Branching the Tel2 pathway for exact fit on phosphatidylinositol 3-kinase-related kinases

Abstract

Phosphatidylinositol 3-kinase-related kinases (PIKKs), are structurally related to phosphatidylinositol 3-kinase (lipid kinase), but possess protein kinase activities. PIKKs include ATM, ATR, DNA-PK, mTOR and SMG1, key regulators of cell proliferation and genome maintenance. TRRAP, which is devoid of protein kinase activity, is the sixth member of the PIKK family. PIKK family members are gigantic proteins in the range of 300-500 kDa. It has become apparent in the last decade that the stability or maturation of the PIKK family members depends on a molecular chaperone called the Tel2-Tti1-Tti2 (TTT) complex. Several lines of evidence have established a model in which TTT connects to the Hsp90 chaperone through the Rvb1-Rvb2-Tah1-Pih1 (R2TP) complex in mammalian and yeast cells. However, recent studies of yeast cells indicate that TTT is able to form different complexes. These observations raise a possibility that several different mechanisms regulate TTT-mediated protein stability of PIKKs.

Keywords: Asa1; Casein kinase; Cdc37; Mec1; Protein folding; Tel1.

Fig. 1.. HSP90-Cdc37-dependent protein kinase stabilization

Protein kinase folding requires Hsp90 chaperone and the co-chaperone Cdc37. Casein kinase II (CK2) phosphorylates Cdc37 and stimulates Cdc37-client kinase interaction. In turn Hsp90 recognizes the Cdc37-client kinase complex and promotes the maturation of the client kinase.

Fig. 2.. Requirement of the co-chaperone Tel2-Tti1-Tti2 (TTT) complex for PIKK stabilization

The TTT complex interacts with newly synthesized PIKKs and plays a key role in protein kinase maturation. TTT also collaborates with Hsp90.

Fig. 3.. Interaction of Tel2 with PIKKs through the HEAT repeat domain

The kinase domains (KDs) of PIKKs are located near C-termini and are flanked by the conserved FRAP-ATM-TRRAP (FAT) and FAT C-terminal (FATC) domains [18]. Nterminal and internal regions of PIKKs contain numerous α-helical Huntington-elongation factor 3-A subunit of protein phosphatase 2A-TOR1 (HEAT) repeats [21]. Human Tel2 has been shown to interact with ATM and mTOR through the HEAT repeat regions.

Fig. 4.. TTT pathway in mammalian cells

The TTT-R2TP pathway contributes mainly to protein stabilization of mTOR and SMG1. TTT appears to connect Hsp90 independently of R2TP and regulate protein stabilization of ATM, ATR and DNA-PK.

Fig. 5.. TTT pathway in budding yeast

The TTT-Asa1 pathway plays a key role in protein stabilization of newly synthesized PIKKs whereas the TTT-R2TP pathway contributes to protein stabilization of Mec1^ATR and Tel1^ATM at higher temperatures.

Fig. 6.. TTT pathway in fission yeast

The TTT pathway plays a key role in protein stabilization of newly synthesized PIKKs. CK2 phosphorylates Tel2, but phosphorylation is dispensable for protein stabilization of PIKKs. No Pih1 or Tah1 counterpart is found in fission yeast.