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

doi:10.1016/j.chembiol.2009.10.005

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

Physiology & Pharmacology

Research output: Contribution to journal › Article › peer-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 language	English (US)
Pages (from-to)	1190-1196
Number of pages	7
Journal	Chemistry and Biology
Volume	16
Issue number	11
DOIs	https://doi.org/10.1016/j.chembiol.2009.10.005
State	Published - Dec 21 2009

Keywords

CELLBIO
CHEMBIO
SIGNALING

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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Membrane-Permeant Phosphoinositide Derivatives as Modulators of Growth Factor Signaling and Neurite Outgrowth. / Laketa, Vibor; Zarbakhsh, Sirus; Morbier, Eva; Subramanian, Devaraj; Dinkel, Carlo; Brumbaugh, Justin; Zimmermann, Pascale; Pepperkok, Rainer; Schultz, Carsten.

In: Chemistry and Biology, Vol. 16, No. 11, 21.12.2009, p. 1190-1196.

Research output: Contribution to journal › Article › peer-review

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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.",

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AU - Subramanian, Devaraj

AU - Dinkel, Carlo

AU - Brumbaugh, Justin

AU - Zimmermann, Pascale

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