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Small GTP Binding Proteins and the Control of Phagocytic Uptake

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Phagocytosis is a conserved cellular process in Eukaryotes. A multi-step process, it involves the recognition of particulate material, e.g., microbes and apoptotic cells, their F-actin-driven engulfment and the subsequent destruction of the phagocytized material in phagolysosomes. Distinct sets of small GTP-binding proteins (Rap1, Arf6, Rho and Rab proteins) control and coordinate the successive steps of the phagocytic process. Moreover, these proteins are often targeted by microbial virulence factors. This review summarizes and discusses the evidence implicating Ras, Rho, Arf and Rab-family GTPases in the signalling pathways driving particle recognition and uptake.

Definitions

Phagocytic uptake: a restricted view of phagocytosis, limited to the binding and internalisation of particulate material.

Small GTP-binding protein: signalling molecule and molecular switch (a.k.a. small GTPase, Ras-subfamily member) that is active when bound to GTP and inactive when bound to GDP.

Downstream effector: protein that binds specifically to the active, GTP-bound form of the small GTP-binding proteins and mediates its function.

Virulence factor: a product that contribute to the ability of a microbe to cause disease.

Toxin: a virulence factor that is secreted extracellularly.

Introduction

The last ten years have witnessed amazing progress in the understanding of the molecular basis of phagocytosis. Not only have the fundamental similarities between conventional macrophage phagocytosis and bacterial invasion of ‘non-professional’ phagocytes been recognized but high throughput technologies, new genetic systems1 and the recent developments in cellular microbiology have contributed to draw the picture of a strong conservation in the mechanisms that underlie phagocytosis. The identification of new phagocytic receptors and signalling cascades has refined our understanding of the common features and individual variations amongst phagocytic pathways.

This review will focus on the role of small GTP-binding proteins in phagocytic uptake. Ras-like GTPases are a vast family of > 100 molecular switches that control a plethora of essential aspects of cell biology, including cytoskeletal remodelling and vesicular trafficking, in a GTP-dependent manner. Their function, mediated by downstream effectors that bind specifically to the GTP-bound, active Ras proteins is tightly regulated by several classes of molecules: activators (Guanine nucleotide Exchange Factors, GEFs) and inactivators (GTPase-activating proteins, GAPs). Importantly, the relatively simple biochemistry of Ras-like GTPases has allowed the development of a variety of tools (e.g., epitope-tagged wild-type GTPases or mutant alleles, either dominant negative -thought to titrate endogenous GEFs- or constitutively active -thought to mimic the function of active GTP-binding proteins-) and assays (e.g., GTP-pull down assays, that use the GTPase-binding domain of specific downstream effectors to monitor the levels of active GTP-binding proteins in cells) for the analysis of GTPase function in cells.2

Rho Proteins and Actin Polymerisation

The most universal feature of phagocytic uptake is its actin-dependency and, indeed, actin polymerisation is the driving force that underlies both the zipper-like capture of phagocytic targets by phagocytes and the triggered intake of invasive bacteria by non professional phagocytes.3 Unsurprisingly, like most other actin-dependent processes, phagocytosis generally requires the activity of Rho GTP-binding proteins, the evolutionarily conserved proteins that control cytoskeletal dynamics.4 Therefore, whether a given phagocytic object is uptaken or not will depend primarily on how the phagocytic encounter affects Rho GTPase activity in host cells. However, which specific Rho family member(s) and regulators control actin polymerisation and uptake will vary.

Type I Phagocytosis (Rac/Cdc42)

The best understood phagocytic pathway links Fc receptors (FcR) on mammalian macrophages to the uptake of immunoglobulin (Ig)-opsonized targets. Referred to as type I phagocytosis, it involves the extension of pseudopods around the particle. FcR-mediated phagocytosis (mediated by either FcγR or FcεR), a known tyrosine kinase-dependent process, requires Cdc42 and Rac -but not Rho- activity, as proven using Clostridium difficile toxin B and overexpressed inhibitory constructs.5-7 Rac and Cdc42 are also recruited to the site of particle binding during phagocytosis.7 Moreover, phagocytic ligation of FcγR increases the levels of active Rac and Cdc42 in cells, suggesting that it activates these GTPases.8-10 Finally, Rac and Cdc42 are activated independently of each other downstream of FcγR, respectively via the Rac GEF Vav and via an unknown Cdc42 exchange factor (fig. 1).8

Figure 1. Activation of Rho, Rac and Cdc42 controls actin polymerization during phagocytosis.

