Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Carcinoma / metabolism
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Carcinoma / pathology
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Cattle
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Cell Division / drug effects
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Cell Line, Tumor
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Cells, Cultured
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Humans
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Insulin-Like Growth Factor Binding Protein 3 / antagonists & inhibitors
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Insulin-Like Growth Factor Binding Protein 3 / metabolism
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Insulin-Like Growth Factor Binding Protein 3 / pharmacology*
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Liver / chemistry
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Low Density Lipoprotein Receptor-Related Protein-1 / chemistry
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Low Density Lipoprotein Receptor-Related Protein-1 / genetics
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Low Density Lipoprotein Receptor-Related Protein-1 / physiology*
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Mice
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Mice, Knockout
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Precipitin Tests
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Receptors, Cell Surface / metabolism
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Receptors, Transforming Growth Factor beta / chemistry
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Receptors, Transforming Growth Factor beta / isolation & purification
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Receptors, Transforming Growth Factor beta / physiology*
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Sequence Homology, Amino Acid
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Transfection
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / pharmacology*
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Transforming Growth Factor beta1
Substances
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Insulin-Like Growth Factor Binding Protein 3
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Low Density Lipoprotein Receptor-Related Protein-1
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Receptors, Cell Surface
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Receptors, Transforming Growth Factor beta
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TGFB1 protein, human
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Tgfb1 protein, mouse
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Transforming Growth Factor beta
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Transforming Growth Factor beta1