P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT and MEK/ERK signaling in breast cancer.
P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT and MEK/ERK signaling in breast cancer.
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Phosphatidylinositol 3-kinase (PI3K) promotes cancer cell survival, migration, growth, and proliferation by generating phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the inner leaflet of the plasma membrane. PIP3 recruits pleckstrin homology (PH) domain-containing proteins to the membrane to activate oncogenic signaling cascades. Anti-cancer therapeutics targeting the PI3K/AKT/mTOR pathway are in clinical development. In a mass spectrometric screen to identify PIP3-regulated proteins in breast cancer cells, levels of the Rac activator PIP3-dependent Rac exchange factor 1 (P-REX1) increased in response to PI3K inhibition, and decreased upon loss of the PI3K antagonist PTEN. P-REX1 mRNA and protein levels were positively correlated with ER expression, and inversely correlated with PI3K pathway activation in breast tumors as assessed by gene expression and phosphoproteomic analyses. P-REX1 increased activation of Rac1, PI3K/AKT, and MEK/ERK signaling in a PTEN-independent manner, and promoted cell and tumor viability. Loss of P-REX1 or inhibition of Rac suppressed PI3K/AKT and MEK/ERK, and decreased viability. P-REX1 also promoted insulin-like growth factor-1 receptor (IGF-1R) activation, suggesting that P-REX1 provides positive feedback to activators upstream of PI3K. In support of a model where PIP3-driven P-REX1 promotes both PI3K/AKT and MEK/ERK signaling, high levels of P-REX1 mRNA (but not phospho-AKT or a transcriptomic signature of PI3K activation) were predictive of sensitivity to PI3K inhibitors among breast cancer cell lines. P-REX1 expression was highest in ER+ breast tumors compared to many other cancer subtypes, suggesting that neutralizing the P-REX1/Rac axis may provide a novel therapeutic approach to selectively abrogate oncogenic signaling in breast cancer cells.
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影响因子：
11.2
作者：
Miller TW;Pérez-Torres M;Narasanna A;Guix M;Stål O;Pérez-Tenorio G;Gonzalez-Angulo AM;Hennessy BT;Mills GB;Kennedy JP;Lindsley CW;Arteaga CL
通讯作者：
Arteaga CL
影响因子：
64.5
作者：
Fritsch R;de Krijger I;Fritsch K;George R;Reason B;Kumar MS;Diefenbacher M;Stamp G;Downward J
通讯作者：
Downward J
影响因子：
4.8
作者：
Khatri, Shikha;Yepiskoposyan, Hasmik;Plas, David R.
通讯作者：
Plas, David R.
影响因子：
64.8
作者：
MANSER, E;LEUNG, T;LIM, L
通讯作者：
LIM, L
影响因子：
5.7
作者：
Maira, Sauveur-Michel;Pecchi, Sabina;Voliva, Charles F.
通讯作者：
Voliva, Charles F.