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First published online August 6, 2008
doi: 10.1242/10.1242/jcs.018077
Cell Science at a Glance |
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892-4256, USA
* Author for correspondence (e-mail: parentc{at}mail.nih.gov)
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Introduction |
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 Top Introduction Chemoattractants and their...Signal transduction pathways and...The cytoskeleton and its...Signal relay and chemotaxis...PerspectivesReferences |
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Chemoattractants and their receptors |
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TopIntroductionChemoattractants and their...Signal transduction pathways and...The cytoskeleton and its...Signal relay and chemotaxis...PerspectivesReferences |
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). Folic acid, a bacterial by-product, acts as a directional cue to attract Dictyostelium to their food source during growth, as these organisms live as single cells that feed on bacteria. Under conditions of starvation, Dictyostelium enter a developmental program and lose their ability to sense folic acid. Within 4-5 hours, they then acquire the chemotactic machinery that is responsible for the detection, synthesis and degradation of cAMP, the most potent chemoattractant for Dictyostelium (Manahan et al., 2004; Saran et al., 2002). Concurrently, starved cells become highly chemotactic and migrate directionally to form aggregates that later differentiate into a multicellular structure that can resist harsh environmental conditions (Chisholm and Firtel, 2004).
Receptors for folic acid and cAMP belong to the G-protein-coupled receptor (GPCR) family, each member of which comprises an extracellular N-terminal domain followed by seven transmembrane helices and a C-terminal tail (Milligan and Kostenis, 2006). These receptors mediate most of their effects through heterotrimeric G proteins, although a subset of responses occur independently of G proteins (Brzostowski and Kimmel, 2001). Four distinct cAMP receptors (cAR1 to cAR4), which are expressed at different times during Dictyostelium development, have been cloned. cAR1 is expressed during early development, when the cells are highly chemotactic, and is linked to the G protein G
2β
(Parent and Devreotes, 1996). Both cAR1 and G proteins are uniformly distributed around the cell periphery and remain this way during chemotaxis (Parent and Devreotes, 1999). The folic-acid receptor, which is linked to G4β, has yet to be cloned.
Leukocyte chemotaxis is induced by several chemoattractants and chemokines that signal through pertussis-toxin-sensitive Gi-coupled as well as G12- and G13-coupled GPCRs (Baggiolini, 2001; Niggli, 2003; Stephens et al., 2008). Classical chemoattractants include formylated peptides that are secreted by bacteria [such as N-formylmethionyl-leucyl-phenylalanine (fMLP)], products of the complement cascade (such as C5a) and phospholipid metabolites [such as leukotriene B4 (LTB4)], whereas the family of chemokines includes chemotactic mediators that are derived from a variety of cells. As first observed for cAR1 in Dictyostelium, C5a receptors remain uniformly distributed around the plasma membrane in chemotaxing neutrophils (Niggli, 2003; Parent, 2004). Although an even distribution of receptors around the cell periphery provides optimal sensitivity to highly dynamic chemoattractant gradients, there are cases in which chemokine receptors redistribute to the front of migrating cells; such behavior characterizes CXC-chemokine receptor 4 (CXCR4) in hematopoietic progenitor cells and CC-chemokine receptor 5 (CCR5) in Jurkat cells (Manes et al., 2005).
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Signal transduction pathways and their effectors |
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TopIntroductionChemoattractants and their...Signal transduction pathways and...The cytoskeleton and its...Signal relay and chemotaxis...PerspectivesReferences |
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- and β-subunits. In both Dictyostelium and mammalian neutrophils, the β dimer acts as the main transducer of chemotactic signals and activates several downstream effectors, including adenylyl cyclase, guanylyl cyclase and phospholipase C (PLC) (Bagorda et al., 2006; Stephens et al., 2008). The Gβ stimulation is locally transduced via the activation of phosphoinositide 3-kinase (PI3K) at the front of cells in a Ras-dependent manner, although Gβ can directly regulate PI3K in neutrophils (Kolsch et al., 2008; Stephens et al., 2008). PI3K converts phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2) into phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), thereby promoting a localized PtdIns(3,4,5)P3 production. In Dictyostelium, the spatial restriction of the PtdIns(3,4,5)P3 signal to the front is ensured by the presence of PTEN (the 3'-phosphatase) at the sides and back of cells (Parent, 2004). The PtdIns(3,4,5)P3 that is locally generated and retained at the front of cells provides a binding site for a subset of PH-domain-containing proteins, which eventually translocate to the leading edge and act as nucleation factors to activate key effectors of migration (Iijima et al., 2002).
