Fig. 1.

Involvement of IGFBP-3 in the DNA damage response. IGFBP-3 interacts with EGFR in lipid rafts and, in response to a DNA-damaging stimulus, translocates to the nucleus where both proteins complex with DNA-PK to facilitate non-homologous end-joining. This effect is blocked by EGFR kinase inhibition. IGFBP-3 promotes survival by inhibiting the production of pro-apoptotic ceramide, and increasing sphingosine-1-phosphate, but in response to genotoxic stress, it can increase apoptosis by activating ceramide synthesis. SMase, sphingomyelinase; SphK, sphingosine kinase; S1P, sphingosine-1-phosphate