TGF BETA RECEPTOR DYNAMICS

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DESCRIPTION: 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.