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J Biol Chem, Vol. 275, Issue 15, 10779-10787, April 14, 2000
From the Dana-Farber Cancer Institute, Harvard Medical School,
Boston, Massachusetts 02115, the 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 (p70S6k) 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 p70S6k. 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
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*
,
,
Whitehead
Institute for Biomedical Research, Cambridge, Massachusetts 02142, the § Department of Biochemistry, McGill Cancer Center,
McGill University, Montreal, Quebec H3G1Y6, Canada, the
¶ Department of Microbiology, University of Connecticut Health
Center, Farmington, Connecticut 06030, and the Department of
Radiation and Cellular Oncology, University of Chicago,
Chicago, Illinois 60637
/ 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.
*
This work was supported by United States Public Health
Service Grant CA75216 (to S. K.) awarded by the NCI, National
Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 617-632-2938;
Fax: 617-632-2934; E-mail: surender_kharbanda@dfci.harvard.edu.
**
Present address: Pulmonary Division, Children's Hospital, 320 Longwood Ave. Boston, MA 02115.
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