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(Journal of Leukocyte Biology. 2000;68:593-602.)
© 2000 by Society for Leukocyte Biology

Cellular signaling in macrophage migration and chemotaxis

Gareth E. Jones

The Randall Centre for Molecular Mechanisms of Cell Function, King’s College London, United Kingdom

Correspondence: Gareth E. Jones, The Randall Centre for Molecular Mechanisms of Cell Function, King’s College London, New Hunt’s House, Guy’s Campus, London SE1 1UL, UK. E-mail: gareth.jones{at}kcl.ac.uk


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ABSTRACT
 
Whereas most cells in adult tissues are fixed in place by cell junctions, leukocytes are motile and able to migrate actively through the walls of blood vessels into surrounding tissues. The actin cytoskeleton of these cells plays a central role in locomotion, phagocytosis, and the regulation of cell shape that are crucial elements of neutrophil and monocyte/macrophage function. This review will concentrate on how macrophages in particular control the actin cytoskeleton to generate cell movement and the shape changes required for chemotaxis. It has recently become evident that a complex of seven proteins known as the Arp2/3 complex regulates the assembly of new actin filament networks at the leading front of moving cells. Proteins of the Wiskott-Aldrich Syndrome Protein (WASP) family bind directly to the Arp2/3 complex and stimulate its ability to promote the nucleation of new actin filaments. Upstream of the WASP family proteins, receptor tyrosine kinases, G-protein-coupled receptors, phosphoinositide-3-OH kinase (PI 3-kinase), and the Rho family of GTPases receive and transduce the signals that lead to actin nucleation through WASP-Arp2/3 action. Although many gaps remain in our understanding, we are now in a position to consider completing signaling pathways that are initiated from outside the cell to the actin rearrangements that drive cell motility and chemotaxis.

Key Words: phosphoinositide 3-kinases • GTPases • signal transduction • actin cytoskeleton • cell polarity • cell locomotion • review


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INTRODUCTION
 
The chemoattraction of macrophages and neutrophils into tissues is an essential step in the host response to infection. It is commonly held that this so-called innate or nonspecific immune response protects us from at least 98% of the pathogens we encounter, so there is little doubt that the migratory capacity of these leukocytes is of fundamental importance to our survival. Although the dynamics of cell migration are most frequently analyzed in tissue-cultured fibroblasts [1 , 2 ], there are fundamental similarities in the locomotory steps within all vertebrate cells that suggest that they share a common motile machinery. This concept is best demonstrated by the observation that isolated cultured macrophages display short surface protrusions, termed filopodia or microspikes, which are extensions of about 0.1–0.2 µm in diameter and up to 20 µm in length, supported by a core of bundled actin filaments (microfilaments). In both macrophages and fibroblasts filopodia support thin veils or sheets of membrane-enclosed cytoplasm, termed lamellipodia, containing a meshwork of myosin II-associated microfilaments. In macrophages, as in other cell types, the actin meshwork within the lamellipodia, in association with numerous structural and regulatory proteins, constitutes the molecular motor for cell locomotion. Interested readers are referred to the excellent core reviews cited above plus more recent material [3 ].

The locomotory apparatus of most cells works against cell-to-substratum adhesions usually referred to as focal contacts or focal adhesions. These structures link adhesive extracellular matrix proteins to myosin II-containing bundles of cytoplasmic microfilaments (stress fibers) via members of the integrin family of proteins [4 ]. While integrin-mediated contacts to the substratum also exist in macrophages, these take two forms: focal complexes that are structurally related to focal contacts but lack stress fibers [5 ], and podosomes, distinct circular structures that seem to be largely restricted to cells of the myeloid lineage [6 , 7 ].

