CK2 phospho-dependent binding of R2TP complex to TEL2 is essential for mTOR and SMG1 stability

Mol Cell. 2010 Sep 24;39(6):839-50. doi: 10.1016/j.molcel.2010.08.037.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Animals
  • Apoptosis Regulatory Proteins
  • Ataxia Telangiectasia Mutated Proteins
  • Binding Sites / physiology
  • Carrier Proteins / metabolism
  • Casein Kinase II / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cytoplasm / metabolism
  • DNA Helicases / metabolism
  • DNA-Binding Proteins / metabolism
  • Enzyme Stability
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Mice
  • Models, Biological
  • Molecular Chaperones / metabolism
  • Multiprotein Complexes / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-ets / metabolism*
  • Recombinant Proteins / metabolism
  • Serine / metabolism
  • TOR Serine-Threonine Kinases / metabolism*
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism
  • Tumor Suppressor Proteins / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • ETV7 protein, human
  • HSP90 Heat-Shock Proteins
  • Molecular Chaperones
  • Multiprotein Complexes
  • Proto-Oncogene Proteins c-ets
  • RPAP3 protein, human
  • Recombinant Proteins
  • Tel2 protein, mouse
  • Telomere-Binding Proteins
  • Tumor Suppressor Proteins
  • prefoldin
  • Serine
  • Atr protein, mouse
  • MTOR protein, human
  • mTOR protein, mouse
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Casein Kinase II
  • Protein Serine-Threonine Kinases
  • SMG1 protein, human
  • Smg1 protein, mouse
  • TOR Serine-Threonine Kinases
  • ATPases Associated with Diverse Cellular Activities
  • DNA Helicases
  • RUVBL1 protein, human
  • RUVBL2 protein, human