The type V TGF-beta receptor (TbetaR) is a 400-kDa acidotropic Ser/Thr- specific protein kinase which co-expresses with the type I, type II and type III TGF-beta receptors (TbetaR-I, TbetaR-II and TbetaR-III) in most cell types. Its selective absence in most epithelial tumor cells studied suggests that loss of TbetaR-V expression may be a step toward tumorigenesis of epithelial cells. The novel finding that TbetaR-V is the receptor of insulin-like growth factor binding protein 3 (IGFBP-3) which mediates the IGF-independent growth inhibition has provided the strongest evidence to support the function of TbetaR-V in mediating growth inhibition. We have recently found that the IGFBP-3 growth inhibition is reversed by insulin/IGF-1 and TGF-beta growth inhibition is partially reversed by insulin/IGF-I in the presence of a cyclic RGD peptide. These observations have uncovered intriguing """"""""cross-talk"""""""" interactions of TbetaR-V, TbetaR-I/TbetaR-II and insulin receptor/IGF-I receptor signaling pathways. The broad goal of the proposed research is to define the mechanism of TbetaR-V-mediated growth inhibition and to test the hypothesis that TbetaR-V is the product of a tumor suppressor gene. The proposal has three specific aims: 1) To determine the mechanisms by which insulin/IGF-I block the IGFBP-3 growth inhibition mediated by TbetaR-V. We will determine the roles of IRS-1 and IRS-2 in this insulin/IGF-I effect in DR26 cells by over-expressing IRS-1/IRS-2, by blocking IRS-1/IRS-2 expression with antisense mRNA and by cell biological methods. 2) To characterize the TbetaR-V-mediated signaling using IGFP-3 as a specific ligand. We will determine the effects of IGFBP-3 on TbetaR-V/TbetaR-I heterocomplex formation, phosphorylation/complex formation/nuclear translocation of Smad2/Smad3/Smad4, and the expressions and activities of the key components regulating cell cycle transmission from G/1-to-S phase using cell biological methods. 3) To clone, sequence and express TbetaR-V cDNA. We will clone the kinase domain and full-length cDNA of TbetaR-V from liver cDNA libraries by PCR and immunoscreening and express the chimera of TbetaR-I and TbetaR-II extracellular domains/TbetaR-V kinase domain and full-length TbetaR-V cDNA in carcinoma cells lacking TbetaR-V in an attempt to restore TGF-beta growth inhibition and to reverse the transformed phenotype of these carcinoma cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Endocrinology Study Section (END)
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Blair, Donald G
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Saint Louis University
Schools of Medicine
Saint Louis
United States
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Chen, Chun-Lin; Huang, Shuan Shian; Huang, Jung San (2008) Cholesterol modulates cellular TGF-beta responsiveness by altering TGF-beta binding to TGF-beta receptors. J Cell Physiol 215:223-33
Chen, Chun-Lin; Liu, I-Hua; Fliesler, Steven J et al. (2007) Cholesterol suppresses cellular TGF-beta responsiveness: implications in atherogenesis. J Cell Sci 120:3509-21
Huang, S S; Liu, I-Hua; Smith, Tracy et al. (2006) CRSBP-1/LYVE-l-null mice exhibit identifiable morphological and functional alterations of lymphatic capillary vessels. FEBS Lett 580:6259-68
Huang, Shuan S; Huang, Jung S (2005) TGF-beta control of cell proliferation. J Cell Biochem 96:447-62
Huang, Shuan Shian; Leal, Sandra M; Chen, Chun-Lin et al. (2004) Identification of insulin receptor substrate proteins as key molecules for the TbetaR-V/LRP-1-mediated growth inhibitory signaling cascade in epithelial and myeloid cells. FASEB J 18:1719-21
Huang, Shuan Shian; Leal, Sandra M; Chen, Chun-Lin et al. (2004) Cellular growth inhibition by TGF-beta1 involves IRS proteins. FEBS Lett 565:117-21
Ling, Thai-Yen; Chen, Chun-Lin; Huang, Yen-Hua et al. (2004) Identification and characterization of the acidic pH binding sites for growth regulatory ligands of low density lipoprotein receptor-related protein-1. J Biol Chem 279:38736-48
Tseng, Wen-Fang; Huang, Shuan Shian; Huang, Jung San (2004) LRP-1/TbetaR-V mediates TGF-beta1-induced growth inhibition in CHO cells. FEBS Lett 562:71-8
Huang, Shuan Shian; Ling, Thai-Yen; Tseng, Wen-Fang et al. (2003) Cellular growth inhibition by IGFBP-3 and TGF-beta1 requires LRP-1. FASEB J 17:2068-81
Huang, Shuan Shian; Tang, Fen-Mei; Huang, Yen-Hua et al. (2003) Cloning, expression, characterization, and role in autocrine cell growth of cell surface retention sequence binding protein-1. J Biol Chem 278:43855-69

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