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

虽然转化生长因子-<$（TGF-<$）在肿瘤发生中具有双重肿瘤抑制/肿瘤促进作用， 其他TGF-β超家族配体的作用，包括骨形态发生蛋白（BMP）， 定义了TGF-β超家族配体利用信号传导辅助受体，III型TGF-β受体（T β RIII）， 通过I型和II型TGF-β超家族受体介导和调节配体结合和信号传导。 T <$RIII还经历胞外域脱落以产生天然可溶形式的T <$RIII（sT <$RIII）， 在人体血浆中检测到我们最近确定T ² RIII也作为BMP辅助受体发挥作用 并且是某些BMP介导的生物学所必需的，并且T？RIII和BMP在胰腺癌中起作用 EMT和进展。为了探讨T <$RIII在人胰腺癌中的作用机制， 提出了以下假设：BMP对胰腺癌进展具有二分作用， 自分泌BMP反应性，部分通过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sT <$RIII表达的丧失，然后促进 通过EMT介导的细胞运动性和侵袭性增加的癌症进展。这一假设将 有四个具体目标。具体目标1：T <$RIII编排相对目标的机制 TGF-β超家族配体在胰腺癌中的生物活性将通过定义结构来探索。 决定因子介导的T <$RIII配体结合BMP，确定TGF-β的相对配体结合层次， T <$RIII和sT <$RIII的超家族配体，确定sT <$RIII是否作为BMP的拮抗剂 信号转导以及T <$RIII和sT <$RIII的相对表达是否调节TGF-β 1的细胞效应。 胰腺癌细胞中的超家族配体。特定目标2：T <$RIII选择性地 通过ALK-6增加BMP信号传导将通过确定T？RIII是否选择性介导 ALK-6与抑制蛋白2相互作用，选择性介导ALK-6的内化， T？RIII介导的ALK-3/ALK-6内化是否是BMP信号传导和BMP介导的 生物学特异性目的3：细胞表面T <$RIII、循环sT <$RIII和循环活性TGF-β水平 将在鼠模型和人样本中建立超家族成员，以确定这些超家族成员是否 水平在胰腺癌进展过程中协调调节。具体目标4： 在小鼠胰腺癌模型中增加或减少T <$RIII和/或sT <$RIII表达， 将确定进展以确定T <$RIII和/或sT <$RIII是否对胰腺癌具有相反的作用。 癌症的发生和发展。这些研究将确定T-RIII协调TGF-β的机制。 超家族信号传导调节胰腺癌的发生和发展，定义了胰腺癌的生物学机制。 在胰腺癌的背景下，T <$RIII胞外域脱落的影响，并帮助靶向这些 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.