TY - JOUR
T1 - IGFBP7 binds to the IGF-1 receptor and blocks its activation by insulin-like growth factors
AU - Evdokimova, Valentina
AU - Tognon, Cristina E.
AU - Benatar, Tania
AU - Yang, Wenyi
AU - Krutikov, Konstantin
AU - Pollak, Michael
AU - Sorensen, Poul H.B.
AU - Seth, Arun
PY - 2012/12/18
Y1 - 2012/12/18
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84871482509&partnerID=8YFLogxK
U2 - 10.1126/scisignal.2003184
DO - 10.1126/scisignal.2003184
M3 - Article
C2 - 23250396
AN - SCOPUS:84871482509
SN - 1945-0877
VL - 5
JO - Science signaling
JF - Science signaling
IS - 255
M1 - ra92
ER -