Abstract

The hypothesis to be investigated is that distinct elements within the cytoplasmic and/or transmembrane domain(s) of the type 1 and type 2 TGF-beta heteromeric receptors mediate heteromeric receptor association with clathrin coated pit proteins and receptor downregulation. Since the homomeric type 1 or type 2 receptors can be internalized but are not down-regulated and cannot signal, it is further hypothesized that there is ligand dependent crosstalk between the heteromeric partners. A chimeric TGF-beta receptor model will be used for the proposed studies: murine AKR-2B mesenchymal (fibroblast) cell clones expressing chimeric TGF-beta receptors consisting of the extracellular ligand binding domain of the GM-CSF alpha or beta receptors fused with the transmembrane and cytoplasmic domain of the type 1 or type 2 TGF-beta receptors. This chimeric model system permits investigation of the signaling capacity of TGF-beta receptor type 1/type 1 homomers, type 2/type 2 homomers and type1/type 2 heteromers.
The specific aims are: 1. identification and characterization of the receptor elements mediating downregulation of heteromeric type 1/type 2 receptor complexes; 2. determination how TGF-beta receptors are sorted following association with the clathrin lattice; 3. determination whether TGF-beta receptor kinase activity or phosphorylation modulates receptor trafficking.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM055816-01
Application #
2024368
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1997-05-01
Project End
2001-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905

  Publications

Jung, Mi-Yeon; Kang, Jeong-Han; Hernandez, Danielle M et al. (2018) Fatty acid synthase is required for profibrotic TGF-? signaling. FASEB J 32:3803-3815
Yin, Xueqian; Kang, Jeong-Han; Andrianifahanana, Mahefatiana et al. (2017) Basolateral delivery of the type I transforming growth factor beta receptor is mediated by a dominant-acting cytoplasmic motif. Mol Biol Cell 28:2701-2711
Kang, Jeong-Han; Jung, Mi-Yeon; Yin, Xueqian et al. (2017) Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-? signaling. J Clin Invest 127:2541-2554
Andrianifahanana, Mahefatiana; Hernandez, Danielle M; Yin, Xueqian et al. (2016) Profibrotic up-regulation of glucose transporter 1 by TGF-? involves activation of MEK and mammalian target of rapamycin complex 2 pathways. FASEB J 30:3733-3744
Wilkes, Mark C; Repellin, Claire E; Kang, Jeong-Han et al. (2015) Sorting nexin 9 differentiates ligand-activated Smad3 from Smad2 for nuclear import and transforming growth factor ? signaling. Mol Biol Cell 26:3879-91
Nallet-Staub, Flore; Yin, Xueqian; Gilbert, Cristèle et al. (2015) Cell density sensing alters TGF-? signaling in a cell-type-specific manner, independent from Hippo pathway activation. Dev Cell 32:640-51
Andrianifahanana, Mahefatiana; Wilkes, Mark C; Gupta, Shiv K et al. (2013) Profibrotic TGF? responses require the cooperative action of PDGF and ErbB receptor tyrosine kinases. FASEB J 27:4444-54
Yin, Xueqian; Murphy, Stephen J; Wilkes, Mark C et al. (2013) Retromer maintains basolateral distribution of the type II TGF-? receptor via the recycling endosome. Mol Biol Cell 24:2285-98
Torres, Vicente E; Leof, Edward B (2011) Fibrosis, regeneration, and aging: playing chess with evolution. J Am Soc Nephrol 22:1393-6
Hong, Min; Wilkes, Mark C; Penheiter, Sumedha G et al. (2011) Non-Smad transforming growth factor-? signaling regulated by focal adhesion kinase binding the p85 subunit of phosphatidylinositol 3-kinase. J Biol Chem 286:17841-50

Showing the most recent 10 out of 34 publications