Regulation of the rapamycin and FKBP-target 1/mammalian target of rapamycin and cap-dependent initiation of translation by the c-Abl protein-tyrosine kinase.
The c-Abl protein-tyrosine kinase is activated by ionizing radiation and certain other DNA-damaging agents. The rapamycin and FKBP-target 1 (RAFT1), also known as FKBP12-rapamycin-associated protein (FRAP, mTOR), regulates the p70S6 kinase (p70(S6k)) and the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). The present results demonstrate that c-Abl binds directly to RAFT1 and phosphorylates RAFT1 in vitro and in vivo. c-Abl inhibits autophosphorylation of RAFT1 and RAFT1-mediated phosphorylation p70(S6k). The functional significance of the c-Abl-RAFT1 interaction is further supported by the finding that eIF4E-dependent translation in mouse embryo fibroblasts from Abl(-/-) mice is significantly higher than that compared in wild-type cells. The results also demonstrate that exposure of cells to ionizing radiation is associated with c-Abl-mediated binding of 4E-BP1 to eIF4E and inhibition of translation. These findings with the c-Abl tyrosine kinase represent the first demonstration of a negative physiologic regulator of RAFT1-mediated 5' cap-dependent translation.
Kumar
V
V
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sabatini
D
D
Pandey
P
P
Gingras
A C
AC
Majumder
P K
PK
Kumar
M
M
Yuan
Z M
ZM
Carmichael
G
G
Weichselbaum
R
R
Sonenberg
N
N
Kufe
D
D
Kharbanda
S
S
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D039561:Eukaryotic Initiation Factor-4E; D006801:Humans; D010448:Peptide Initiation Factors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor); D014176:Protein Biosynthesis; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D012315:RNA Caps / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
D002352:Carrier Proteins; D039561:Eukaryotic Initiation Factor-4E; D010448:Peptide Initiation Factors; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D016315:Proto-Oncogene Proteins c-abl; D012315:RNA Caps; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse