Signaling Activity of Homologous and Heterologous Transforming Growth Factor-β Receptor Kinase Complexes (*)
Signaling Activity of Homologous and Heterologous Transforming Growth Factor-β Receptor Kinase Complexes (*)
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同源和异源转化生长因子-β 受体激酶复合物的信号传导活性 (*)
DOI：
--
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发表时间：
1995
影响因子：
4.8
通讯作者：
J. Massagué
中科院分区：
文献类型：
--
作者：
Denis Vivien;L. Attisano;J. Wrana;J. Massagué
Mv1Lu 肺上皮细胞中的转化生长因子-β (TGF-β) 信号传导需要 TGF-β 受体 I (TβR-I) 和 II (TβR-II) 的共表达，这两种远亲相关的跨膜丝氨酸/苏氨酸激酶在配体结合时形成异聚复合物。在这里，我们研究了 TGF-β 受体同源寡聚物的形成及其对信号传导的可能贡献。 TβR-I可以接触与TβR-II结合的配体，但不能接触介质中游离的配体，因此不能形成配体诱导的同源寡聚物。 TβR-II 本身结合配体，当在转染的 COS 细胞中过表达时形成寡聚复合物。然而，这些复合物很大程度上不依赖于配体，并且涉及不成熟的受体蛋白。由于野生型TGF-β受体无法获得配体诱导的同源寡聚体，因此我们通过使用受体嵌合体研究了受体胞质结构域同源寡聚化。 TβR-II的胞外结构域与TβR-I的跨膜和胞质结构域融合，产生TβR-II/I，并且TβR-I的胞外结构域与TβR-II的跨膜和胞质结构域融合，产生TβR-I/II。当与野生型受体共转染并暴露于配体时，TβR-II/I与TβR-I形成复合物，并且TβR-I/II与TβR-II形成复合物，从而产生具有同源胞质结构域的复合物。单独转染TβR-II/I或与TβR-I一起转染并不能恢复TβR-II缺陷细胞突变体中的TGF-β反应性。此外，TβR-II/I 以显性失活方式发挥作用，抑制 TβR-II 缺陷细胞中共转染的 TβR-II 和 TβR-I 缺陷细胞中共转染的 TβR-I 的 TGF-β 反应性恢复。类似地，单独转染TβR-I/II或与TβR-II一起转染的TβR-I/II不能恢复TGF-β反应性并且以显性负向方式对抗TβR-I。结合之前的遗传和生化证据，这些结果表明 TGF-β 通过异聚 TβR-I•TβR-II 复合物而不是同源寡聚 TβR-I 或 TβR-II 复合物介导转录和抗增殖反应。
Transforming growth factor-β (TGF-β) signaling in Mv1Lu lung epithelial cells requires coexpression of TGF-β receptors I (TβR-I) and II (TβR-II), two distantly related transmembrane serine/threonine kinases that form a heteromeric complex upon ligand binding. Here, we examine the formation of TGF-β receptor homooligomers and their possible contribution to signaling. TβR-I can contact ligand bound to TβR-II, but not ligand free in the medium, and thus cannot form ligandinduced homo-oligomers. TβR-II, which binds ligand on its own, formed oligomeric complexes when overexpressed in transfected COS cells. However, these complexes were largely ligand-independent and involved immature receptor protein. Since ligand-induced homo-oligomers could not be obtained with the wild-type TGF-β receptors, we studied receptor cytoplasmic domain homo-oligomerization by using receptor chimeras. The extracellular domain of TβR-II was fused to the transmembrane and cytoplasmic domains of TβR-I, yielding TβR-II/I, and the extracellular domain of TβR-I was fused to the transmembrane and cytoplasmic domains of TβR-II, yielding TβR-I/II. When cotransfected with wild-type receptors and exposed to ligand, TβR-II/I formed a complex with TβR-I, and TβR-I/II formed a complex with TβR-II, thus yielding complexes with homologous cytoplasmic domains. TβR-II/I transfected alone or with TβR-I did not restore TGF-β responsiveness in TβR-II-defective cell mutants. Furthermore, TβR-II/I acted in a dominant negative fashion, inhibiting restoration of TGF-β responsiveness by a cotransfected TβR-II in TβR-II-defective cells and by a cotransfected TβR-I in TβR-I-defective cells. Similarly, TβR-I/II transfected alone or with TβR-II did not restore TGF-β responsiveness and acted in a dominant negative fashion against TβR-I. Together with previous genetic and biochemical evidence, these results suggest that TGF-β mediates transcriptional and antiproliferative responses through the heteromeric TβR-I•TβR-II complex and not through homo-oligomeric TβR-I or TβR-II complexes.
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DOI：
10.1016/s0021-9258(18)37487-8
发表时间：
1988-11
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
S. Cheifetz;J. Andres;J. Massagué
通讯作者：
S. Cheifetz;J. Andres;J. Massagué
TGF-β 抗性细胞突变体中 I 型和 II 型转化生长因子 (TGF)-β 受体同时丧失，表明两种受体类型都参与信号转导。
DOI：
--
发表时间：
1990
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Laiho,M;Weis,MB;Massagué,J
通讯作者：
Massagué,J
通过 TGF-β 受体 I 和 II 缺陷的细胞之间的基因互补，恢复对转化生长因子-β (TGF-β) 的反应性。
DOI：
--
发表时间：
1991
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Laiho,M;Weis,FM;Boyd,FT;Ignotz,RA;Massagué,J
通讯作者：
Massagué,J
DOI：
--
发表时间：
1994-06
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
P. Dijke;Hidetoshi Yamashitas;-T.;Kuber Sampathfl;Reddill;Miguel Estevez;Donald;-L.;Riddle
通讯作者：
P. Dijke;Hidetoshi Yamashitas;-T.;Kuber Sampathfl;Reddill;Miguel Estevez;Donald;-L.;Riddle
DOI：
--
发表时间：
1990-11
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
S. Cheifetz;H. Hernandez;M. Laiho;P. Dijke;K. Iwata;J. Massagué
通讯作者：
S. Cheifetz;H. Hernandez;M. Laiho;P. Dijke;K. Iwata;J. Massagué