Figure 1

Activation of Rho, Rac and Cdc42 controls actin polymerization during phagocytosis. Left, a general model for phagocytic signalling. Phagocytosis generally involves the receptor-mediated, GEF-dependent activation of one or more Rho GTP-binding proteins, (more...)

Likewise, Rac-1 and Cdc42 but not Rho control phagocytosis of Neisseria gonorrhoae by epithelial cells, after initial recognition of the adhesin/invasin Opa57 by CEACAM3, a member of the CEACAM (Carcinoma Embryonic Antigen-related Cellular Adhesion Molecules) family of receptors, which like phagocytic FcRs, contains an ITAM (Immunoreceptor Tyrosine Activated Motif ) sequence in its cytosolic domain.11 Similarly, interaction of Opa52-expressing N. gonorrhoae with human phagocytes through another CEACAM family member, CD66 requires Rac activity; in our opinion the possibility that Cdc42 is also involved has not been formally ruled out in this study.12 Other bacteria bypass the need for receptor-induced activation of the Rho GTPases and inject bacterial effectors that will directly activate endogenous Rho GTPases in the host cell and thereby induce their uptake.13 For example, Salmonella typhimurium induces a trigger-like uptake mechanism by injecting SopE/SopE2, two GEFs for Cdc42 and Rac in the target cell (fig. 1).14 Remarkably, these GEFs do not display the conventional Dbl homology domain that, in mammalian GEFs, is responsible for catalyzing nucleotide exchange.15

In mammalian cells, apoptotic cell (AC) uptake is another example of a Cdc42/Rac-dependent, Rho-independent process (fig. 1).16,17 GTP-pull down analysis has shown the reciprocal regulation of Rho and Rac activities in mammalian cells upon AC phagocytosis.18 Unlike FcγR-mediated uptake, however, the activation of Rac induced upon AC binding is controlled by an unconventional bipartite exchange factor consisting of Dock180 and Elmo-1, that would be recruited to the site of ingestion by a Dock180-binding partner, CrkII.19,20 A very similar signalling pathway operates in C. elegans, where the nematode orthologs of CrkII, Dock180, Rac and Elmo, called respectively CED-2, 5, 10 and 12 control apoptotic cell uptake.21-24 Nevertheless, in the nematode as in other non-mammalian organisms, Rac—not Cdc42—seems to be the major regulator of phagocytic uptake. RacC controls phagocytosis in Dictyostelium,25 while the use of SCAR mutants suggests a role for Rac in Drosophila phagocytosis.26 SCAR is indeed a conserved regulator of actin polymerisation downstream of Rac.27,28

Altogether, analysis of the phagocytic pathways that are associated with the formation of protrusions (type I) has revealed a common requirement for Cdc42 and Rac function in mammalian cells but only for Rac in Dictyostelium, an organism that lacks a clear Cdc42 homolog29 and in C. elegans, where a Cdc42 homolog has been identified.30 One may wonder what is the exact function of Cdc42 during mammalian phagocytosis as local activation of Rac, but not Cdc42 at the plasma membrane is sufficient to promote uptake.31 Nonetheless, the main classes of protrusion-associated phagocytic pathways are regulated by Rac (plus Cdc42 in mammalian cells), with no apparent role for Rho in uptake, whilst they differ in the specific signalling pathways and GEFs that control Rac (and maybe Cdc42) activation (fig. 1).

Type II Phagocytosis (Rho)

A second class of phagocytic events has been identified, that do not involve such a dramatic extension of protrusions.32 Type II phagocytosis is mediated in mammals by the complement receptor 3 (CR3, Mac-1, CD11b/CD18, αMβ2), which signals to the actin cytoskeleton in a Cdc42/Rac-independent but Rho-dependent manner. Rho (but not Rac or Cdc42) is also recruited to forming CR3 phagosomes.7 The molecular mechanisms underlying Rho recruitment and function at phagosomes are still poorly understood, although Rho kinase, a Rho effector is clearly mediating Rho effects on the cytoskeleton during phagocytosis (fig. 1).33

G-protein-coupled receptor proteinase activated receptor-2 (PAR-2) mediates melanosome uptake in human keratinocytes in a Rho- and Rho kinase-dependent manner.34 Whether phagocytosis through this receptor is the second known example of type II phagocytosis will have to await further investigation. In particular, the roles of Rac and Cdc42 should be tested in this model.

