Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha.
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Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha. / Sun, Minghao; Hillmann, Petra; Hofmann, Bianca T.; Hart, Jonathan R; Vogt, Peter K.
In: P NATL ACAD SCI USA, Vol. 107, No. 35, 35, 2010, p. 15547-15552.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha.
AU - Sun, Minghao
AU - Hillmann, Petra
AU - Hofmann, Bianca T.
AU - Hart, Jonathan R
AU - Vogt, Peter K
PY - 2010
Y1 - 2010
N2 - Cancer-specific mutations in the iSH2 (inter-SH2) and nSH2 (N-terminal SH2) domains of p85alpha, the regulatory subunit of phosphatidylinositide 3-kinase (PI3K), show gain of function. They induce oncogenic cellular transformation, stimulate cellular proliferation, and enhance PI3K signaling. Quantitative determinations of oncogenic activity reveal large differences between individual mutants of p85alpha. The mutant proteins are still able to bind to the catalytic subunits p110alpha and p110beta. Studies with isoform-specific inhibitors of p110 suggest that expression of p85 mutants in fibroblasts leads exclusively to an activation of p110alpha, and p110alpha is the sole mediator of p85 mutant-induced oncogenic transformation. The characteristics of the p85 mutants are in agreement with the hypothesis that the mutations weaken an inhibitory interaction between p85alpha and p110alpha while preserving the stabilizing interaction between p85alpha iSH2 and the adapter-binding domain of p110alpha.
AB - Cancer-specific mutations in the iSH2 (inter-SH2) and nSH2 (N-terminal SH2) domains of p85alpha, the regulatory subunit of phosphatidylinositide 3-kinase (PI3K), show gain of function. They induce oncogenic cellular transformation, stimulate cellular proliferation, and enhance PI3K signaling. Quantitative determinations of oncogenic activity reveal large differences between individual mutants of p85alpha. The mutant proteins are still able to bind to the catalytic subunits p110alpha and p110beta. Studies with isoform-specific inhibitors of p110 suggest that expression of p85 mutants in fibroblasts leads exclusively to an activation of p110alpha, and p110alpha is the sole mediator of p85 mutant-induced oncogenic transformation. The characteristics of the p85 mutants are in agreement with the hypothesis that the mutations weaken an inhibitory interaction between p85alpha and p110alpha while preserving the stabilizing interaction between p85alpha iSH2 and the adapter-binding domain of p110alpha.
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Amino Acid Sequence
KW - Base Sequence
KW - Cell Proliferation
KW - Blotting, Western
KW - Cell Line
KW - Transfection
KW - Immunoprecipitation
KW - Protein Binding
KW - Cell Transformation, Neoplastic/genetics
KW - Mutation
KW - Thiazolidinediones/pharmacology
KW - Fibroblasts/cytology/metabolism
KW - Quinazolines/pharmacology
KW - Chick Embryo
KW - Adenine/analogs & derivatives/pharmacology
KW - Catalytic Domain/genetics
KW - Dioxoles/pharmacology
KW - Morpholines/pharmacology
KW - Neoplasms/enzymology/genetics
KW - Phosphatidylinositol 3-Kinases/antagonists & inhibitors/genetics/metabolism
KW - Protein Subunits/antagonists & inhibitors/genetics/metabolism
KW - Pyrimidinones/pharmacology
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Amino Acid Sequence
KW - Base Sequence
KW - Cell Proliferation
KW - Blotting, Western
KW - Cell Line
KW - Transfection
KW - Immunoprecipitation
KW - Protein Binding
KW - Cell Transformation, Neoplastic/genetics
KW - Mutation
KW - Thiazolidinediones/pharmacology
KW - Fibroblasts/cytology/metabolism
KW - Quinazolines/pharmacology
KW - Chick Embryo
KW - Adenine/analogs & derivatives/pharmacology
KW - Catalytic Domain/genetics
KW - Dioxoles/pharmacology
KW - Morpholines/pharmacology
KW - Neoplasms/enzymology/genetics
KW - Phosphatidylinositol 3-Kinases/antagonists & inhibitors/genetics/metabolism
KW - Protein Subunits/antagonists & inhibitors/genetics/metabolism
KW - Pyrimidinones/pharmacology
M3 - SCORING: Journal article
VL - 107
SP - 15547
EP - 15552
JO - P NATL ACAD SCI USA
JF - P NATL ACAD SCI USA
SN - 0027-8424
IS - 35
M1 - 35
ER -