TY - JOUR
T1 - Membrane-Permeant Phosphoinositide Derivatives as Modulators of Growth Factor Signaling and Neurite Outgrowth
AU - Laketa, Vibor
AU - Zarbakhsh, Sirus
AU - Morbier, Eva
AU - Subramanian, Devaraj
AU - Dinkel, Carlo
AU - Brumbaugh, Justin
AU - Zimmermann, Pascale
AU - Pepperkok, Rainer
AU - Schultz, Carsten
N1 - Funding Information:
We thank H. Stichnoth for cultured cells and J. Gross (University of Heidelberg) for high resolution mass determination. Funding was provided by the VW foundation (I/81 597) and the Helmholtz Initiative for Systems Biology (SBCancer) to C.S. R.P. is supported by a grant from the German Federal Ministry of Education and Research within the framework of NGFN2 SMP Cell (01GR0423).
PY - 2009
Y1 - 2009
N2 - 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)P3] mimic: phosphatidylinositol 3,4,5,6-tetrakisphosphate [PtdIns(3,4,5,6)P4]. The membrane-permeant PtdIns(3,4,5,6)P4 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)P3 and PtdIns(3,4)P2 derivatives in the absence of receptor stimulation. In addition, we demonstrate that treatment of PC12 cells with the membrane-permeant PtdIns(3,4)P2, PtdIns(3,4,5)P3, and PtdIns(3,4,5,6)P4 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.
AB - 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)P3] mimic: phosphatidylinositol 3,4,5,6-tetrakisphosphate [PtdIns(3,4,5,6)P4]. The membrane-permeant PtdIns(3,4,5,6)P4 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)P3 and PtdIns(3,4)P2 derivatives in the absence of receptor stimulation. In addition, we demonstrate that treatment of PC12 cells with the membrane-permeant PtdIns(3,4)P2, PtdIns(3,4,5)P3, and PtdIns(3,4,5,6)P4 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.
KW - CELLBIO
KW - CHEMBIO
KW - SIGNALING
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U2 - 10.1016/j.chembiol.2009.10.005
DO - 10.1016/j.chembiol.2009.10.005
M3 - Article
C2 - 19942142
AN - SCOPUS:71949131536
SN - 1074-5521
VL - 16
SP - 1190
EP - 1196
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 11
ER -