Variations and Anomalies

A number of other, opsonin-independent phagocytic encounters illustrate variations on the type I/Rac-Cdc42 and type II/Rho paradigm. Receptor-mediated uptake of the parasite Leishmania amazonensis amastigotes by Chinese hamster ovary cells is an actin-, tyrosine kinase-, PI3-kinase- and myosin-dependent process that is accompanied by activation of Cdc42 but not Rac and that requires Rho and Cdc42 but not Rac function.35 Likewise, the activation of both Rho and Cdc42 but not Rac was shown to be necessary for the internalization of virulent encapsulated N. meningitidis following their type IV pilus-mediated adhesion to vascular endothelial cells.36 In contrast to the trigger-like mechanism induced by Salmonella typhimurium, Listeria monocytogenes actively promotes its entry into mammalian cells by inducing a zipper-like uptake process.37 Listeria entry into epithelial cells is therefore likely to resemble conventional phagocytosis and to involve a receptor-mediated, Rho GTPase-dependent uptake process, accompanied by GTPase recruitment and activation. In line with this, YopE -a Yersinia type III secretion system (TTSS) effector with GAP activity against Rho, Rac and Cdc42 (see below)- blocks Listeria uptake.38 Moreover, in non phagocytic cells, the uptake of beads coated with internalin B -one of the two main surface expressed bacterial proteins that mediate Listeria entry- is independent of Rho but requires Rac (and in some cell lines also Cdc42) activity.39 By contrast, all three prototypical Rho GTPases (Cdc42, Rac and Rho) control the trigger-like invasion of epithelial cells by Shigella flexneri.40 Cdc42 and Rac are required for actin polymerization at the site of Shigella entry and expression of the TTSS effector IpaC in host cells is sufficient to induce Cdc42/Rac-mediated cytoskeletal changes.41 More recently, it was demonstrated that VirA, a TTSS effector protein essential for Shigella invasion42 binds tubulin, promotes microtubule destabilization, triggers Rac activation (through an unknown mechanism) and Rac1-dependent membrane ruffling.43 Rho allows the transformation of the initial surface extensions into a more stable adhesive-like structure that is permissive for entry.44 Rho, Rac and Cdc42 activities also control the uptake of Brucella abortus by human epithelial cells and invasin-mediated uptake of Yersinia enterocolitica by professional phagocytes.45,46 However, adhesin-mediated, β1 integrin-dependent invasion of epithelial cells by Y. pseudotuberculosis, a process accompanied by the recruitment of Rho, Rac and Cdc42 to the site of particle binding, only requires Rac function.47,48 The origin of these discrepancies in Yersinia-induced signalling and uptake remains unclear.

Importantly, the central role of Rho GTPases in phagocytosis explains why they are targeted by so many bacterial toxins and virulence factors.49,50 Toxins secreted by members of the Clostridium genus, and some strains of Escherichia coli, Yersinia and Bordetella modulate bacterial uptake by activating or inactivating specific sets of small GTPases, either from the Rho subfamily, or from both the Rho and Ras subfamilies.50 Unsurprisingly, toxins that inhibit Rho activity block phagocytic uptake while the activating toxins promote phagocytosis (fig.1).13,50 Likewise, several TTSS effectors directly perturb the Rho GTPase activation cycle. The Yersinia cystein protease, YopT, inactivates Rho, Rac and Cdc42 in vivo, by cleaving both the GTPand GDP-bound forms of the protein and extracting them from membranes.51-54 Yersinia YopE, and Pseudomonas aeruginosa ExoS and ExoT, display RhoGAP activity in vitro and can inactivate RhoA, Rac and Cdc42, but not Ras or Ral.55-57 Therefore, these bacteria are able to inhibit their phagocytosis by forcing the conversion of Rho family members to their GDP-bound, inactive states, preventing them from activating downstream effectors and actin polymerisation.

