한빛사논문
- 조회1,903
Abstract
Moon Hee Yanga,b,c,d, Seth Nickersone, Eric T. Kimf, Caroline Liotg,h,i, Gaelle Laurentj, Robert Spangj, Mark R. Philipsg,h,i, Yibing Shanf, David E. Shawf,k, Dafna Bar-Sagie, Marcia C. Haigisj, and Kevin M. Haigisa,b,c,d,1
aMolecular Pathology Unit,
bCenter for Cancer Research, and
cCenter for Systems Biology, Massachusetts General Hospital, Charlestown, MA 02129;
Departments of dPathology and
jCell Biology, Harvard Medical School, Boston, MA 02115;
Departments of eBiochemistry,
gMedicine,
hCell Biology, and
iPharmacology, New York University School of Medicine, New York, NY 10016;
fD. E. Shaw Research, New York, NY 10036; and
kCenter for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032
Abstract
Members of the RAS small GTPase family regulate cellular responses to extracellular stimuli by mediating the flux through downstream signal transduction cascades. RAS activity is strongly dependent on its subcellular localization and its nucleotide-binding status, both of which are modulated by posttranslational modification. We have determined that RAS is posttranslationally acetylated on lysine 104. Molecular dynamics simulations suggested that this modification affects the conformational stability of the Switch II domain, which is critical for the ability of RAS to interact with guanine nucleotide exchange factors. Consistent with this model, an acetylation-mimetic mutation in K-RAS4B suppressed guanine nucleotide exchange factor-induced nucleotide exchange and inhibited in vitro transforming activity. These data suggest that lysine acetylation is a negative regulatory modification on RAS. Because mutations in RAS family members are extremely common in cancer, modulation of RAS acetylation may constitute a therapeutic approach.
Footnotes
1To whom correspondence should be addressed.
Author contributions: M.R.P., Y.S., D.B.-S., M.C.H., and K.M.H. designed research; M.H.Y., S.N., E.T.K., C.L., G.L., R.S., and Y.S. performed research; M.R.P., Y.S., and D.E.S. contributed new reagents/analytic tools; M.H.Y., S.N., E.T.K., C.L., G.L., R.S., M.R.P., Y.S., D.B.-S., M.C.H., and K.M.H. analyzed data; and M.H.Y., S.N., C.L., M.R.P., Y.S., D.B.-S., M.C.H., and K.M.H. wrote the paper.
논문정보
- Research article
- 2012년 06월 (BRIC 등록일 )
- 국외 연구진
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