The forward movement of macrophages can be divided into steps: protrusion of filopodia and lamellipodia at the leading front, adhesion of the protruding edge to the substratum via focal complexes, contraction of the cytoplasmic actomyosin, and finally release from contact sites at the tail of the cell [8 , 9 ]. A number of molecular events need to be integrated in order to allow a cell to move across a substratum, and it appears that this coordination is largely mediated by the actin microfilaments within the cytoplasm. In addition, the actin cytoskeleton is a key mediator of cell polarization and the directed migration of macrophages toward chemoattractant (chemotaxis). This review will examine the evidence that supports these conclusions, dealing with aspects of chemoattractant signals, regulatory intracellular signaling pathways, and cytoskeletal reorganization as appropriate.


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CHEMOATTRACTANT SIGNALS AND RECEPTORS
 
Leukocytes sense a wide variety of chemoattractants that can in principle guide their migratory path within tissues [10 , 11 ]. Cells are responsive to bacterial components, leukotrienes, complement factors, and chemokines, an ever-expanding family of attractants controlling leukocyte migration [12 ]. All these attractants in both neutrophils and monocytes/macrophages interact with specific serpentine (heptahelical) receptors [13 ], embedded in the plasma membrane, that transduce ligand-induced signals by coupling to heterotrimeric G proteins (Fig. 1 ). The G protein complex dissociates into {alpha} and ß{gamma} subunits, which in turn bind and activate target enzymes such as phospholipase C, phosphoinositide 3-kinase (PI 3-kinase), or adenyl cyclase. These enzymes generate intracellular messengers that initiate a cascade of events that culminate in the cytoskeletal and chemoattraction response to ligand-induced receptor activation. Similar systems are also found in primitive organisms such as the free-living amoeba Dictyostelium discoideum [14 ], demonstrating the near-universality of this signal transduction system. Five recent articles [15 16 17 18 19 ] together provide convincing evidence of a role for PI 3-kinase in serpentine receptor signaling and chemotaxis. At least four Class I PI 3-kinase isoforms exist in mammalian cells [20 ], but only one form, a single Class IB variant containing the p110{gamma} catalytic subunit complexed with a 101-kDa regulatory protein, is thought to interact with G-proteins in leukocytes. Because leukocyte chemokine responses are sensitive to pertussis toxin, it has been assumed that chemokine receptors are coupled to a G{alpha}i, and a large number of observations support this view [13 ]. However, this assumption requires modification because there are many data in the literature implicating not only other families of G-protein {alpha} subunits in signaling [21 ], but also Gß{gamma} subunits [22 ]. Whereas some have reported that Class IB PI 3-kinase is responsive to activation by G{alpha} subunits [23 ], others have shown that p110{gamma} becomes activated through an interaction with the ß{gamma} subunits [24 ]. Whatever the case, all appear to converge on a common pathway where the outcome will lead to the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) by activated PI 3-kinase. As a result, phosphatidylinositol-3,4,5-triphosphate (PIP3) is generated (Fig. 1) . The work cited earlier [15 ] on mice lacking the p110{gamma} catalytic subunit of PI 3-kinase convincingly show that leukocytes lacking this G-protein-specific isoform are unable to produce PIP3 and that this has a striking effect on the ability of macrophages and neutrophils to migrate. Chemotaxis mediated via serpentine receptors is severely reduced and there was a general failure to clear bacteria from the peritoneal cavity [17 ].



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  		Figure 1. Early signal transduction events mediated through serpentine receptors. Heterotrimeric G-proteins are made up of an {alpha}, ß, and {gamma} subunit, with the {alpha} subunit being the GDP/GTP binding module. In the GDP-bound form, the {alpha} subunit interacts with the ß and {gamma} subunits to form an inactive heterotrimer that binds to the serpentine receptor. Ligand (chemokine) binding to the receptor induces a conformational change that results in exchange of GDP for GTP on the {alpha} subunit, inducing its dissociation from both the receptor and the Gß{gamma} subunit. The free G{alpha} and Gß{gamma} subunits then interact with and modulate the activity of target proteins such as the Class 1B p101/p110{gamma} PI 3-kinase. Having been recruited to the plasma membrane, PI 3-kinase can now catalyze the production of PIP3 from PIP2.