In striking contrast to the examples listed above, microbial pathogens like enteropathogenic E. coli (EPECs), exert their early effects on the cytoskeleton not by acting on Rho GTPase cycling but rather by bypassing Rho proteins. When EPECs interact with epithelial cells, Tir is inserted into the host cell plasma membrane and directs the formation of actin-rich pedestals, in a Nck-, N-WASP- and Arp2/3-dependent manner.58 However neither Rho, Rac, nor Cdc42 are required for pedestal formation. It is worth mentioning that one or more Rho GTPases are subsequently involved in EPEC invasion of epithelial cells, as it is a toxin B-sensitive process.59 Finally, several protozoan parasites enter host cells independently of the host cell actin-dependent internalization machinery and Rho GTPase activity. Rather, they mobilize their own secretory organelles, such as the micronemes, rhoptries and dense granules of Plasmodium and Toxoplasma, in order to deliver microbial products at the host-pathogen interface and invade the host cell cytosol. For example, during Trypanosoma cruzi invasion, binding of an unidentified parasite product to host cells causes an increase in intracellular calcium, which destabilizes the cortical actin cytoskeleton and induces the microtubule-mediated recruitment and fusion of lysosomes to the plasma membrane.60 No data is available on host cell Rho GTPases in this context, although they are obviously very unlikely to be involved. A very surprising result comes from another protozoan, Entamoeba histolytica, in which increased Rac activity has been correlated with inhibition of phagocytosis.61

Regardless of their Rho GTPase-dependency, most of the actin-driven phagocytic pathways we discussed converge onto the Arp2/3 complex to promote a local and oriented F-actin polymerization at the site of particle binding (fig. 1). This is true for example for type I and type II phagocytosis62,33 in mammals, and in Dictyostelium.63 This is not surprising, as several mechanisms can account for Arp2/3 recruitment and activation, all relying on signal-induced exposure of the Arp2/3-binding, acidic domain of an adapter protein.64 The best understood example of such an adapter is the Wiskott-Aldrich syndrome protein (WASp), a Cdc42 downstream effector that mediates activation of the Arp2/3 complex in a phosphatidylinositol 4,5-bisphosphate-dependent manner65 and regulates type I phagocytosis in mammals.66,67

Ras Proteins and Receptor Activation

Whereas the evidence linking Rho GTPases to phagocytic uptake is compelling, the role of other small GTP-binding proteins is far less understood and often restricted to one receptor-mediated pathway. Several members of the Ras subfamily of GTPases have been linked with phagocytic uptake in mammalian and Dictyostelium cells. Importantly, several clostridial toxins can inactivate Ras proteins -in addition to Rac- and cause inhibition of phagocytosis as well as complete rounding of the cell body and detachment from the substratum.68-70

CR3, an integrin expressed at the surface of mammalian phagocytes and involved in phagocyte adhesion and motility mediates binding and type II-phagocytosis of particles opsonized with the complement fragment C3bi (see above).71 CR3 is constitutively inactive in resting phagocytes and an activation signal is required to enable binding of most of the CR3 ligands.72,73 Binding of C3bi-opsonised particles and subsequent CR3-mediated phagocytosis by activated macrophages are blocked by a dominant negative mutant of Rap1. Conversely, a constitutively active Rap1 mutant induces a two- to threefold increase in the number of C3bi-opsonised particles that bind to resting macrophages, thereby bypassing the need for an activation signal. Altogether, these results show the essential role of Rap1 in CR3 activation, a prerequisite step for the uptake of complement-opsonised particles.72 However, the mechanisms controlling CR3 activation downstream of Rap1 are still unknown; in particular whether Rap1 controls a change in integrin affinity or avidity is unclear.74 By contrast, Rap1 activity does not influence the binding of IgG-opsonised targets to FcγR72, a process known to be constitutively active.75 Although the requirement for Rap1 activation in mammalian phagocytosis is at the moment restricted to the αMβ2/CR3 receptor, the general role of this small GTP-binding protein in adhesion-related processes76 makes it likely that other integrin-dependent phagocytic events mediated by mammalian phagocytes, such as αVβ3 and αVβ5-mediated apoptotic cell uptake77-79 will be controlled by Rap1.

Interestingly, DdRap1, the Dictyostelium discoideum Rap1 homolog80 is also essential for phagocytosis.81 D. discoideum strains expressing constitutively active or wild type Rap1 internalise twice as many latex beads or E. coli bacteria as compared to the wild type strain. However, a strain expressing dominant negative Rap1 shows a 50% decrease in phagocytosis compared to the wild type strain. Although D. discoideum does not express integrins,82 other adhesive receptors have been suggested to control phagocytosis, an EDTA-sensitive process in this organism. DdCad-1 (Ca2+-dependent cell-cell adhesion molecule-1) and two nine-transmembrane receptors, Phg1 and SadA (Substrate adhesion-deficient A) all localise to phagosomes during uptake. However, only Phg1- and SadA- (not Dd-Cad-1)-deficient mutants show a phagocytic defect.82-84 Therefore, the function of Rap1 could be a common, conserved requirement during phagocytosis through adhesion receptors, both in Dictyostelium and in mammalian cells.

