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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Apoptosis / genetics
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Survival / genetics
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Eukaryotic Initiation Factors
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Female
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Humans
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Insulin-Like Growth Factor Binding Proteins / genetics
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Insulin-Like Growth Factor Binding Proteins / metabolism*
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Insulin-Like Growth Factor I / genetics
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Insulin-Like Growth Factor I / metabolism*
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Insulin-Like Growth Factor II / genetics
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Insulin-Like Growth Factor II / metabolism*
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Mice
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein Binding / genetics
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Protein Biosynthesis / genetics
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / metabolism*
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Signal Transduction / genetics
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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Eif4ebp1 protein, mouse
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Eukaryotic Initiation Factors
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IGF2 protein, human
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IGF2 protein, mouse
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Insulin-Like Growth Factor Binding Proteins
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Neoplasm Proteins
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Phosphoproteins
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insulin-like growth factor binding protein-related protein 1
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insulin-like growth factor-1, mouse
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Insulin-Like Growth Factor I
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Insulin-Like Growth Factor II
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Receptor, IGF Type 1