The Dictyostelium cytosolic regulator of adenylyl cyclase (CRAC) protein was the first PH-domain-containing protein that was shown to translocate specifically to the front of chemotaxing cells. CRAC, originally identified as regulator for adenylyl-cyclase activity, also regulates chemotaxis. Another PH-domain-containing protein, Akt/PKB (protein kinase B), also translocates to the cell front and controls chemotaxis and cell polarity (Bagorda et al., 2006). Interestingly, PI3K, although necessary for the chemotaxis of Dictyostelium in shallow chemical gradients, appears to become dispensable in steeper gradient conditions. Indeed, Dictyostelium cells that lack the five class I PI3Ks as well as PTEN move surprisingly well in steep gradients, suggesting that other pathways are required to control chemotaxis. Recently, phospholipase A2 (PLA2) and guanylyl cyclase were proposed to represent candidate pathways to regulate chemotaxis in parallel with PI3K signaling (Insall and Andrew, 2007; Kolsch et al., 2008). In addition, components of the target of rapamycin complex 2 (TORC2) have been shown to control Dictyostelium chemotaxis (Sasaki and Firtel, 2006), although the cellular distribution of this complex remains to be determined.
The use of Akt/PKB-GFP fusions revealed that PtdIns(3,4,5)P3 is also enriched at the leading edge of chemotaxing neutrophils (Iijima et al., 2002; Rickert et al., 2000). In addition, neutrophils that are harvested from mice that lack PI3K, the principal PI3K isoform that is activated following chemoattractant stimulation, show reduced chemotaxis, although this trait appears to be environment- and chemokine-dependent (Ferguson et al., 2007; Franca-Koh et al., 2007; Liu et al., 2007; Stephens et al., 2008). Interestingly, in contrast to Dictyostelium, neutrophils that have been isolated from mice that lack PTEN do not show significant chemotaxis defects. Instead, in these cells, the 5'-PtdIns(3,4,5)P3 phosphatase SHIP1 regulates chemotaxis – ship1–/– neutrophils behave much like PTEN-deficient Dictyostelium cells (Nishio et al., 2007). However, the cellular distribution of SHIP1 during neutrophil chemotaxis has yet to be determined. These findings provide evidence that PtdIns(3,4,5)P3 pathways are important regulators during mouse neutrophil chemotaxis.
Studies that were performed using HL-60 cells, a pluripotent human hematopoietic cell line that can be differentiated into neutrophil-like cells, showed that the PI3K-dependent PtdIns(3,4,5)P3 enrichment at the cell front is balanced by the local phosphatidylinositol phosphate kinase Iβ (PIPKIβ)- and PIPKI661-dependent PtdIns(4,5)P2 production at the back of chemotaxing neutrophils (Lacalle et al., 2007; Lokuta et al., 2007). Such a balance appears to be crucial for human neutrophil chemotaxis, as abrogation of either kinase impairs neutrophil polarization and directional migration. Furthermore, the signal transduction pathway that is activated during human neutrophil chemotaxis is dependent on the type of chemoattractants. Primary chemoattractants trigger a response that depends on p38 MAPK, whereas secondary chemoattractants act via PI3K (Heit et al., 2002). In addition, and similar to Dictyostelium, other phospholipid signaling pathways that are mediated by PLD and PLC have been shown to impact neutrophil chemotaxis, although the exact mechanism by which this occurs remains to be determined (Kolsch et al., 2008).
