Cellular growth inhibition by IGFBP-3 and TGF-β1 requires LRP-1

The type V TGF-beta receptor (TbetaR-V)/ IGFBP-3 receptor mediates the IGF-independent growth inhibition induced by IGFBP-3. It also mediates the growth inhibitory response to TGF-beta(1), in concert with other TGF-beta receptor types, and its loss may contribute to the malignant phenotype of human carcinoma cells. Here we demonstrate that TbetaR-V is identical to LRP-1/alpha(2)M receptor as shown by MALDI-TOF analysis of tryptic peptides of TbetaR-V purified from bovine liver. In addition, I-125-IGFBP-3 affinity-labeled TbetaR-V in MvlLu cells is immunoprecipitated by antibodies to LRP-l and TbetaR-V. RAP, an LRP-l antagonist, inhibits binding of I-125-TGF-beta(1) and I-125-IGFBP-3 to TbetaR-V and diminishes IGFBP-3-induced growth inhibition in MvlLu cells. Absent or low levels of LRP-1, as with TbetaR-V, have been linked to the malignant phenotype of carcinoma cells. Mutagenized Mv1Lu cells selected for reduced expression of LRP-l have an attenuated growth inhibitory response to TGF-beta(1), and IGFBP-3. LRP-l -deficient mouse embryonic fibroblasts lack a growth inhibitory response to TGF-beta(1), and IGFBP-3. On the other hand, stable transfection of H1299 human lung carcinoma cells with LRP-l cDNA restores the growth inhibitory response. These results suggest that the LRP-1/TbetaR-V/IGFBP-3 receptor is required for the growth inhibitory response to IGFBP-3 and TGF-beta(1).