Although first described in experiments designed to identify genes that could revert the phenotype of K-Ras- transformed fibroblasts,85 Rap1 has since been found to control a complex set of functions, most of which relate to adhesion. In this respect, the regulation of CR3 receptor activation during macrophage phagocytosis is just one of the adhesion-related functions of Rap1.76 Interestingly, in yeast cells, the Rap1 homolog, Bud1p accumulates at sites of polarized growth and budding and is involved in recruiting and activating Cdc24p, a Cdc42 GEF.86,87 Rap1 could serve a similar, polarity-related function during phagocytosis, i.e., determine the direction of engulfment of particles, like a biological compass, and control the recruitment and activation of Rho-family GTPases : RacC in Dictyostelium25,81 and Rho during CR3-mediated phagocytosis in mammalian macrophages.7

Unlike Rap1, the evidence linking Ras to phagocytosis is scarce and contradictory. On the one hand, when dominant negative H-Ras was microinjected into mouse macrophages, CR3-mediated phagocytosis was still observed,72 suggesting that H-Ras activation plays no role in this process. On the other hand, the Dictyostelium H-Ras homolog, RasS was shown to regulate phagocytosis and cell motility: RasS-null cells show impaired fluid phase endocytosis and phagocytosis, but enhanced locomotion.88 As mentionned above there is a strong correlation between adhesion and phagocytosis in Dictyostelium, where cell motility suppresses phagocytic cup formation.88 Overall these results would suggest that there is no direct function for Ras in phagocytic uptake, although it does not exclude a role for Ras in other aspects of the phagocytic process (e.g., phagocytosis-induced transcriptional activation, phagocyte survival).

The other two Ras-family members that have been examined in the context of phagocytosis are R-Ras and RalA, although none of them appears to play a fundamental role. Expression of constitutively active R-Ras but not RalA leads to phagocytosis of C3bi-opsonised particles by resting macrophages.89 However expression of dominant negative R-Ras or RalA in activated macrophages has no effect on CR3-mediated phagocytosis.72 This suggests that R-Ras can promote CR3 activation, as reported for other integrins,90-92 but is not required during CR3-dependent uptake.

Together, these results suggest a conserved albeit not universal role for a few Ras-subfamily proteins in phagocytosis. Rap1 —and possibly Ras- control signalling pathways that enable adhesion-like receptors to perform their phagocytic function.

Arfs and Rabs and the Delivery of Membrane to Forming Phagosomes

It has been realised for a long time that phagocytosis would ultimately result in the net loss of plasma membrane if a mechanism ensuring membrane replenishment did not exist.93,94 There is now strong evidence to suggest that particle uptake requires the delivery of endomembrane to forming phagosomes.95,96 In all eukaryotic cells, vesicular trafficking between subcellular compartments and to the plasma membrane is controlled by Rab and Arf-subfamily GTPases.2 So far, three of these small GTP-binding proteins have been implicated in phagocytic uptake. Interestingly, many more Rab proteins (e.g., Rab2-5, 7, 11, 14) were detected on mammalian phagosomes.97 However some of them like Rab2 (involved in ER to Golgi and intraGolgi transport), Rab5 (early endosome fusion) and Rab7 (a late endosome marker) are more likely to be involved in the maturation -rather than the formation of phagosomes.98,99

