scholarly journals Ligand-dependent and -independent Transforming Growth Factor-β Receptor Recycling Regulated by Clathrin-mediated Endocytosis and Rab11

2004 ◽  
Vol 15 (9) ◽  
pp. 4166-4178 ◽  
Author(s):  
Hugh Mitchell ◽  
Amit Choudhury ◽  
Richard E. Pagano ◽  
Edward B. Leof
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Endocytic Pathway ◽  
Type I ◽  
Receptor Recycling ◽  
Coated Pits ◽  
Down Regulation ◽  
Independent Mechanism ◽  
Β Receptor

Proteins in the transforming growth factor-β (TGF-β) family recognize transmembrane serine/threonine kinases known as type I and type II receptors. Binding of TGF-β to receptors results in receptor down-regulation and signaling. Whereas previous work has focused on activities controlling TGF-β signaling, more recent studies have begun to address the trafficking properties of TGF-β receptors. In this report, it is shown that receptors undergo recycling both in the presence and absence of ligand activation, with the rates of internalization and recycling being unaffected by ligand binding. Recycling occurs as receptors are most likely internalized through clathrin-coated pits, and then returned to the plasma membrane via a rab11-dependent, rab4-independent mechanism. Together, the results suggest a mechanism wherein activated TGF-β receptors are directed to a distinct endocytic pathway for down-regulation and clathrin-dependent degradation after one or more rounds of recycling.

scholarly journals Transforming Growth Factor β Receptor Signaling and Endocytosis Are Linked through a COOH Terminal Activation Motif in the Type I Receptor

2001 ◽  
Vol 12 (9) ◽  
pp. 2881-2893 ◽  
Author(s):  
Nandor Garamszegi ◽  
Jules J. E. Doré ◽  
Sumedha G. Penheiter ◽  
Maryanne Edens ◽  
Diying Yao ◽  
...  
Keyword(s):  
Amino Acids ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Kinase Domain ◽  
Type I ◽  
Receptor Signaling ◽  
Down Regulation ◽  
Critical Function ◽  
Β Receptor

Transforming growth factor β (TGF-β) coordinates a number of biological events important in normal and pathophysiological growth. In this study, deletion and substitution mutations were used to identify receptor motifs modulating TGF-β receptor activity. Initial experiments indicated that a COOH-terminal sequence between amino acids 482–491 in the kinase domain of the type I receptor was required for ligand-induced receptor signaling and down-regulation. These 10 amino acids are highly conserved in mammalian, Xenopus, andDrosophila type I receptors. Although mutation or deletion of the region (referred to as the NANDOR BOX, for nonactivating non–down-regulating) abolishes TGF-β–dependent mitogenesis, transcriptional activity, type I receptor phosphorylation, and down-regulation in mesenchymal cultures, adjacent mutations also within the kinase domain are without effect. Moreover, a kinase-defective type I receptor can functionally complement a mutant BOX expressing type I receptor, documenting that when the BOX mutant is activated, it has kinase activity. These results indicate that the sequence between 482 and 491 in the type I receptor provides a critical function regulating activation of the TGF-β receptor complex.

scholarly journals Type II Transforming Growth Factor-β Receptor Recycling Is Dependent upon the Clathrin Adaptor Protein Dab2

2010 ◽  
Vol 21 (22) ◽  
pp. 4009-4019 ◽  
Author(s):  
Sumedha G. Penheiter ◽  
Raman Deep Singh ◽  
Claire E. Repellin ◽  
Mark C. Wilkes ◽  
Maryanne Edens ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Density Lipoprotein ◽  
Adaptor Protein ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Type Ii ◽  
Receptor Recycling ◽  
Smad2 Phosphorylation ◽  
Β Receptor

Transforming growth factor (TGF)-β family proteins form heteromeric complexes with transmembrane serine/threonine kinases referred to as type I and type II receptors. Ligand binding initiates a signaling cascade that generates a variety of cell type-specific phenotypes. Whereas numerous studies have investigated the regulatory activities controlling TGF-β signaling, there is relatively little information addressing the endocytic and trafficking itinerary of TGF-β receptor subunits. In the current study we have investigated the role of the clathrin-associated sorting protein Disabled-2 (Dab2) in TGF-β receptor endocytosis. Although small interfering RNA-mediated Dab2 knockdown had no affect on the internalization of various clathrin-dependent (i.e., TGF-β, low-density lipoprotein, or transferrin) or -independent (i.e., LacCer) cargo, TGF-β receptor recycling was abrogated. Loss of Dab2 resulted in enlarged early endosomal antigen 1-positive endosomes, reflecting the inability of cargo to traffic from the early endosome to the endosomal recycling compartment and, as documented previously, diminished Smad2 phosphorylation. The results support a model whereby Dab2 acts as a multifunctional adaptor in mesenchymal cells required for TGF-β receptor recycling as well as Smad2 phosphorylation.

scholarly journals Internalization-Dependent and -Independent Requirements for Transforming Growth Factor β Receptor Signaling via the Smad Pathway

