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

Vibor Laketa, Sirus Zarbakhsh, Eva Morbier, Devaraj Subramanian, Carlo Dinkel, Justin Brumbaugh, Pascale Zimmermann, Rainer Pepperkok, Carsten Schultz

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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)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.

Original languageEnglish (US)
Pages (from-to)1190-1196
Number of pages7
JournalChemistry and Biology
Volume16
Issue number11
DOIs
StatePublished - 2009
Externally publishedYes

Keywords

  • CELLBIO
  • CHEMBIO
  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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