Regulation of eIF-4E BP1 phosphorylation by mTOR.
The proteins eIF-4E BP1 and p70 S6 kinase each undergo an insulin/mitogen-stimulated phosphorylation in situ that is partially inhibited by rapamycin. Previous work has established that the protein known as mTOR/RAFT-1/FRAP is the target through which the rapamycin.FKBP12 complex acts to dephosphorylate/deactivate the p70 S6 kinase; thus, some mTOR mutants that have lost the ability to bind to the rapamycin.FKBP12 complex in vitro can protect the p70 S6 kinase against rapamycin-induced dephosphorylation/deactivation in situ. We show herein that such mTOR mutants also protect eIF-4E BP1 against rapamycin-induced dephosphorylation, and for both p70 S6 kinase and eIF-4E BP1, such protection requires that the rapamycin-resistant mTOR variant retains an active catalytic domain. In contrast, mutants of p70 S6 kinase rendered intrinsically resistant to inhibition by rapamycin in situ are not able to protect coexpressed eIF-4E BP1 from rapamycin-induced dephosphorylation. We conclude that mTOR is an upstream regulator of eIF-4E BP1 as well as the p70 S6 kinase; moreover, these two mTOR targets are regulated in a parallel rather than sequential manner.
Hara
K
K
Diabetes Unit and Medical Services, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts 02129, USA.
Yonezawa
K
K
Kozlowski
M T
MT
Sugimoto
T
T
Andrabi
K
K
Weng
Q P
QP
Kasuga
M
M
Nishimoto
I
I
Avruch
J
J
D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002352:Carrier Proteins; D002460:Cell Line; D006224:Cricetinae; D018076:DNA, Complementary; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011090:Polyenes / Q000494:pharmacology; D011494:Protein Kinases; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases
D002352:Carrier Proteins; D018076:DNA, Complementary; D010750:Phosphoproteins; D011090:Polyenes; D011994:Recombinant Proteins; D011494:Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus