Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation.
Members of the mammalian phosphoinositide-3-OH kinase (PI3K) family of proteins are critical regulators of various cellular process including cell survival, growth, proliferation, and motility. Oncogenic activating mutations in the p110alpha catalytic subunit of the heterodimeric p110/p85 PI3K enzyme are frequent in human cancers. Here we show the presence of frequent mutations in p85alpha in colon cancer, a majority of which occurs in the inter-Src homology-2 (iSH2) domain. These mutations uncouple and retain p85alpha's p110-stabilizing activity, while abrogating its p110-inhibitory activity. The p85alpha mutants promote cell survival, AKT activation, anchorage-independent cell growth, and oncogenesis in a p110-dependent manner.
Jaiswal
Bijay S
BS
Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
Janakiraman
Vasantharajan
V
Kljavin
Noelyn M
NM
Chaudhuri
Subhra
S
Stern
Howard M
HM
Wang
Weiru
W
Kan
Zhengyan
Z
Dbouk
Hashem A
HA
Peters
Brock A
BA
Waring
Paul
P
Dela Vega
Trisha
T
Kenski
Denise M
DM
Bowman
Krista K
KK
Lorenzo
Maria
M
Li
Hong
H
Wu
Jiansheng
J
Modrusan
Zora
Z
Stinson
Jeremy
J
Eby
Michael
M
Yue
Peng
P
Kaminker
Josh S
JS
de Sauvage
Frederic J
FJ
Backer
Jonathan M
JM
Seshagiri
Somasekar
S
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D019869:Phosphatidylinositol 3-Kinases