DNA Damage Response Laboratory, London Research Institute, Clare Hall, South Mimms, UK.
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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