Synthesis and Function of 3-Phosphorylated Inositol Lipids

Vanhaesebroeck, Bart; Leevers, Sally J.; Ahmadi, Khatereh; Timms, John F.; Katso, Roy; Driscoll, Paul C.; Woscholski, Rüdiger; Parker, Peter J.; Waterfield, Michael D.

doi:10.1146/annurev.biochem.70.1.535

Cited by 1,437 publications

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“…They are activated downstream transmembrane receptors [1] and are involved in several cellular responses such as metabolic regulation, survival, proliferation, cell migration and adhesion. PI3K convert PtdIns(4,5)P 2 into PtdIns(3,4,5)P 3 , a second lipid messenger product forming a docking site for various proteins harboring lipid binding modules such as the pleckstrin homology domain [2].…”

Section: Introductionmentioning

confidence: 99%

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

et al. 2009

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Phosphoinositide 3-kinase c (PI3Kc) plays a fundamental role in mediating leukocyte migration to inflammation sites. However, the downstream cytoplasmic events triggered by its signaling activity are still largely obscure. To address this issue, tyrosine and serine/threonine phosphorylated proteins of chemokine-stimulated WT or PI3Kc-null macrophages were investigated. Among the proteins analyzed, the intermediate filament vimentin was found as a downstream effector of the PI3Kc signaling pathway. Specific analysis of the phosphorylation state of vimentin in macrophages showed that this protein becomes rapidly phosphorylated in both tyrosine and serine residues upon chemokine stimulation. In the absence of PI3Kc or the kinase activity of PI3Kc (PI3Kc KD/KD ), phosphorylation of vimentin was reduced. PI3Kc-null macrophages displayed impaired chemokine-driven vimentin fiber disassembly as well as reduced ability to transmigrate across endothelial cells. While WT macrophages infected with a vimentin mutant resistant to N-terminal serine phosphorylation showed a reduction in transendothelial migration, infection of PI3Kc-null macrophages with a vimentin mutant mimicking serine phosphorylation of N-terminal residues rescued the transendothelial migration defect. These results define vimentin N-terminal phosphorylation and fiber reorganization as a target of chemokine-dependent PI3Kc signaling in leukocytes.Key words: Cell migration . Intermediate filaments . Phosphoinositide 3-kinases .Signal transduction IntroductionPhosphoinositide 3-kinases (PI3K) are a family of ubiquitously expressed lipid and protein kinases. They are activated downstream transmembrane receptors [1] and are involved in several cellular responses such as metabolic regulation, survival, proliferation, cell migration and adhesion. PI3K convert PtdIns(4,5)P 2 into PtdIns(3,4,5)P 3 , a second lipid messenger product forming a docking site for various proteins harboring lipid binding modules such as the pleckstrin homology domain [2].Ã These authors contributed equally to this work. 1136Class I PI3K are heterodimeric proteins composed of a p110 catalytic subunit (a, b, g and d) and a regulatory adaptor subunit. According to their mechanism of activation, these enzymes can be further classified into two subclasses: while class IA PI3K (PI3Ka, b and d) include an adaptor protein of the p85 family and are activated by tyrosine kinase receptors, the sole known element of class IB, PI3Kg, is specifically activated by G protein-coupled receptors (GPCR) [3]. This effect is regulated by the interaction of PI3Kg with Gbg subunits of active G proteins through the involvement of either the p101 adaptor or its homologue p84/p87 [4]. Among mammalian tissues, the highest level of PI3Kg expression is found in leukocytes where this enzyme directs the chemotactic response to GPCR agonists [3]. Indeed, PI3Kg-null granulocytes show a significant reduction in chemotaxis toward chemokines and severely impaired bacteria-elicited peritoneal recruitment [5,6]. This migrati...

