15. Transcriptional downregulation of transforming growth factor β (TGFβ) receptor types I, II and III provides a growth advantage for hepatocytes after partial hepatectomy

1994 ◽  
Vol 167 (4) ◽  
pp. 450
Author(s):  
RS Chari ◽  
DT Price ◽  
SR Sue ◽  
RL Jirtle ◽  
WC Meyers
Keyword(s):  
Growth Factor ◽  
Partial Hepatectomy ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tgfβ Receptor

scholarly journals A Novel Transforming Growth Factor-β Receptor-interacting Protein That Is Also a Light Chain of the Motor Protein Dynein

2002 ◽  
Vol 13 (12) ◽  
pp. 4484-4496 ◽  
Author(s):  
Qian Tang ◽  
Cory M. Staub ◽  
Guofeng Gao ◽  
Qunyan Jin ◽  
Zhengke Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Light Chain ◽  
Transforming Growth Factor ◽  
Motor Protein ◽  
Transforming Growth Factor Β ◽  
Cytoplasmic Dynein ◽  
Epithelial Cell Line ◽  
Tgfβ Receptors ◽  
Tgfβ Receptor ◽  
Intermediate Chain

The phosphorylated, activated cytoplasmic domains of the transforming growth factor-β (TGFβ) receptors were used as probes to screen an expression library that was prepared from a highly TGFβ-responsive intestinal epithelial cell line. One of the TGFβ receptor-interacting proteins isolated was identified to be the mammalian homologue of the LC7 family (mLC7) of dynein light chains (DLCs). This 11-kDa cytoplasmic protein interacts with the TGFβ receptor complex intracellularly and is phosphorylated on serine residues after ligand-receptor engagement. Forced expression of mLC7-1 induces specific TGFβ responses, including an activation of Jun N-terminal kinase (JNK), a phosphorylation of c-Jun, and an inhibition of cell growth. Furthermore, TGFβ induces the recruitment of mLC7-1 to the intermediate chain of dynein. A kinase-deficient form of TGFβ RII prevents both mLC7-1 phosphorylation and interaction with the dynein intermediate chain (DIC). This is the first demonstration of a link between cytoplasmic dynein and a natural growth inhibitory cytokine. Furthermore, our results suggest that TGFβ pathway components may use a motor protein light chain as a receptor for the recruitment and transport of specific cargo along microtublules.

scholarly journals Distinct Endocytic Responses of Heteromeric and Homomeric Transforming Growth Factor β Receptors

1997 ◽  
Vol 8 (11) ◽  
pp. 2133-2143 ◽  
Author(s):  
Robert A. Anders ◽  
Sandra L. Arline ◽  
Jules J.E. Doré ◽  
Edward B. Leof
Keyword(s):  
Growth Factor ◽  
Ligand Binding ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Surface Receptor ◽  
Type I ◽  
Type Ii ◽  
Down Regulation ◽  
Tgfβ Receptors ◽  
Tgfβ Receptor

Transforming growth factor β (TGFβ) family ligands initiate a cascade of events capable of modulating cellular growth and differentiation. The receptors responsible for transducing these cellular signals are referred to as the type I and type II TGFβ receptors. Ligand binding to the type II receptor results in the transphosphorylation and activation of the type I receptor. This heteromeric complex then propagates the signal(s) to downstream effectors. There is presently little data concerning the fate of TGFβ receptors after ligand binding, with conflicting reports indicating no change or decreasing cell surface receptor numbers. To address the fate of ligand-activated receptors, we have used our previously characterized chimeric receptors consisting of the ligand binding domain from the granulocyte/macrophage colony-stimulating factor α or β receptor fused to the transmembrane and cytoplasmic domain of the type I or type II TGFβ receptor. This system not only provides the necessary sensitivity and specificity to address these types of questions but also permits the differentiation of endocytic responses to either homomeric or heteromeric intracellular TGFβ receptor oligomerization. Data are presented that show, within minutes of ligand binding, chimeric TGFβ receptors are internalized. However, although all the chimeric receptor combinations show similar internalization rates, receptor down-regulation occurs only after activation of heteromeric TGFβ receptors. These results indicate that effective receptor down-regulation requires cross-talk between the type I and type II TGFβ receptors and that TGFβ receptor heteromers and homomers show distinct trafficking behavior.

