In the absence of type III receptor, the transforming growth factor (TGF)-β type II-B receptor requires the type I receptor to bind TGF-β2
In the absence of type III receptor, the transforming growth factor (TGF)-β type II-B receptor requires the type I receptor to bind TGF-β2
复制标题
DOI：
10.1074/jbc.m401350200
复制
发表时间：
2004-05-21
影响因子：
4.8
通讯作者：
Lin, HY
中科院分区：
文献类型：
--
作者：
del Re, E;Babitt, JL;Lin, HY
转化生长因子β(TGF-β)配体通过II型(TbetaRII)和I型受体(TbetaRI)发挥其生物学作用。与 TGF-β1 和 -β3 不同，TGF-β2 似乎需要辅助受体 β 聚糖（III 型受体，TbetaRIII）来实现高亲和力结合和信号传导。最近，产生了 TbetaRIII 无效小鼠，并显示出与 TGF-β2 无效小鼠显着的非重叠表型，这意味着存在 TbetaRIII 独立的 TGF-β2 信号转导机制。由于 II 型受体的变体 II-B 型受体 (TbetaRII-B) 被认为在 TbetaRIII 不存在的情况下介导 TGF-β2 信号转导，因此我们直接测试了 TbetaRII-B 结合 TGF-β2 的能力。在这里，我们发现 II-B 型受体的可溶性胞外结构域 (sTbetaRII-B.Fc) 以高亲和力结合 TGF-β1 和 TGF-β3（K-d 值分别 = 31.7 +/- 22.8 和 74.6 +/- 15.8 pM），但在相应剂量下检测不到 TGF-β2 结合。可溶性 II 型受体 (sTbetaRII.Fc) 也获得了类似的结果。然而，sTbetaRII。 Fc或sTbetaRII-B.Fc与可溶性I型受体(sTbetaRI.Fc)组合形成结合TGF-β2的高亲和力复合物，并且该复合物在生物抑制测定中抑制TGF-β2。这些结果表明，当存在足够的TGF-β2、TbetaRI和TbetaRII或TbetaRII-B时，TGF-β2在不存在TbetaRIII的情况下具有发出信号的潜力。我们的数据还支持受体-配体相互作用的合作模型，正如 TGF-β 受体和配体的结晶研究所表明的那样。我们的无细胞结合测定系统将允许在晶体结构的实际解决方案之前测试受体-配体复合物的模型。
Transforming growth factor beta( TGF-beta) ligands exert their biological effects through type II ( TbetaRII) and type I receptors ( TbetaRI). Unlike TGF-beta1 and - beta3, TGF- beta2 appears to require the co- receptor betaglycan ( type III receptor, TbetaRIII) for high affinity binding and signaling. Recently, the TbetaRIII null mouse was generated and revealed significant non- overlapping phenotypes with the TGF-beta2 null mouse, implying the existence of TbetaRIII independent mechanisms for TGF-beta2 signaling. Because a variant of the type II receptor, the type II- B receptor ( TbetaRII- B), has been suggested to mediate TGF-beta2 signaling in the absence of TbetaRIII, we directly tested the ability of TbetaRII- B to bind TGF-beta2. Here we show that the soluble extracellular domain of the type II- B receptor ( sTbetaRII- B. Fc) bound TGF- beta1 and TGF- beta3 with high affinity ( K-d values = 31.7 +/- 22.8 and 74.6 +/- 15.8 pM, respectively), but TGF-beta2 binding was undetectable at corresponding doses. Similar results were obtained for the soluble type II receptor ( sTbetaRII. Fc). However, sTbetaRII. Fc or sTbetaRII- B. Fc in combination with soluble type I receptor ( sTbetaRI. Fc) formed a high affinity complex that bound TGF-beta2, and this complex inhibited TGF-beta2 in a biological inhibition assay. These results show that TGF-beta2 has the potential to signal in the absence of TbetaRIII when sufficient TGF-beta2, TbetaRI, and TbetaRII or TbetaRII- B are present. Our data also support a cooperative model for receptor- ligand interactions, as has been suggested by crystallization studies of TGF-beta receptors and ligands. Our cell- free binding assay system will allow for testing of models of receptor- ligand complexes prior to actual solution of crystal structures.