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Section: Introductionmentioning

confidence: 99%

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

et al. 2009

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“…Among all these, the polarized distribution of a phospholipid, PIP 3 , which was initially observed in Dictyostelium [16] and later in neutrophils [17] and other cells [18], appears to occur prior to other polarization events. PIP3 is converted from PIP 2 by PI3K [19]. Some of the Pleckstrin homology (PH) domains specifically recognize PIP 3 , thus leading to the translocation of the PH domain-containing proteins to the plasma membrane.…”

Section: Mechanism Of Cell Polarization In Regulation Of Chemotaxismentioning

confidence: 99%

“…Some of the Pleckstrin homology (PH) domains specifically recognize PIP 3 , thus leading to the translocation of the PH domain-containing proteins to the plasma membrane. Such translocation often leads to the regulation of the activity of these proteins that include many protein kinases, GEFs, and structural proteins [19][20][21][22]. Chemoattractants have been shown to stimulate PIP 3 production in leukocytes, presumably by activating a PI3K.…”

Section: Mechanism Of Cell Polarization In Regulation Of Chemotaxismentioning

confidence: 99%

“…Studies from Dictyostelium suggest that PTEN is one of the negative regulators that helps establishing and maintaining the PIP 3 gradient [45,46]. PTEN is a protein and phospholipid phosphatase that can dephosphorylate PIP 3 [19,[47][48][49][50][51]. In chemotaxing Dictyostelium cells, PTEN was found to be translocated to the posterior membranes of the cells [45,46].…”

Section: Mechanism Of Cell Polarization In Regulation Of Chemotaxismentioning

confidence: 99%

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Signaling mechanisms for regulation of chemotaxis

2005

Cell Res

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Chemotaxis is a fascinating biological process, through which a cell migrates along a shallow chemoattractant gradient that is less than 5% difference between the anterior and posterior of the cell. Chemotaxis is composed of two independent, but interrelated processes-motility and directionality, both of which are regulated by extracellular stimuli, chemoattractants. In this mini-review, recent progresses in the understanding of the regulation of leukocyte chemotaxis by chemoattractant signaling are reviewed.

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“…The phosphoinositide (PI) 3 kinase (PI3K) pathway plays an important role in various signaling pathways, such as insulin signaling, membrane trafficking and the regulation of cell dynamics, via production of the second messenger PI(3,4,5,)P 3 [1,2]. Arap3 (Arf GAP, Rho GAP, Ankyrin repeat and PH domains) is a PI3K effector protein that was first identified through its ability to bind PI(3,4,5,)P 3 lipids [3].…”

Section: Introductionmentioning

confidence: 99%

The PI3K effector Arap3 interacts with the PI(3,4,5)P3 phosphatase SHIP2 in a SAM domain-dependent manner

Raaijmakers

Deneubourg

Rehmann

et al. 2007

Cellular Signalling

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Arap3 is a phosphoinositide (PI) 3 kinase effector that serves as a GTPase activating protein (GAP) for both Arf and Rho G-proteins. The protein has multiple pleckstrin homology (PH) domains that bind preferentially phosphatidyl-inositol-3,4,5-trisphosphate (PI(3,4,5,)P 3 ) to induce translocation of Arap3 to the plasma membrane upon PI3K activation. Arap3 also contains a Ras association (RA) domain that interacts with the small G-protein Rap1 and a sterile alpha motif (SAM) domain of unknown function. In a yeast two-hybrid screen for new interaction partners of Arap3, we identified the PI 5′-phosphatase SHIP2 as an interaction partner of Arap3. The interaction between Arap3 and SHIP2 was observed with endogenous proteins and shown to be mediated by the SAM domain of Arap3 and SHIP2. In vitro, these two domains show specificity for a heterodimeric interaction. Since it was shown previously that Arap3 has a higher affinity for PI(3,4,5,)P 3 than for PI(3,4)P 2 , we propose that the SAM domain of Arap3 can function to recruit a negative regulator of PI3K signaling into the effector complex.

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Synthesis and Function of 3-Phosphorylated Inositol Lipids

Cited by 1,437 publications

References 432 publications

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

Signaling mechanisms for regulation of chemotaxis

The PI3K effector Arap3 interacts with the PI(3,4,5)P3 phosphatase SHIP2 in a SAM domain-dependent manner

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