Evidence That the Kinase-Truncated c-Src Regulates NF-κB Signaling by Targeting NEMO
Evidence That the Kinase-Truncated c-Src Regulates NF-κB Signaling by Targeting NEMO
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DOI：
10.1002/jcb.23170
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发表时间：
2011-09-01
影响因子：
4
通讯作者：
Abu-Amer, Y.
中科院分区：
文献类型：
--
作者：
Dai, S.;Abu-Amer, W.;Abu-Amer, Y.
酪氨酸激酶 c-Src 和转录因子 NF-kappa B 被认为是正常破骨细胞生成所需的关键成分。任一途径的基因消除都会导致小鼠出现有害的骨硬化表型。同样，任一途径的阻塞都会阻止破骨细胞生成并减少各种形式的骨质流失。此前已有研究表明，表达激酶结构域截短的 c-Src（称为 Src251）的小鼠会因破骨细胞凋亡增加而出现严重的骨硬化症。进一步表明这种现象与 Akt 激酶活性降低有关。然而，Src251 破骨细胞抑制作用的确切机制仍不清楚。 C-Src 与 TRAF6-p62 相互作用，与 NF-kappa B (RANK) 远端区域的受体激活剂相互作用，并且该复合物促进 RANK 下游信号转导级联的激活，包括 NF-kappa B。鉴于破骨细胞中 c-Src 和 NF-kappa B 信号传导之间的这种接近性，我们推测 Src251 对破骨细胞生成的抑制可能是通过抑制 NF-kappa B 信号传导来实现的。我们最近证明，IKK 复合物的调节亚基 NEMO 对于破骨细胞生成至关重要，并与破骨细胞祖细胞中的 c-Src 相互作用。我们使用各种形式的 c-Src 和 NEMO 进行转染研究，结果表明 c-Src 的显性失活形式（即 Src251）介导 NEMO 降解，从而阻止 NF-kappa B 信号传导。此外，NEMO 的降解需要其位于泛素化结构域的完整锌指结构域。该过程还需要 Src251 适当的细胞定位，因为删除其肉豆蔻酰化结构域会削弱其降解能力。支持这些发现的是，从 Src251 转基因小鼠收集的单核细胞中，NEMO 和 NF-κ B 信号传导的表达显着降低。 J.细胞。生物化学。 112:24632470, 2011。(C) 2011 Wiley-Liss, Inc.
The tyrosine kinase c-Src and transcription factor NF-kappa B are considered crucial components required for normal osteoclastogenesis. Genetic ablation of either pathway leads to detrimental osteopetrotic phenotypes in mice. Similarly, obstruction of either pathway halts osteoclastogenesis and lessens various forms of bone loss. It has been shown previously that mice expressing a kinase domain-truncated c-Src, termed Src251, develop severe osteopetrosis owing to increased osteoclast apoptosis. It was further suggested that this phenomenon is associated with reduced Akt kinase activity. However, the precise mechanism underlying the osteoclast inhibitory effect of Src251 remains obscure. C-Src associates with TRAF6-p62 interacting with receptor activator of NF-kappa B (RANK) distal region and the complex facilitate activation of RANK down stream signal transduction cascades including NF-kappa B. Given this proximity between c-Src and NF-kappa B signaling in osteoclasts, we surmised that inhibition of osteoclastogenesis by Src251 may be achieved through inhibition of NF-kappa B signaling. We have demonstrated recently that NEMO, the regulatory subunit of the IKK complex, is crucial for osteoclastogenesis and interacts with c-Src in osteoclast progenitors. Transfection studies, in which we employed various forms of c-Src and NEMO, revealed that the dominant negative form of c-Src, namely Src251, mediates degradation of NEMO thus halting NF-kappa B signaling. Furthermore, degradation of NEMO requires its intact zinc finger domain which is located at the ubiquitination domain. This process also requires appropriate cellular localization of Src251, since deletion of its myristoylation domain ablates its degradation capacity. Buttressing these findings, the expression of NEMO and NF-kappa B signaling were significantly reduced in monocytes collected from Src251 transgenic mice. J. Cell. Biochem. 112:24632470, 2011. (C) 2011 Wiley-Liss, Inc.