Laketa Vibor, Zarbakhsh Sirus, Morbier Eva, Subramanian Devaraj, Dinkel Carlo, Brumbaugh Justin, Zimmermann Pascale, Pepperkok Rainer, Schultz Carsten
Cell Biology and Cell Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
Chem Biol. 2009 Nov 25;16(11):1190-6. doi: 10.1016/j.chembiol.2009.10.005.
Phosphoinositides are important signaling molecules that govern a large number of cellular processes such as proliferation, differentiation, membrane remodeling, and survival. Here we introduce a fully synthetic membrane-permeant derivative of a novel, easily accessible, and very potent phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] mimic: phosphatidylinositol 3,4,5,6-tetrakisphosphate [PtdIns(3,4,5,6)P(4)]. The membrane-permeant PtdIns(3,4,5,6)P(4) derivative activated pathways downstream of phosphatidylinositol 3-kinase (PI3K), including protein kinase B, p70S6K, mitogen-activated protein kinase, and protein kinase C, more potently than similar membrane-permeant PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2) derivatives in the absence of receptor stimulation. In addition, we demonstrate that treatment of PC12 cells with the membrane-permeant PtdIns(3,4)P(2), PtdIns(3,4,5)P(3), and PtdIns(3,4,5,6)P(4) derivatives increases the number of neurites per cell in the presence of NGF. This work establishes membrane-permeant phosphoinositides as powerful tools to study PI3K signaling and directly demonstrates that 3-phosphorylated phosphoinositides are instrumental for neurite initiation.
磷酸肌醇是重要的信号分子，调控着大量细胞过程，如增殖、分化、膜重塑和存活。在此，我们介绍一种新型、易于获取且强效的磷脂酰肌醇3,4,5-三磷酸[PtdIns(3,4,5)P(3)]模拟物的全合成膜渗透性衍生物：磷脂酰肌醇3,4,5,6-四磷酸[PtdIns(3,4,5,6)P(4)]。在无受体刺激的情况下，这种膜渗透性PtdIns(3,4,5,6)P(4)衍生物比类似的膜渗透性PtdIns(3,4,5)P(3)和PtdIns(3,4)P(2)衍生物更有效地激活磷脂酰肌醇3-激酶(PI3K)下游的信号通路，包括蛋白激酶B、p70S6K、丝裂原活化蛋白激酶和蛋白激酶C。此外，我们证明，在存在神经生长因子(NGF)的情况下，用膜渗透性PtdIns(3,4)P(2)、PtdIns(3,4,5)P(3)和PtdIns(3,4,5,
