Cellular growth inhibition by IGFBP-3 and TGF-beta1 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-beta1 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/alpha2M receptor as shown by MALDI-TOF analysis of tryptic peptides of TbetaR-V purified from bovine liver. In addition, 125I-IGFBP-3 affinity-labeled TbetaR-V in Mv1Lu cells is immunoprecipitated by antibodies to LRP-1 and TbetaR-V. RAP, an LRP-1 antagonist, inhibits binding of 125I-TGF-beta1 and 125I-IGFBP-3 to TbetaR-V and diminishes IGFBP-3-induced growth inhibition in Mv1Lu 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-1 have an attenuated growth inhibitory response to TGF-beta1 and IGFBP-3. LRP-1-deficient mouse embryonic fibroblasts lack a growth inhibitory response to TGF-beta1 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/TbetaR-V/IGFBP-3 receptor is required for the growth inhibitory response to IGFBP-3 and TGF-beta1.
Huang
Shuan Shian
SS
Department of Biochemistry, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, Missouri 63104, USA. huangss@slu.edu
Ling
Thai-Yen
TY
Tseng
Wen-Fang
WF
Huang
Yen-Hwa
YH
Tang
Fen-Mei
FM
Leal
Sandra M
SM
Huang
Jung San
JS
D000818:Animals; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000737:chemistry; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011233:Precipitin Tests; D011956:Receptors, Cell Surface / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000302:isolation & purification / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
D018972:Insulin-Like Growth Factor Binding Protein 3; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1