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
PY - 2009/12/21
Y1 - 2009/12/21
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
UR - http://www.scopus.com/inward/record.url?scp=71949131536&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=71949131536&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2009.10.005
DO - 10.1016/j.chembiol.2009.10.005
M3 - Article
C2 - 19942142
AN - SCOPUS:71949131536
VL - 16
SP - 1190
EP - 1196
JO - Cell Chemical Biology
JF - Cell Chemical Biology
SN - 2451-9448
IS - 11
ER -