scholarly journals Heart and Liver Defects and Reduced Transforming Growth Factor β2 Sensitivity in Transforming Growth Factor β Type III Receptor-Deficient Embryos

2003 ◽  
Vol 23 (12) ◽  
pp. 4371-4385 ◽  
Author(s):  
Kaye L. Stenvers ◽  
Melinda L. Tursky ◽  
Kenneth W. Harder ◽  
Nicole Kountouri ◽  
Supavadee Amatayakul-Chantler ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Gene Activation ◽  
Transforming Growth Factor Β ◽  
Somatic Development ◽  
Type Iii ◽  
Tgfβ Receptor ◽  
Primary Fibroblasts ◽  
Signaling Receptors

ABSTRACT The type III transforming growth factor β (TGFβ) receptor (TβRIII) binds both TGFβ and inhibin with high affinity and modulates the association of these ligands with their signaling receptors. However, the significance of TβRIII signaling in vivo is not known. In this study, we have sought to determine the role of TβRIII during development. We identified the predominant expression sites of ΤβRIII mRNA as liver and heart during midgestation and have disrupted the murine TβRIII gene by homologous recombination. Beginning at embryonic day 13.5, mice with mutations in ΤβRIII developed lethal proliferative defects in heart and apoptosis in liver, indicating that TβRIII is required during murine somatic development. To assess the effects of the absence of TβRIII on the function of its ligands, primary fibroblasts were generated from TβRIII-null and wild-type embryos. Our results indicate that TβRIII deficiency differentially affects the activities of TGFβ ligands. Notably, TβRIII-null cells exhibited significantly reduced sensitivity to TGFβ2 in terms of growth inhibition, reporter gene activation, and Smad2 nuclear localization, effects not observed with other ligands. These data indicate that TβRIII is an important modulator of TGFβ2 function in embryonic fibroblasts and that reduced sensitivity to TGFβ2 may underlie aspects of the TβRIII mutant phenotype.

scholarly journals Activation of Key Profibrotic Mechanisms in Transgenic Fibroblasts Expressing Kinase-deficient Type II Transforming Growth Factor-β Receptor (TβRIIΔk)

2005 ◽  
Vol 280 (16) ◽  
pp. 16053-16065 ◽  
Author(s):  
Christopher P. Denton ◽  
Gisela E. Lindahl ◽  
Korsa Khan ◽  
Xu Shiwen ◽  
Voon H. Ong ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transgene Expression ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Myofibroblast Differentiation ◽  
Type Ii ◽  
Wild Type ◽  
Tgfβ Receptor ◽  
High Level

We have generated transgenic mice expressing a kinase-deficient type II transforming growth factor-β (TGFβ) receptor selectively on fibroblasts (TβRIIΔk-fib). These mice develop dermal and pulmonary fibrosis. In the present study we explore activation of TGFβ signaling pathways in this strain and examine the profibrotic properties of explanted transgenic fibroblasts including myofibroblast differentiation and abnormal metalloproteinase production. Gene expression profiles of littermate wild type or transgenic fibroblasts were compared using high-density gene arrays and validated by Taqman reverse transcriptase-PCR, Northern and Western blotting. Using a specific inhibitor (SD-208) we demonstrate that the abnormal phenotype of these cells is dependent upon TβRI kinase (ALK5) activity, and that transgenic fibroblasts show enhanced expression and activation of TGFβ together with increased levels of wild type TβRII. Moreover, we confirm that transgene expression is itself regulated by TGFβ and that expression at low levels facilitates signaling, whereas high level expression is inhibitory. For a subset of TGFβ responsive genes basal up-regulation is normalized or suppressed by exogenous recombinant TGFβ1 at time points coincident with increased transgene expression. These findings explain the profound refractoriness of TβRIIΔk-fib fibroblasts to exogenous TGFβ1, despite their activated phenotype. Thus, transgenic fibroblasts recapitulate many hallmark biochemical properties of fibrotic cells, including high level CTGF (CCN2) expression and type I collagen overproduction, altered MMP production, and myofibroblast differentiation. These cells also show an enhanced ability to contract collagen gel matrices. Our study demonstrates that altered high affinity TGFβ receptor function may lead to ligand-dependent activation of downstream signaling, and provides further evidence of a pivotal role for sustained TGFβ overactivity in fibrosis.

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