CK2 Phospho-Dependent Binding of R2TP Complex to TEL2 Is Essential for mTOR and SMG1 Stability

SummaryTEL2 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.

Graphical AbstractFigure optionsDownload high-quality image (276 K)Download as PowerPoint slideHighlights
► Tel2 is constitutively phosphorylated on serines 487/491 by casein kinase 2 (CK2)
► R2TP/prefoldin-like cochaperone complex binds to the CK2 phosphosite in Tel2
► R2TP complex subunit PIH1D1 directly binds the CK2 phosphosite in Tel2
► CK2 phosphosite in Tel2 is essential for mTOR and SMG1 stability in vivo