Essential role of PI3-kinase and phospholipase A2 in <i>Dictyostelium discoideum</i> chemotaxis

Haastert, Peter J.M. van; Keizer‐Gunnink, Ineke; Kortholt, Arjan

doi:10.1083/jcb.200701134

Cited by 100 publications

(99 citation statements)

References 31 publications

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“…Through mutagenesis and combinational chemical inhibitor assays, PLA was shown to function in the chemotaxis pathway in Dictyostelium, where the PLA pathway is parallel to the PI3K pathway. Upon inhibition of both pathways, a severe defect of chemotaxis occurs in Dictyostelium in response to the cAMP gradient (39,40). The co-existence of these redundant pathways allows cells greater flexibility to respond to different environmental circumstances, such as gradients of high or low steepness.…”

Section: Discussionmentioning

confidence: 99%

Parallel Phosphatidylinositol 3-Kinase (PI3K)-dependent and Src-dependent Pathways Lead to CXCL8-mediated Rac2 Activation and Chemotaxis

Sai

Raman

Liu

et al. 2008

Journal of Biological Chemistry

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The requirement for phosphatidylinositol 3-kinase (PI3K) in the establishment of cell polarity and motility in a number of cell types has recently come into question. In this study, we demonstrate that inhibition of PI3K by wortmannin in neutrophil-like differentiated HL60 cells expressing CXCR2 resulted in reduced cell motility but normal chemotaxis in response to a gradient of CXCL8. However, wortmannin inhibition of PI3K did impair the ability of cells to re-orient their polarity and respond quickly to a change in the direction of the CXCL8 gradient. We hypothesized that Src-regulated ELMO-Dock2-Rac2 activation mediates chemotaxis in the absence of PI3K activity. Inhibition of Src with the small molecule inhibitor, PP2, or inhibition of Dock2 by shRNA knockdown confirmed the functional role of Src and Dock2 in regulating chemotaxis when PI3K was inhibited. Moreover, neutrophils isolated from bone marrow of hck ؊/؊ fgr ؊/؊ lyn ؊/؊ mice exhibited much more severe inhibition of chemotaxis when PI3K was blocked with wortmannin as compared with neutrophils isolated from bone marrow of wild-type mice. Thus, PI3K and Src-ELMO-Dock2 pathways work in parallel to activate Rac2 and modulate chemotaxis in response to a CXCL8 gradient in neutrophils.Chemotaxis is the process by which cells migrate toward a chemical gradient. It has been reported that phosphatidylinositol 3-kinases (PI3K) 2 and their product, phosphatidylinositol 3,4,5-trisphosphate (PIP3), play an important role in sensing and polarizing the cell toward a chemoattractant gradient(1-4). PI3K␥, the dominant class I PI3K in neutrophils, catalyzes the 3Ј-phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate PIP3. In PI3K␥ knockout mice, recruitment of neutrophils to sites of inflammation was significantly reduced, though not completely inhibited. Additionally, in vitro chemotaxis assays showed incomplete inhibition of chemotaxis for neutrophils derived from these mice (5-7). Based on these data, it has been hypothesized that a PI3K-independent pathway exists in neutrophils that allows these cells to move toward a gradient of chemokine. Src family kinases (SFK) are a group of tyrosine kinases that play fundamental roles in mediating cell proliferation, survival, and focal adhesion regulation in response to a variety of environmental stimuli. In certain G protein-coupled receptor-mediated signal transduction pathways, SFK can bind and be activated by G␣ i and G␣ s subunits of the heterotrimeric G-protein (8). This PI3K-independent signal transduction pathway activated directly by heterotrimeric G proteins may lead to a different cascade of signal activation.Members of the Rho family of small GTPases are essential for regulation of cell cytoskeleton reorganization during motility and thus have great impact on cell morphology (polarized versus non-polarized). Activation of Rac has been shown to be required for extension of pseudopodia at the leading edge of moving cells. Rac2, as a hematopoietic-specific member of Rac, plays critical roles i...

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Section: Discussionmentioning

confidence: 99%

Parallel Phosphatidylinositol 3-Kinase (PI3K)-dependent and Src-dependent Pathways Lead to CXCL8-mediated Rac2 Activation and Chemotaxis

Sai

Raman

Liu

et al. 2008

Journal of Biological Chemistry

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“…These results indicate that a parallel pathway for F-actin polymerization and chemotaxis must function independently of PIP 3 formation (Figure 4). Two independent research groups have now identified PLA 2 as an alternative mediator of chemotaxis (Chen et al, 2007;van Haastert et al, 2007;Figures 4,5). PLA 2 catalyzes the cleavage of phospholipids into fatty acids (e.g.…”

Section: Pla 2 -Signalingmentioning

confidence: 99%

“…For each concentration, the WT response is arbitrarily set to 100. Data are adapted and summarize the work of multiple groups (Chen et al, 2007;van Haastert et al, 2007;Hoeller and Kay, 2007;Takeda et al, 2007). Chemotaxis of polarized Dictyostelium to 1 μM cAMP.…”

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confidence: 99%

Oscillatory signaling and network responses during the development of Dictyostelium discoideum

McMains

Liao

Kimmel

2008

Ageing Research Reviews

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Periodic biological variations reflect interactions among molecules and cells, or even organisms. The Dictyostelium cAMP oscillatory circuit is a highly robust example. cAMP oscillations in Dictyostelium arise intracellularly by a complex interplay of activating and inhibiting pathways, are transmitted extracellularly, and synchronize an entire local population. Once established, cAMP signal-relay persists stably for hours. On a two-dimensional surface, >100,000 cells may form a single coordinated territory. In suspension culture, >10 10 cells can oscillate in harmony. This review focuses on molecular mechanisms that cyclically activate and attenuate signal propagation and on chemotactic responses to oscillatory wave progression.

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“…In chemoattraction, PLA2 is also involved in directional sensing but its role in chemorepulsion is unknown (Chen et al, 2007;Takeda et al, 2007;Van Haastert et al, 2007). While results have shown that PI3K is not essential for a cell to exhibit chemoattractive migration, it has been found to be necessary for a chemorepulsive response in the experimental studies performed .…”

Section: Introductionmentioning

confidence: 97%

A mathematical modelling framework for understanding chemorepulsive signal transduction in Dictyostelium

Alam-Nazki

Krishnan

2010

Journal of Theoretical Biology

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Chemorepulsion is the process by which an organism or a cell moves in the direction of decreasing chemical concentration. While a few experimental studies have been performed, no mathematical models exist for this process. In this paper we have modelled gradient sensing, the first subprocess of chemorepulsion, in D. discoideum-a well characterized model eukaryotic system. We take the first steps towards achieving a comprehensive mechanistic understanding of chemorepulsion in this system. We have used, as a basis, the biochemical network of the Keizer-Gunnink et al. (2007)

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Essential role of PI3-kinase and phospholipase A2 in Dictyostelium discoideum chemotaxis

Cited by 100 publications

References 31 publications

Parallel Phosphatidylinositol 3-Kinase (PI3K)-dependent and Src-dependent Pathways Lead to CXCL8-mediated Rac2 Activation and Chemotaxis

Parallel Phosphatidylinositol 3-Kinase (PI3K)-dependent and Src-dependent Pathways Lead to CXCL8-mediated Rac2 Activation and Chemotaxis

Oscillatory signaling and network responses during the development of Dictyostelium discoideum

A mathematical modelling framework for understanding chemorepulsive signal transduction in Dictyostelium

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