TGF BETA RECEPTOR DYNAMICS

描述：要研究的假设是不同的元素 在 1 型和 1 型的细胞质和/或跨膜结构域内 2 TGF-β异聚受体介导异聚受体关联 网格蛋白包被的凹坑蛋白和受体下调。 自从 同聚型 1 型或 2 型受体可以被内化，但不能 下调并且不能发出信号，进一步假设有 异聚伙伴之间的配体依赖性串扰。 嵌合体 TGF-β受体模型将用于拟议的研究：小鼠 表达嵌合 TGF-β 的 AKR-2B 间充质（成纤维细胞）细胞克隆 受体由细胞外配体结合结构域组成 GM-CSF α或β受体与跨膜和细胞质融合 1 型或 2 型 TGF-β 受体的结构域。 这种嵌合模型 系统允许研究 TGF-β 受体的信号传导能力 1型/1型同聚体、2型/2型同聚体和1型/2型异聚体。 具体目标是： 1. 识别和表征 介导 1 型/2 型异聚体下调的受体元件 受体复合物； 2. 确定TGF-β受体如何排序 与网格蛋白晶格关联； 3. 判断是否 TGF-β受体激酶活性或磷酸化调节受体 贩运。

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.