Membrane-permeant phosphoinositide derivatives as modulators of growth factor signaling and neurite outgrowth

Chemistry & Biology
Vibor LaketaCarsten Schultz

Abstract

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.

References

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Citations

Jan 16, 2014·Science Signaling·Vibor LaketaCarsten Schultz
May 7, 2014·The Journal of Cell Biology·Alessandra ReversiStefano De Renzis
May 16, 2012·FEBS Letters·Mateusz Putyrski, Carsten Schultz
Dec 17, 2014·Biochimica Et Biophysica Acta·Olof Idevall-Hagren, Pietro De Camilli
Sep 30, 2014·Biochimica Et Biophysica Acta·York PosorVolker Haucke
Sep 29, 2011·Chemistry & Biology·Mateusz Putyrski, Carsten Schultz
Jun 30, 2015·Angewandte Chemie·Ahmed E Fouda, Mary Kay H Pflum
Apr 7, 2010·Nature Chemical Biology·Devaraj SubramanianCarsten Schultz
Jun 19, 2010·Nature Chemical Biology·Carsten Schultz
Sep 12, 2012·Chembiochem : a European Journal of Chemical Biology·Matthias P Wymann, Carsten Schultz
May 28, 2015·Angewandte Chemie·Igor PavlovicHenning J Jessen
Mar 16, 2011·Angewandte Chemie·Matthias MentelCarsten Schultz
May 22, 2019·Nature Reviews. Molecular Cell Biology·Benoit BilangesBart Vanhaesebroeck

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