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Carboxyl‐terminal region conserved among phosphoinositide‐kinase‐related kinases is indispensable for mTOR function in vivo and in vitro
Author(s) -
Takahashi Tetsuya,
Hara Kenta,
Inoue Hitomi,
Kawa Yoshitaka,
Tokunaga Chiharu,
Hidayat Sujuti,
Yoshino Kenichi,
Kuroda Yoshikazu,
Yonezawa Kazuyoshi
Publication year - 2000
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1046/j.1365-2443.2000.00365.x
Subject(s) - p70 s6 kinase 1 , biology , mtorc2 , pi3k/akt/mtor pathway , kinase , rptor , microbiology and biotechnology , biochemistry , signal transduction , mtorc1
Background The mammalian target of rapamycin (mTOR) belongs to the family of phosphoinositide (PI)‐kinase‐related kinases that includes the ataxia‐telangiectasia gene product (ATM). mTOR plays a critical role in controlling translational effectors such as p70 S6 kinase α (p70α) and eukaryotic initiation factor 4E binding protein 1 (4EBP1). Results We show that the C‐terminal region of mTOR, which is highly conserved among the PI‐kinase‐related kinases, plays a critical role in the mTOR protein kinase activity. Deletion of the C‐terminal residues did not adversely affect the expression of mTOR, but caused a nearly complete loss of the mTOR protein kinase activity toward both 4EBP1 and p70α in vitro . These deletions also abolished the ability of a rapamycin‐resistant mTOR mutant to rescue the activity of p70α from inhibition induced by rapamycin in vivo . Furthermore, replacement of Trp2545, a conserved residue in the C‐terminal region throughout the PI‐kinase‐related kinase family, abolished the function of the mTOR kinase, both in vivo and in vitro . However, substitution of 32 C‐terminal residues of mTOR with those of ATM did not restore the mTOR function. Conclusions These findings define an indispensable role for the noncatalytic C‐terminal region of mTOR and indicate that, although this highly conserved region may be important throughout the PI‐kinase‐related kinase family, it is not functionally interchangeable within the family.