A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.
Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.
Carpten
John D
JD
Division of Integrated Cancer Genomics, Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, Arizona 85004, USA.
Faber
Andrew L
AL
Horn
Candice
C
Donoho
Gregory P
GP
Briggs
Stephen L
SL
Robbins
Christiane M
CM
Hostetter
Galen
G
Boguslawski
Sophie
S
Moses
Tracy Y
TY
Savage
Stephanie
S
Uhlik
Mark
M
Lin
Aimin
A
Du
Jian
J
Qian
Yue-Wei
YW
Zeckner
Douglas J
DJ
Tucker-Kellogg
Greg
G
Touchman
Jeffrey
J
Patel
Ketan
K
Mousses
Spyro
S
Bittner
Michael
M
Schevitz
Richard
R
Lai
Mei-Huei T
MH
Blanchard
Kerry L
KL
Thomas
James E
JE
D000818:Animals; D001798:Blood Proteins / Q000737:chemistry*; D001943:Breast Neoplasms / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics; D004252:DNA Mutational Analysis; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D006801:Humans; D007938:Leukemia / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics; D010750:Phosphoproteins / Q000737:chemistry*; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D001798:Blood Proteins; D010750:Phosphoproteins; C039077:platelet protein P47; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt