title: IGFBP7 binds to the IGF-1 receptor and blocks its activation by insulin-like growth factors.
abstract: Insulin-like growth factor-binding protein 7 (IGFBP7) is a secreted factor that suppresses growth, and the abundance of IGFBP7 inversely correlates with tumor progression. Here, we showed that pretreatment of normal and breast cancer cells with IGFBP7 interfered with the activation and internalization of insulin-like growth factor 1 receptor (IGF1R) in response to insulin-like growth factors 1 and 2 (IGF-1/2), resulting in the accumulation of inactive IGF1R on the cell surface and blockade of downstream phosphatidylinositol 3-kinase (PI3K)-AKT signaling. Binding of IGFBP7 and IGF-1 to IGF1R was mutually exclusive, and the N-terminal 97 amino acids of IGFBP7 were important for binding to the extracellular portion of IGF1R and for preventing its activation. Prolonged exposure to IGFBP7 resulted in activation of the translational repressor 4E-binding protein 1 (4E-BP1) and enhanced sensitivity to apoptosis in IGF1R-positive cells. These results support a model whereby IGFBP7 binds to unoccupied IGF1R and suppresses downstream signaling, thereby inhibiting protein synthesis, cell growth, and survival.
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Valentina
authors.initials: V
authors.lastname: Evdokimova
authors.forename: Cristina E
authors.initials: CE
authors.lastname: Tognon
authors.forename: Tania
authors.initials: T
authors.lastname: Benatar
authors.forename: Wenyi
authors.initials: W
authors.lastname: Yang
authors.forename: Konstantin
authors.initials: K
authors.lastname: Krutikov
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.forename: Poul H B
authors.initials: PH
authors.lastname: Sorensen
authors.forename: Arun
authors.initials: A
authors.lastname: Seth
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D039642:Eukaryotic Initiation Factors; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; C035170:IGF2 protein, human; C513121:IGF2 protein, mouse; D018969:Insulin-Like Growth Factor Binding Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; C102529:insulin-like growth factor binding protein-related protein 1; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1