title: Quantitative analysis of insulin-like growth factor 2 receptor and insulin-like growth factor binding proteins to identify control mechanisms for insulin-like growth factor 1 receptor phosphorylation.
abstract: BACKGROUND
  The insulin-like growth factor (IGF) system impacts cellular development by regulating proliferation, differentiation, and apoptosis, and is an attractive therapeutic target in cancer. The IGF system is complex, with two ligands (IGF1, IGF2), two receptors (IGF1R, IGF2R), and at least six high affinity IGF-binding proteins (IGFBPs) that regulate IGF ligand bioavailability. While the individual components of the IGF system are well studied, the question of how these different components integrate as a system to regulate cell behavior is less clear.
  
  
  RESULTS
  To analyze the relative importance of different mechanisms that control IGF network activity, we developed a mass-action kinetic model incorporating cell surface binding, phosphorylation, and intracellular trafficking events. The model was calibrated and validated using experimental data collected from OVCAR5, an immortalized ovarian cancer cell line. We then performed model analysis to examine the ability of IGF2R or IGFBPs to counteract phosphorylation of IGF1R, a critical step for IGF network activation. This analysis suggested that IGF2R levels would need to be 320-fold greater than IGF1R in order to decrease pIGF1R by 25 %, while IGFBP levels would need to be 390-fold greater. Analysis of The Cancer Genome Atlas (TCGA) data set suggested that this level of overexpression is unlikely for IGF2R in ovarian, breast, and colon cancer. In contrast, IGFBPs can likely reach these levels, suggesting that IGFBPs are the more critical regulator of IGF1R network activity. Levels of phosphorylated IGF1R were insensitive to changes in parameters regulating the IGF2R arm of the network.
  
  
  CONCLUSIONS
  Using a mass-action kinetic model, we determined that IGF2R plays a minor role in regulating the activity of IGF1R under a variety of conditions and that due to their high expression levels, IGFBPs are the dominant mechanism to regulating IGF network activation.
authors: Department of Biomedical Engineering, 4553 WI Institute Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI, 53705, USA. dtian@wisc.edu.
authors: Dan
authors: D
authors: Tian
authors: Department of Biomedical Engineering, 4553 WI Institute Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI, 53705, USA. imitchell@wisc.edu.
authors: Isaiah
authors: I
authors: Mitchell
authors: Department of Biomedical Engineering, 4553 WI Institute Medical Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI, 53705, USA. kreeger@wisc.edu.|University of Wisconsin Carbone Cancer Center, 600 Highland Ave, Madison, WI, 53792, USA. kreeger@wisc.edu.
authors: Pamela K
authors: PK
authors: Kreeger
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D011487:Protein Conformation; D021381:Protein Transport; D017527:Receptor, IGF Type 2 / Q000378:metabolism*
chemical_list: C035170:IGF2 protein, human; D018969:Insulin-Like Growth Factor Binding Proteins; D017527:Receptor, IGF Type 2; D007335:Insulin-Like Growth Factor II