Hamidi Anahita, Song Jie, Thakur Noopur, Itoh Susumu, Marcusson Anders, Bergh Anders, Heldin Carl-Henrik, Landström Maréne
Ludwig Institute for Cancer Research and Science for Life Laboratory, Uppsala University, Uppsala SE 751 24, Sweden.
Unit of Pathology, Department of Medical Biosciences, Umeå University, Umeå SE 901 85, Sweden.
Sci Signal. 2017 Jul 4;10(486):eaal4186. doi: 10.1126/scisignal.aal4186.
Transforming growth factor-β (TGF-β) is a pluripotent cytokine that regulates cell fate and plasticity in normal tissues and tumors. The multifunctional cellular responses evoked by TGF-β are mediated by the canonical SMAD pathway and by noncanonical pathways, including mitogen-activated protein kinase (MAPK) pathways and the phosphatidylinositol 3'-kinase (PI3K)-protein kinase B (AKT) pathway. We found that TGF-β activated PI3K in a manner dependent on the activity of the E3 ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6). TRAF6 polyubiquitylated the PI3K regulatory subunit p85α and promoted the formation of a complex between the TGF-β type I receptor (TβRI) and p85α, which led to the activation of PI3K and AKT. Lys-linked polyubiquitylation of p85α on Lys and Lys in the iSH2 (inter-Src homology 2) domain was required for TGF-β-induced activation of PI3K-AKT signaling and cell motility in prostate cancer cells and activated macrophages. Unlike the activation of SMAD pathways, the TRAF6-mediated activation of PI3K and AKT was not dependent on the kinase activity of TβRI. In situ proximity ligation assays revealed that polyubiquitylation of p85α was evident in aggressive prostate cancer tissues. Thus, our data reveal a molecular mechanism by which TGF-β activates the PI3K-AKT pathway to drive cell migration.
转化生长因子-β（TGF-β）是一种多能细胞因子，可调节正常组织和肿瘤中的细胞命运及可塑性。TGF-β引发的多功能细胞反应由经典的SMAD信号通路以及非经典信号通路介导，包括丝裂原活化蛋白激酶（MAPK）信号通路和磷脂酰肌醇3'-激酶（PI3K）-蛋白激酶B（AKT）信号通路。我们发现，TGF-β以一种依赖于E3泛素连接酶肿瘤坏死因子受体相关因子6（TRAF6）活性的方式激活PI3K。TRAF6对PI3K调节亚基p85α进行多聚泛素化修饰，并促进TGF-β I型受体（TβRI）与p85α之间形成复合物，进而导致PI3K和AKT的激活。在前列腺癌细胞和活化巨噬细胞中，TGF-β诱导的PI3K-AKT信号激活及细胞迁移需要p85α在iSH2（Src同源结构域之间）结构域中的赖氨酸和赖氨酸位点上发生赖氨酸连接的多聚泛素化。与SMAD信号通路的激活不同，TRAF6介导的PI3K和AKT激活不依赖于TβRI的激酶活性。原位邻近连接分析显示，p85α的多聚泛素化在侵袭性前列腺癌组织中很明显。因此，我们的数据揭示了一种TGF-β激活PI3K-AKT信号通路以驱动细胞迁移的分子机制。