In Dictyostelium, the activity of RabD, a close homolog of mammalian Rab14, conditions the rate of phagocytic uptake.100 Whether these results are solely explained by a positive role for RabD, a marker of the endolysosomal and contractile vacuole systems, on membrane delivery to forming phagosomes, or whether overexpressed RabD mutants have also a general effect on the size or binding ability of Dictyostelium cells, remains unclear. Rab11 was also involved in phagocytosis, both in Dictyostelium and in mammalian phagocytes. However, inhibition of Rab11 activity has opposite effects on uptake in the two cell systems. In single cell amoebae, where Rab11 associates primarily with the contractile vacuole system and not with endosomes, expression of a dominant negative Rab11 allele doubles the rate of particle association to cells.101 By contrast, in mammalian cells Rab11 regulates endosome recycling and Rab11 activity is required for optimal FcγR-mediated phagocytosis, as dominant negative Rab11 halves the number of IgG-opsonized red blood cells (RBCs) that are taken up.102 These results are compatible with a model where Rab11 activity influences uptake by controlling the availability of distinct sources of intracellular membrane : the vacuolar system, which enlarges when dominant negative Rab11 is expressed in Dictyostelium, and the Rab11-controlled recycling endosome pool in macrophages. Finally Arf6, a known regulator of membrane trafficking, cell polarity, adhesion and motility103 is the sole Arf-family member to be involved in phagocytic uptake. Indeed, phagocytosis is insensitive to brefeldin A, a fungal metabolite that inhibits most high molecular weight ArfGEFs and therefore the functions mediated by Arf1-5.104 Whilst Arf6 gets activated following FcγR ligation and also recruited to early phagosomes, overexpression of dominant negative Arf6 mutants blocks FcγR-mediated uptake.10,104 Although Arf6 was first thought to play a dual role in actin polymerization and membrane delivery during uptake, a recent study has shown that Arf6 function is essential for pseudopod extension around IgG-opsonized RBCs but dispensable for actin polymerisation (fig. 2). Specifically, Arf6 controls the exocytosis of VAMP3-positive recycling endosomes at nascent FcγR phagosomes.10

Figure 2. Distinct small GTPase subfamilies control different steps during phagocytosis.

Figure 2

Distinct small GTPase subfamilies control different steps during phagocytosis. In this theoretical model, particle binding induces two GTPase-mediated cascades that coordinate phagocytic uptake by controlling actin polymerization and membrane delivery (more...)

A handful of studies have recently indicated that Arf6 and Rab GTPases play a role in uptake, by controlling the recruitment of membrane to extending pseudopodia. It will be interesting to see whether mammalian Rab14 and other Rab proteins (e.g., Rab3, a known regulator of exocytosis) also influence the delivery of membrane during phagocytosis. Another important question to address is the universality105 and conservation of Arf6/Rab involvement in the different phagocytic systems that have become available. A more daunting task will be to understand both the signals that activate Arf6, Rab11 and possibly other Rabs and the mechanisms by which these GTP-binding proteins coordinate membrane recruitment during uptake.

Conclusions and Perspectives

The parallel analysis of the molecular basis of phagocytosis and bacterial pathogenesis has revealed a major role for several small GTP-binding proteins in regulating particle uptake. Remarkably, distinct GTPase subfamilies control successive steps of the phagocytic process (fig. 2). First, a Ras-like GTPase, Rap1, controls the ability of activation-dependent adhesion receptors (e.g., integrin-family members like CR3) to bind their ligand. Second, once particles have bound to host cells, Rho proteins control the remodelling of the actin cytoskeleton that drives uptake. Generally, particle binding triggers the local recruitment and activation of one or several Rho proteins, which mediate actin polymerisation in an Arp2/3-dependent manner. Which particular signalling pathway and Rho protein are activated during uptake will depend, however, on the nature of the initial receptor/ligand interaction at the cell surface. In line with their conserved, essential role in phagocytosis, Rho proteins and the pathways they control are frequently targeted by bacterial virulence factors and toxins, which thereby influence -positively or negatively- bacterial uptake. Third, optimal phagocytosis requires the delivery of endosome-derived membranes to forming phagosomes, a process controlled by an Arf-family member, Arf6 and by Rab proteins. The available evidence suggests that the GTPase-controlled pathways leading to membrane delivery and actin polymerisation are independently activated upon particle binding. How the distinct signalling cascades that mediate the different steps of the uptake process are activated and coordinated remains unknown. It is clear, however, that small GTP-binding proteins play a crucial role not only in phagocytic uptake but also in several responses associated to phagocytosis, such as the activation of the NADPH oxidase106,107 and phagosome maturation (fig. 2). There is little doubt that the detailed analysis of small GTPase function during phagocytosis will continue to further our understanding of this essential cell function.

Acknowledgements

The authors thank Céline Cougoule for critical reading of the manuscript. Research in the Caron laboratory is supported by grants from the Wellcome Trust and the BBSRC (Biotechnology and Biological Sciences Research Council).

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