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

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 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.