Membrane-Permeant Phosphoinositide Derivatives as Modulators of Growth Factor Signaling and Neurite Outgrowth

Cell Biology and Cell Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
Chemistry & biology (Impact Factor: 6.65). 11/2009; 16(11):1190-6. DOI: 10.1016/j.chembiol.2009.10.005
Source: PubMed


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.

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    • "For example, the addition of aminophospholipid increases endocytosis in living cells (Farge et al. 1999) and adding the biologically active isoform, but not other isoforms, of LBPA reduces cholesterol overload in NPC cells (Chevallier et al. 2008). Finally, a promising approach has been elaborated by Carsten Schultz and colleagues that developed very elegant strategies to introduce membrane-permeant versions of phosphoinositides into cells so that the lipid is released upon cleavage by cytosolic esterases (Laketa et al. 2009; Mentel et al. 2011). Such strategies, together with the development of novel chemical biology tools, offer promising new ways to study the function of membrane lipids (Riezman and Johnsson 2011; Wymann and Schultz 2012). "
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    • "Once inside the cell the ester groups are removed by host esterases yielding the original IP5 molecule (available from SiChem). A similar approach can now be applied to phosphoinositides yielding new cell permeant tools for studying these signaling pathways [24,25]. "
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