CK2 phospho-dependent binding of R2TP complex to TEL2 is essential for mTOR and SMG1 stability.
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.
Horejsí
Zuzana
Z
DNA Damage Response Laboratory, London Research Institute, Clare Hall, South Mimms, UK.
Takai
Hiroyuki
H
Adelman
Carrie A
CA
Collis
Spencer J
SJ
Flynn
Helen
H
Maslen
Sarah
S
Skehel
J Mark
JM
de Lange
Titia
T
Boulton
Simon J
SJ
D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D001665:Binding Sites / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D047390:Casein Kinase II / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004795:Enzyme Stability; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000074183:ATPases Associated with Diverse Cellular Activities; D051017:Apoptosis Regulatory Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D002352:Carrier Proteins; D047390:Casein Kinase II; D018797:Cell Cycle Proteins; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D050783:Proto-Oncogene Proteins c-ets; D011994:Recombinant Proteins; D012694:Serine; D058570:TOR Serine-Threonine Kinases; D034501:Telomere-Binding Proteins; D025521:Tumor Suppressor Proteins; C409823:ETV7 protein, human; C472351:RPAP3 protein, human; C528081:Tel2 protein, mouse; C112806:prefoldin; C576897:Atr protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C576324:ATM protein, human; C576597:ATR protein, human; C576325:Atm protein, mouse; C514704:SMG1 protein, human; C551743:Smg1 protein, mouse; C486549:RUVBL1 protein, human; C122079:RUVBL2 protein, human