The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling.
The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling.
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DOI：
10.1126/scisignal.2005379
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发表时间：
2015-01-06
影响因子：
7.3
通讯作者：
Rehemtulla A
中科院分区：
文献类型：
--
作者：
Nyati S;Schinske-Sebolt K;Pitchiaya S;Chekhovskiy K;Chator A;Chaudhry N;Dosch J;Van Dort ME;Varambally S;Kumar-Sinha C;Nyati MK;Ray D;Walter NG;Yu H;Ross BD;Rehemtulla A
转化生长因子-β（TGFβ）信号传导调节细胞增殖、分化和发育。TGFβ与TGFβ受体2（TGFBRII）的结合诱导TGFβ受体1（TGFBRI）和TGFBRII之间的相互作用，导致转录调节因子SMAD 2和SMAD 3的磷酸化和激活。使用人激酶组的siRNA筛选和TGFBR活性的活细胞报告基因，我们鉴定了BUB 1（不受苯并咪唑-1抑制的出芽），一种Ser/Thr激酶，作为TGFβ信号传导的重要介质。BUB 1在TGFβ刺激下与TGFBRI相互作用，并促进TGFBRI和TGFBRI II的异源二聚化。此外，BUB 1与TGFBRII相互作用，表明形成三元复合物。敲低BUB 1阻止SMAD 3募集到受体复合物、SMAD 2/3的磷酸化及其与SMAD 4的相互作用、SMAD依赖性转录和TGFβ介导的细胞表型变化，包括上皮-间充质转化（EMT）、迁移和侵袭。由激酶AKT和p38 MAPK介导的TGFβ途径的非经典信号级联也由BUB 1介导，表明BUB 1在TGFβ途径中的上游定位。虽然BUB 1的底物是难以捉摸的，但其促进TGFβ信号传导的功能依赖于其激酶功能：BUB 1激酶的小分子抑制剂（2 OH-BNPP 1）和BUB 1的激酶缺陷突变体消除了TGFβ信号传导和各种正常和癌细胞系中三元复合物的形成。对携带肺癌异种移植物的小鼠施用2 OH-BNPP 1减少了肿瘤组织中磷酸化SMAD 2的量。这些发现为BUB 1作为激酶在介导TGFβ依赖性信号传导中的作用提供了证据，超出了其在细胞周期调节和染色体凝聚中的既定功能。
Transforming growth factor-β (TGFβ) signaling regulates cell proliferation, differentiation, and development. The binding of TGFβ to TGFβ receptor 2 (TGFBRII) induces the interaction between TGFβ receptor 1 (TGFBRI) and TGFBRII, leading to the phosphorylation and activation of transcriptional regulators SMAD2 and SMAD3. Using an siRNA screen of the human kinome and a live-cell reporter for TGFBR activity, we identified BUB1 (budding uninhibited by benzimidazoles-1), a Ser/Thr kinase, as an essential mediator of TGFβ signaling. BUB1 interacted with TGFBRI in response to stimulation with TGFβ and promoted the heterodimerization of TGFBRI and TGFBRII. Additionally, BUB1 interacted with TGFBRII, suggesting the formation of a ternary complex. Knocking down BUB1 prevented the recruitment of SMAD3 to the receptor complex, the phosphorylation of SMAD2/3 and their interaction with SMAD4, SMAD-dependent transcription, and TGFβ-mediated changes in cellular phenotype including epithelial-mesenchymal transition (EMT), migration, and invasion. Non-canonical signaling cascades of the TGFβ pathway mediated by the kinases AKT and p38 MAPK also mediated by BUB1, suggesting an upstream positioning for BUB1 in the TGFβ pathway. Although the substrate for BUB1 was elusive, its function in promoting TGFβ signaling was dependent on its kinase function: A small-molecule inhibitor of BUB1 kinase (2OH-BNPP1) and a kinase-deficient mutant of BUB1 abrogated TGFβ signaling and formation of the ternary complex in various normal and cancer cell lines. 2OH-BNPP1 administration to mice bearing lung carcinoma xenografts reduced the amount of phosphorylated SMAD2 in tumor tissue. These findings provide evidence for a role of BUB1 as a kinase in mediating TGFβ-dependent signaling beyond its established function in cell-cycle regulation and chromosome cohesion.
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影响因子：
4.8
作者：
KAWABATA, M;CHYTIL, A;MOSES, HL
通讯作者：
MOSES, HL
DOI：
10.1073/pnas.1214014110
发表时间：
2013-01-29
影响因子：
11.1
作者：
Izrailit, Julia;Berman, Hal K.;Reedijk, Michael
通讯作者：
Reedijk, Michael
影响因子：
5.3
作者：
Kim, TK;Mo, EK;Kim, YW
通讯作者：
Kim, YW
影响因子：
4.8
作者：
Lawler, S;Feng, XH;Derynck, R
通讯作者：
Derynck, R
影响因子：
64.8
作者：
Hata, A;Lo, RS;Massague, J
通讯作者：
Massague, J