Function of TbRIII as a BMP Co-receptor in Human Cancer

而转化生长因子β在肿瘤发生中具有肿瘤抑制和肿瘤促进双重作用， 包括骨形态发生蛋白(BMP)在内的其他转化生长因子-β超家族配体的作用才刚刚开始 已定义。转化生长因子超家族配体利用信号辅助受体，即III型转化生长因子受体(T？RIII)，来 通过I型和II型转化生长因子超家族受体介导和调节配体结合和信号转导。 T？RIII也经历了胞外结构域的脱落，以产生一种天然的T？RIII(ST？RIII)，我们 已经在人类血浆中检测到。我们最近证实，T？RIII也是BMP的联合受体 在某些BMP介导的生物学中是必需的，并且T？RIII和BMP在胰腺癌中起作用 EMT与进展期。探讨T？RIII在人胰腺癌中的作用机制 提出如下假说：BMP在胰腺癌进展过程中有两种作用，即缺失 自分泌BMP的反应性，部分是通过T？RIII表达的丧失和ALK-6信号的减少， 促进癌症的发生和BMP水平的升高，部分是通过失去ST？RIII的表达，然后促进 通过EMT介导的细胞运动性和侵袭性增加的癌症进展。这一假说将 应通过四个具体目标加以解决。特定目标1：T？RIII协调相对关系的机制 转化生长因子超家族配体在胰腺癌中的生物活性将通过定义结构来探讨 介导T？RIII配体与BMP结合的决定因素，确定了转化生长因子-3的相对配体结合层级 ？T？RIII和ST？RIII的超家族配体，确定ST？RIII是否为BMP的拮抗剂 信号转导及T？RIII和ST？RIII的相对表达是否调节转化生长因子-β的细胞效应 胰腺癌细胞中的超家族配体。特异性AIM2：T？RIII选择性作用的机制 通过ALK-6增加BMP信号将通过定义T？RIII是否选择性地介导 ALK-6与？-arrestin2的相互作用选择性介导ALK-6的内化并建立 T？RIII介导的ALK-3/ALK-6内化是否是BMP信号和BMP所必需的 生物学。特异性Aim3：细胞表面T？RIII、循环ST？RIII和循环活性转化生长因子-β的水平 超家族成员将在小鼠模型和人类标本中建立，以确定这些 在胰腺癌进展过程中，水平受到协调调节。特定目标4：影响 小鼠胰腺癌模型中T？RIII和/或ST？RIII表达的上调或下调 将建立进展以确定T？RIII和/或ST？RIII是否对胰腺有相反的影响 癌症的发生和发展。这些研究将确定T？RIII协调转化生长因子的机制 超家族信号调控胰腺癌的发生和发展，定义生物学 T？RIII胞外结构域脱落在胰腺癌中的意义及其靶向的帮助 预防和治疗人类癌症的途径。

While transforming growth factor-¿ (TGF-¿) has a dual tumor suppressor/tumor promoter role in tumorigenesis, the role of other TGF-¿ superfamily ligands, including the bone morphogenetic proteins (BMPs), is just being defined. TGF-¿ superfamily ligands utilize a signaling coreceptor, the type III TGF-¿ receptor (T¿RIII), to mediate and regulate ligand binding and signaling through the type I and type II TGF-¿ superfamily receptors. T¿RIII also undergoes ectodomain shedding to produce a natural soluble form of T¿RIII (sT¿RIII), which we have detected in human plasma. We have recently established that T¿RIII also functions as a BMP co-receptor and is required for some BMP-mediated biology, and that T¿RIII and BMP have roles in pancreatic cancer EMT and progression. To investigate the mechanism of T¿RIII function in human pancreatic cancer the following hypothesis is proposed: BMPs have dichotomous effects on pancreatic cancer progression, with loss of autocrine BMP responsiveness, in part through loss of T¿RIII expression and decreased ALK-6 signaling, facilitating cancer initiation and elevated BMP levels, in part through loss of sT¿RIII expression, then promoting cancer progression through EMT-mediated increases in cellular motility and invasiveness. This hypothesis will be addressed by four Specific Aims. Specific Aim1: The mechanism by which T¿RIII orchestrates the relative bioactivity of TGF-¿ superfamily ligands in pancreatic cancer will be explored by defining the structural determinants mediating T¿RIII ligand binding to BMP, determining the relative ligand binding hierarchy of TGF- ¿ superfamily ligands to T¿RIII and sT¿RIII, establishing whether sT¿RIII serves as an antagonist of BMP signaling and whether the relative expression of T¿RIII and sT¿RIII regulate the cellular effects of TGF-¿ superfamily ligands in pancreatic cancer cells. Specific Aim2: The mechanism by which T¿RIII selectively increases BMP signaling through ALK-6 will be established by defining whether T¿RIII selectively mediates the interaction of ALK-6 with ¿-arrestin2 to selectively mediate the internalization of ALK-6 and establishing whether T¿RIII mediated ALK-3/ALK-6 internalization is necessary for BMP signaling and BMP-mediated biology. Specific Aim3: The levels of cell surface T¿RIII, circulating sT¿RIII and circulating active TGF-¿ superfamily members will be established in murine models and human specimens to establish whether these levels are coordinately regulated during pancreatic cancer progression. Specific Aim4: The effect of increasing or decreasing T¿RIII and/or sT¿RIII expression in murine pancreatic cancer models of initiation and progression will be established to define whether T¿RIII and/or sT¿RIII have opposing effects on pancreatic cancer initiation and progression. These studies will define the mechanism by which T¿RIII orchestrates TGF-¿ superfamily signaling to regulate the initiation and progression of pancreatic cancer, define the biological implications of T¿RIII ectodomain shedding in the context of pancreatic cancer and aid in targeting these pathways for the prevention and treatment of human cancers.