The Role of Type III TGF-beta Receptor in ALK1-mediated Tumor Angiogenesis

 描述（由申请人提供）：转化生长因子-β（TGF-β）信号传导在肿瘤进展和血管生成中具有重要作用.在大多数人类癌症中，III型TGF-β受体（T β RIII）（一种TGF-β超家族共受体）表达的丧失与血管生成、肿瘤生长和转移潜能的增加相关。尽管有这些观察结果，TßRIII如何控制血管生成仍然是未知的。我们实验室最近观察到血管内皮细胞表达T β RIII。此外，我们已经确定T β RIII与激活素受体样激酶1（ALK 1）（内皮特异性TGF-β 1超家族受体）形成稳定的复合物。骨形态发生蛋白9（BMP 9）刺激ALK 1导致Smad 1/5/8转录因子激活，促进血管生成。该领域的一个基本知识缺口是TßRIII影响ALK 1信号传导的机制以及TßRIII是否促进ALK 1介导的血管生成。基于初步数据，我们提出以下假设：T β RIII是ALK 1的共受体，BMP 9刺激T β RIII/ALK 1复合物形成和内化，导致Smad 1/5/8信号传导增加和肿瘤血管生成增加。这一假设将通过三个具体目标来解决：目标1。确定T β RIII是否以BMP 9依赖性方式结合ALK 1，以促进内皮细胞中的T β RIII/ALK 1复合物内化和Smad磷酸化。目标2.确定T β RIII是否以ALK 1依赖性方式增强血管生成。目标3。确定内皮细胞T β RIII是否在体内以ALK 1依赖性方式促进肿瘤血管生成。这些研究将揭示T β RIII在血管生成中的新作用，阐明癌症进展的机制，并潜在地提供对基于抗TGF β受体的靶向治疗的毒性的机理性见解。

 DESCRIPTION (provided by applicant): Transforming growth factor-ß (TGF-ß) signaling has important roles in tumor progression and angiogenesis. In most human cancers, loss of expression of the type III TGF-ß receptor (TßRIII), a TGF-ß superfamily co-receptor, correlates with increased angiogenesis, tumor growth and metastatic potential. Despite these observations, how TßRIII controls angiogenesis remains unknown. Our lab has recently observed that vascular endothelial cells express TßRIII. Moreover, we have established that TßRIII forms stable complexes with Activin receptor-Like Kinase 1 (ALK1), an endothelium-specific TGF-ß superfamily receptor. ALK1 stimulation by bone morphogenetic protein 9 (BMP9) leads to activation of Smad 1/5/8 transcription factors, promoting angiogenesis. A fundamental knowledge gap in the field is the mechanism by which TßRIII affects ALK1 signaling and whether TßRIII promotes ALK1-mediated angiogenesis. Based on preliminary data, we propose the following hypothesis: TßRIII is a co-receptor for ALK1, with BMP9 stimulating TßRIII/ALK1 complex formation and internalization, leading to increased Smad1/5/8 signaling and increased tumor angiogenesis. This hypothesis will be addressed by three specific aims: Aim 1. Determine whether TßRIII binds ALK1 in a BMP9-dependent manner to promote TßRIII/ALK1 complex internalization and Smad phosphorylation in endothelial cells. Aim 2. Determine whether TßRIII enhances angiogenesis in an ALK1-dependent manner. Aim 3. Determine whether endothelial TßRIII promotes tumor angiogenesis in an ALK1- dependent manner in vivo. These studies will uncover a novel role for TßRIII in angiogenesis, elucidate mechanisms of cancer progression, and potentially provide mechanistic insight into the toxicity of anti-TGFß- receptor based targeted therapies.