epidermal-growth-factor and triciribine-phosphate

epidermal-growth-factor has been researched along with triciribine-phosphate* in 1 studies

Other Studies

1 other study(ies) available for epidermal-growth-factor and triciribine-phosphate

Article	Year
The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane. Cell death and differentiation, 2010, Volume: 17, Issue:11 Persistently hyperphosphorylated Akt contributes to human oncogenesis and resistance to therapy. Triciribine (TCN) phosphate (TCN-P), the active metabolite of the Akt phosphorylation inhibitor TCN, is in clinical trials, but the mechanism by which TCN-P inhibits Akt phosphorylation is unknown. Here we show that in vitro, TCN-P inhibits neither Akt activity nor the phosphorylation of Akt S473 and T308 by mammalian target of rapamycin or phosphoinositide-dependent kinase 1. However, in intact cells, TCN inhibits EGF-stimulated Akt recruitment to the plasma membrane and phosphorylation of Akt. Surface plasmon resonance shows that TCN, but not TCN, binds Akt-derived pleckstrin homology (PH) domain (K(D): 690 nM). Furthermore, nuclear magnetic resonance spectroscopy shows that TCN-P, but not TCN, binds to the PH domain in the vicinity of the PIP3-binding pocket. Finally, constitutively active Akt mutants, Akt1-T308D/S473D and myr-Akt1, but not the transforming mutant Akt1-E17K, are resistant to TCN and rescue from its inhibition of proliferation and induction of apoptosis. Thus, the results of our studies indicate that TCN-P binds to the PH domain of Akt and blocks its recruitment to the membrane, and that the subsequent inhibition of Akt phosphorylation contributes to TCN-P antiproliferative and proapoptotic activities, suggesting that this drug may be beneficial to patients whose tumors express persistently phosphorylated Akt. Topics: 3-Phosphoinositide-Dependent Protein Kinases; Acenaphthenes; Animals; Apoptosis; Cell Line, Tumor; Cell Membrane; Epidermal Growth Factor; Fluorescent Antibody Technique; Gene Amplification; Humans; Intracellular Signaling Peptides and Proteins; Magnetic Resonance Spectroscopy; Membrane Proteins; Phosphoproteins; Phosphorylation; Polymerase Chain Reaction; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Proto-Oncogene Proteins c-akt; Ribonucleotides; Signal Transduction; Surface Plasmon Resonance; TOR Serine-Threonine Kinases	2010

Article

Year

The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane.

Cell death and differentiation, 2010, Volume: 17, Issue:11

Persistently hyperphosphorylated Akt contributes to human oncogenesis and resistance to therapy. Triciribine (TCN) phosphate (TCN-P), the active metabolite of the Akt phosphorylation inhibitor TCN, is in clinical trials, but the mechanism by which TCN-P inhibits Akt phosphorylation is unknown. Here we show that in vitro, TCN-P inhibits neither Akt activity nor the phosphorylation of Akt S473 and T308 by mammalian target of rapamycin or phosphoinositide-dependent kinase 1. However, in intact cells, TCN inhibits EGF-stimulated Akt recruitment to the plasma membrane and phosphorylation of Akt. Surface plasmon resonance shows that TCN, but not TCN, binds Akt-derived pleckstrin homology (PH) domain (K(D): 690 nM). Furthermore, nuclear magnetic resonance spectroscopy shows that TCN-P, but not TCN, binds to the PH domain in the vicinity of the PIP3-binding pocket. Finally, constitutively active Akt mutants, Akt1-T308D/S473D and myr-Akt1, but not the transforming mutant Akt1-E17K, are resistant to TCN and rescue from its inhibition of proliferation and induction of apoptosis. Thus, the results of our studies indicate that TCN-P binds to the PH domain of Akt and blocks its recruitment to the membrane, and that the subsequent inhibition of Akt phosphorylation contributes to TCN-P antiproliferative and proapoptotic activities, suggesting that this drug may be beneficial to patients whose tumors express persistently phosphorylated Akt.

Topics: 3-Phosphoinositide-Dependent Protein Kinases; Acenaphthenes; Animals; Apoptosis; Cell Line, Tumor; Cell Membrane; Epidermal Growth Factor; Fluorescent Antibody Technique; Gene Amplification; Humans; Intracellular Signaling Peptides and Proteins; Magnetic Resonance Spectroscopy; Membrane Proteins; Phosphoproteins; Phosphorylation; Polymerase Chain Reaction; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Proto-Oncogene Proteins c-akt; Ribonucleotides; Signal Transduction; Surface Plasmon Resonance; TOR Serine-Threonine Kinases

2010