Membrane-permeant phosphoinositide derivatives as modulators of growth factor signaling and neurite outgrowth.
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.
Laketa
Vibor
V
Cell Biology and Cell Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
Zarbakhsh
Sirus
S
Morbier
Eva
E
Subramanian
Devaraj
D
Dinkel
Carlo
C
Brumbaugh
Justin
J
Zimmermann
Pascale
P
Pepperkok
Rainer
R
Schultz
Carsten
C
D000818:Animals; D006367:HeLa Cells; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; C547378:phosphatidylinositol 3,4,5,6-tetrakisphosphate; C060974:phosphatidylinositol 3,4,5-triphosphate; C060980:phosphatidylinositol 3,4-diphosphate; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases