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

The type V TGF-β receptor (TβR-V)/ IGFBP-3 receptor mediates the IGF-independent growth inhibition induced by IGFBP-3. It also mediates the growth inhibitory response to TGF-β₁ in concert with other TGF-β receptor types, and its loss may contribute to the malignant phenotype of human carcinoma cells. Here we demonstrate that TβR-V is identical to LRP-1/α₂M receptor as shown by MALDI-TOF analysis of tryptic peptides of TβR-V purified from bovine liver. In addition, ¹²⁵I-IGFBP-3 affinity-labeled TβR-V in Mv1Lu cells is immunoprecipitated by antibodies to LRP-1 and TβR-V. RAP, an LRP-1 antagonist, inhibits binding of ¹²⁵I-TGF-β₁ and ¹²⁵I-IGFBP-3 to TβR-V and diminishes IGFBP-3-induced growth inhibition in Mv1Lu cells. Absent or low levels of LRP-1, as with TβR-V, have been linked to the malignant phenotype of carcinoma cells. Mutagenized Mv1Lu cells selected for reduced expression of LRP-1 have an attenuated growth inhibitory response to TGF-β₁ and IGFBP-3. LRP-1-deficient mouse embryonic fibroblasts lack a growth inhibitory response to TGF-β ₁ and IGFBP-3. On the other hand, stable transfection of H1299 human lung carcinoma cells with LRP-1 cDNA restores the growth inhibitory response. These results suggest that the LRP-1/TβR-V/IGFBP-3 receptor is required for the growth inhibitory response to IGFBP-3 and TGF-β₁.