Regulation of RAS oncogenicity by acetylation.
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.
Molecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Moon Hee
MH
Yang
Seth
S
Nickerson
Eric T
ET
Kim
Caroline
C
Liot
Gaelle
G
Laurent
Robert
R
Spang
Mark R
MR
Philips
Yibing
Y
Shan
David E
DE
Shaw
Dafna
D
Bar-Sagi
Marcia C
MC
Haigis
Kevin M
KM
Haigis
D000107:Acetylation; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D011905:Genes, ras / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D054876:Prenylation / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary / Q000502:physiology; D013329:Structure-Activity Relationship; D018631:ras Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; D006160:Guanosine Triphosphate; D018631:ras Proteins; D008239:Lysine