CK2 磷酸化依赖性 R2TP 复合物与 TEL2 的结合对于 mTOR 和 SMG1 的稳定性至关重要。
CK2 phospho-dependent binding of R2TP complex to TEL2 is essential for mTOR and SMG1 stability.
机构信息
DNA Damage Response Laboratory, London Research Institute, Clare Hall, South Mimms, UK.
出版信息
Mol Cell. 2010 Sep 24;39(6):839-50. doi: 10.1016/j.molcel.2010.08.037.
TEL2 interacts with and is essential for the stability of all phosphatidylinositol 3-kinase-related kinases (PIKKs), but its mechanism of action remains unclear. Here, we show that TEL2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (CK2). Proteomic analyses establish that the CK2 phosphosite of TEL2 confers binding to the R2TP/prefoldin-like complex, which possesses chaperon/prefoldin activities required during protein complex assembly. The PIH1D1 subunit of the R2TP complex binds directly to the CK2 phosphosite of TEL2 in vitro and is required for the TEL2-R2TP/prefoldin-like complex interaction in vivo. Although the CK2 phosphosite mutant of TEL2 retains association with the PIKKs and HSP90 in cells, failure to interact with the R2TP/prefoldin-like complex results in instability of the PIKKs, principally mTOR and SMG1. We propose that TEL2 acts as a scaffold to coordinate the activities of R2TP/prefoldin-like and HSP90 chaperone complexes during the assembly of the PIKKs.
TEL2 与所有磷脂酰肌醇 3-激酶相关激酶（PIKKs）相互作用并对其稳定性至关重要，但它的作用机制尚不清楚。在这里，我们表明 TEL2 被酪蛋白激酶 2（CK2）持续磷酸化在保守的丝氨酸 487 和 491 上。蛋白质组学分析表明，TEL2 的 CK2 磷酸化位点赋予与 R2TP/原折叠样复合物的结合，该复合物具有在蛋白质复合物组装过程中所需的伴侣/原折叠功能。R2TP 复合物的 PIH1D1 亚基在体外直接与 TEL2 的 CK2 磷酸化位点结合，并且在体内需要 TEL2-R2TP/原折叠样复合物相互作用。尽管 TEL2 的 CK2 磷酸化突变体在细胞中保留与 PIKKs 和 HSP90 的关联，但未能与 R2TP/原折叠样复合物相互作用会导致 PIKKs 的不稳定性，主要是 mTOR 和 SMG1。我们提出 TEL2 作为支架在 PIKKs 的组装过程中协调 R2TP/原折叠样和 HSP90 伴侣复合物的活性。
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