1999) indicated that activation of platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor, or EGFR resulted in nearly identical patterns of gene regulation. More recently, it has been shown that insulin receptor and insulin-like growth factor receptor-1 regulate an overlapping but distinct group of genes (Dupont et al, 2001(Dupont et al, , 2003Mulligan et al, 2002). Similar results have now been observed between TGFb receptors, ALK1 and ALK5, and two isoforms of the progesterone receptor (Ota et al, 2002;Richer et al, 2002).…”

Aging of the brain, neurotrophin signaling, and Alzheimer's disease: Is IGF1-R the common culprit?

“…Even though cross-reaction can occur, each receptor binds to its own ligand with a 100-to 1000-fold higher affinity than that of the heterologous peptide. In agreement with these biochemical observations, IR and IGF1-R have certain shared functions, but also very distinct biological roles, and activate completely different sets of genes [40,79].…”

“…The release of the large Nterminal domain allows subsequent γ cleavage, and liberation of Aβ and the signaling active intracellular domain of APP (AICD) (Figure 1). γ cleavage does not seem to be sequence specific and normally occurs either at position 40 or 42 of the Aβ region generating Aβ 40 and Aβ 42 , respectively. Release of Aβ in the extracellular milieu is followed by oligomerization and aggregation in the form of amyloid plaques.…”

Insulin control of placental gene expression shifts from mother to foetus over the course of pregnancy

“…We identified 371 insulin-responsive genes that were specifically regulated in one compartment of the placenta. Some of the genes had also been identified in other microarray studies, which used different cell models, stimulation and analysis modalities [24][25][26][27][28], or by other methods [9,10], thus representing a robust insulin response common to many cell types.…”