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The cytoskeleton and its regulators |
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TopIntroductionChemoattractants and their...Signal transduction pathways and...The cytoskeleton and its...Signal relay and chemotaxis...PerspectivesReferences |
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). In both Dictyostelium and neutrophils, SCAR/WAVE complexes are localized at the front of cells and have been shown to locally bind Rac proteins, which go on to stimulate F-actin assembly during pseudopod extension (Ibarra et al., 2005; Weiner et al., 2006). In neutrophils, Rac proteins are activated by the PH-domain-containing Rac guanine-nucleotide-exchange factors (GEFs) (P-Rex1 and Vav1) as well as DOCK2 (a DOCK180 homologue that is predominantly expressed in hematopoetic cells), the activities of which are regulated by PI3K signaling (Andrews et al., 2007; Stephens et al., 2008). In Dictyostelium, a single RacGEF, RacGEF1, has been identified (Park et al., 2004), although DOCK180 homologues are present in the genome. Although actin reorganization at the front of both Dictyostelium and neutrophils has been suggested to enhance PI3K activity, generating positive-feedback loops to reinforce polarity and directional sensing, the mechanisms by which this takes place, remain elusive (Kolsch et al., 2008; van Haastert and Devreotes, 2004).
The retraction that occurs on the trailing edge of chemotaxing neutrophils is mediated by RhoA, which is activated by G12/13 – another G protein that has been shown to mediate chemotactic processes, and by PDZRhoGEF (PDZ-domain-containing RhoGEF), a RhoAGEF. RhoA, through its effector ROCK (RhoA- and Rho-associated kinase), regulates myosin-II-mediated contractility (Meili and Firtel, 2003; Wong et al., 2007). The RhoA-dependent actomyosin contraction is in turn regulated by Rac (Pestonjamasp et al., 2006) and Cdc42, which is activated at the front of cells by the Cdc42 GEF PIX, and PAK1 (Li et al., 2003). In this manner Rac and Cdc42 control polarity by acting locally at the front to promote actin polymerization, and distally at the back (via RhoA) to mediate retraction (Van Keymeulen et al., 2006). In Dictyostelium, in which no Rho or Cdc42 homologues have been found, cell retraction is controlled by the nucleotide cGMP, which is produced by soluble guanylyl cyclase (sGC) (van Haastert and Devreotes, 2004). High cGMP levels give rise to increased myosin II phosphorylation and assembly. Myosin II assembly is also controlled by PAKa, which localizes at the back of cells. PAKa, however, is phosphorylated by Akt/PKB in a PI3K-dependent fashion (Kolsch et al., 2008). These findings highlight the importance of front-to-back crosstalk during chemotactic signaling in both Dictyostelium and neutrophils (Ridley et al., 2003) – a process that is also evident for the activation of adenylyl cyclase in Dictyostelium (see below).
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Signal relay and chemotaxis amplification |
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TopIntroductionChemoattractants and their...Signal transduction pathways and...The cytoskeleton and its...Signal relay and chemotaxis...PerspectivesReferences |
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). It is proposed that the ACA that is positioned at the back of cells provides a compartment from which cAMP is locally released to attract neighboring cells to migrate in chains.
Interestingly, in neutrophils, the release of purines (such as ATP) has been shown to occur from the leading edge of the cell (Chen et al., 2006). As a neutrophil moves towards a source of chemoattractant, ATP is released and, together with its derived adenosine, provides an autocrine feedback loop by activating transmembrane purinergic receptors, thereby amplifying chemotaxis. Mammalian neutrophils also release a variety of chemokines during migration towards sites of inflammation. For example, chemoattractants such as fMLP and C5a stimulate the production and secretion of LTB4, as well as interleukin-8. Although not much is known about the mechanisms that guide the secretion of chemokines, there is increasing evidence that signal relay is responsible for the amplification of chemotaxis and is a key regulator of inflammatory responses.
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Perspectives |
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TopIntroductionChemoattractants and their...Signal transduction pathways and...The cytoskeleton and its...Signal relay and chemotaxis...PerspectivesReferences |
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). Although the PI3K pathway is highly polarized in migrating cells and has a role in regulating chemotaxis, other parallel pathways are clearly involved. The challenge now resides in identifying additional pathways and, most importantly, in assessing how they work in concert to control polarity and chemotaxis. In this context, powerful Dictyostelium genetic screens will be invaluable and continue to provide key insight. However, as neutrophils are exposed to a complex array of chemotactic agents, more elaborate signaling cascades are surely operational in higher eukaryotes. Continued studies involving gene manipulation in mice as well as specific pharmacological inhibitors will certainly bring significant insight. |
Acknowledgments |
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Footnotes |
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References |
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TopIntroductionChemoattractants and their...Signal transduction pathways and...The cytoskeleton and its...Signal relay and chemotaxis...PerspectivesReferences |
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