2002 ◽  
Vol 22 (13) ◽  
pp. 4750-4759 ◽  
Author(s):  
Sumedha G. Penheiter ◽  
Hugh Mitchell ◽  
Nandor Garamszegi ◽  
Maryanne Edens ◽  
Jules J. E. Doré, ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Transforming Growth Factor Β ◽  
Receptor Activation ◽  
Endocytic Pathway ◽  
Type I ◽  
Smad Pathway ◽  
Sequence Of Events ◽  
Β Receptor

ABSTRACT Members of the transforming growth factor β (TGF-β) family of proteins signal through cell surface transmembrane serine/threonine protein kinases known as type I and type II receptors. The TGF-β signal is extended through phosphorylation of receptor-associated Smad proteins by the type I receptor. Although numerous investigations have established the sequence of events in TGF-β receptor (TGF-βR) activation, none have examined the role of the endocytic pathway in initiation and/or maintenance of the signaling response. In this study we investigated whether TGF-βR internalization modulates type I receptor activation, the formation of a functional receptor/Smad/SARA complex, Smad2/3 phosphorylation or nuclear translocation, and TGF-β-dependent reporter gene activity. Our data provide evidence that, whereas type I receptor phosphorylation and association of SARA and Smad2 with the TGF-βR complex take place independently of clathrin lattice formation, Smad2 or Smad3 activation and downstream signaling only occur after endocytic vesicle formation. Thus, TGF-βR endocytosis is not simply a way to dampen the signaling response but instead is required to propagate signaling via the Smad pathway.

scholarly journals Mechanisms of Transforming Growth Factor-β Receptor Endocytosis and Intracellular Sorting Differ between Fibroblasts and Epithelial Cells

2001 ◽  
Vol 12 (3) ◽  
pp. 675-684 ◽  
Author(s):  
Jules J.E. Doré ◽  
Diying Yao ◽  
Maryanne Edens ◽  
Nandor Garamszegi ◽  
Elizabeth L. Sholl ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Ligand Binding ◽  
Transforming Growth Factor ◽  
Point Mutations ◽  
Type I ◽  
Receptor Complex ◽  
Type Ii ◽  
Down Regulation ◽  
Β Receptor

Transforming growth factor-βs (TGF-β) are multifunctional proteins capable of either stimulating or inhibiting mitosis, depending on the cell type. These diverse cellular responses are caused by stimulating a single receptor complex composed of type I and type II receptors. Using a chimeric receptor model where the granulocyte/monocyte colony-stimulating factor receptor ligand binding domains are fused to the transmembrane and cytoplasmic signaling domains of the TGF-β type I and II receptors, we wished to describe the role(s) of specific amino acid residues in regulating ligand-mediated endocytosis and signaling in fibroblasts and epithelial cells. Specific point mutations were introduced at Y182, T200, and Y249 of the type I receptor and K277 and P525 of the type II receptor. Mutation of either Y182 or Y249, residues within two putative consensus tyrosine-based internalization motifs, had no effect on endocytosis or signaling. This is in contrast to mutation of T200 to valine, which resulted in ablation of signaling in both cell types, while only abolishing receptor down-regulation in fibroblasts. Moreover, in the absence of ligand, both fibroblasts and epithelial cells constitutively internalize and recycle the TGF-β receptor complex back to the plasma membrane. The data indicate fundamental differences between mesenchymal and epithelial cells in endocytic sorting and suggest that ligand binding diverts heteromeric receptors from the default recycling pool to a pathway mediating receptor down-regulation and signaling.

scholarly journals A Novel Protein Distinguishes between Quiescent and Activated Forms of the Type I Transforming Growth Factor β Receptor

1998 ◽  
Vol 273 (16) ◽  
pp. 9365-9368 ◽  
Author(s):  
Min-Ji Charng ◽  
Dou Zhang ◽  
Paı̈vi Kinnunen ◽  
Michael D. Schneider
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Β Receptor ◽  
Novel Protein

scholarly journals Transforming Growth Factor-β Receptor Type I-dependent Fibrogenic Gene Program Is Mediated via Activation of Smad1 and ERK1/2 Pathways

2007 ◽  
Vol 282 (14) ◽  
pp. 10405-10413 ◽  
Author(s):  
Jaspreet Pannu ◽  
Sashidhar Nakerakanti ◽  
Edwin Smith ◽  
Peter ten Dijke ◽  
Maria Trojanowska
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Receptor Type ◽  
Type I ◽  
Β Receptor

scholarly journals Repression of transforming growth factor-β receptor type I promoter expression by Sp1 deficiency

Oncogene ◽  
2000 ◽  
Vol 19 (40) ◽  
pp. 4660-4667 ◽  
Author(s):  
Sumudra Periyasamy ◽  
Sudhakar Ammanamanchi ◽  
Manoranjani PM Tillekeratne ◽  
Michael G Brattain
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Receptor Type ◽  
Type I ◽  
Β Receptor
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