Although it is commonly assumed that the chemotactic behavior induced in leukocytes will act through serpentine receptors [25 ], monocytes, and macrophages at least are also capable of responding to chemoattractants that signal through surface receptor tyrosine kinases [26 ]. This type of receptor (Fig. 2 ) is linked to the signal transduction pathways that regulate mitogenesis and cell differentiation, and indeed monocytes and macrophages posses a canonical receptor tyrosine kinase that regulates just these parameters: colony-stimulating factor-1 receptor (CSF-1R) [27 , 28 ]. However, it was shown some time ago [29 , 30 ] that the actin cytoskeleton was also a target for CSF-1. Re-addition of CSF-1 to quiescent BAC1.2F5 macrophages stimulates rapid cytoskeletal reorganization and cell motility within a few minutes, followed by chemotactic migration up a gradient of diffusing cytokine [31 ]. Given the fact that major sources of endogenous CSF-1 include activated endothelia and tissue fibroblasts as well as macrophage-recruiting mammary gland carcinomas [32 ], the chemotactic properties of this cytokine for macrophages and monocytes is likely to be physiologically significant. Unlike serpentine receptors, receptor tyrosine kinases such as CSF-1R directly interact with a host of substrates after autophosphorylation induced by ligand binding, although in CSF-1-treated mouse macrophages, PI 3-kinase is the major protein associated with the activated receptor [33 ]. A full review of the biology of CSF-1 signal transduction is available [27 ], but it is worth emphasizing that three Class IA isoforms of PI 3-kinase are involved. The p110 subunits in these PI 3-kinases exist in complex with a p85 protein that has two Src-homology-2 (SH2) domains (Fig. 2) . The latter bind to phosphorylated tyrosine residues found on activated CSF-1R, thus allowing translocation to the plasma membrane where their lipid (such as PIP2) and other substrates are found [34 ]. All mammalian cells so far examined express at least one Class IA PI 3-kinase isoform: p110{alpha} and p110ß are widely distributed in tissues, but p110{delta} is normally restricted to leukocytes. It was shown earlier that CSF-1R induces direct interaction of PI 3-kinase (via its p85 subunit) with the SH2/SH3 adaptor protein Grb2 [35 ]. More recently, we found that although all three Class IA p110 isoforms were equally recruited to activated CSF-1R, subsequent signaling to the actin cytoskeleton of macrophages was differentially regulated. Antibody against p110{alpha} blocked CSF-1-induced DNA synthesis but did not affect CSF-1-induced actin rearrangements or cell migration. However, antibodies against p110ß and p110{delta} had the converse effect, with the latter isoform completely abrogating cell migration [36 ]. As was described for serpentine receptors, the net result of PI 3-kinase activation through receptor tyrosine kinases is the generation of PIP3 (Fig. 2) .



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  		Figure 2. Early signal transduction events mediated through receptor tyrosine kinases. Homodimers of cytokine (such as CSF-1) induce a rapid sequence of changes. Ligand-induced covalent dimerization of receptor leads to autophosphorylation at a number of tyrosine residues on the cytoplasmic tail, which initiates signaling events that precede the rapid internalization and subsequent degradation of receptor-ligand complexes. Multiple signaling events occur on activated receptors, including recruitment of Class 1A PI 3-kinase isoforms via binding of the p85 subunit to SH2 binding sites created on the receptor by autophosphorylation. Once again, recruitment to the plasma membrane of any of the p110 catalytic subunits results in the generation of PIP3.

PIP3 is a target for many pleckstrin-homology (PH) domain-containing proteins [37 ], which activate kinases and small GTPases. PIP2- and PIP3-binding PH domains are found in a diverse array of proteins, including nucleotide-exchange factors (e.g., Vav, GRP1, ARNO, Tiam-1, Sos1), GTPase-activating factors (e.g., GAP1m), phospholipases (e.g., PLC{gamma}2), protein kinases (e.g., PKB, Btk, PDK1), and adaptor proteins [38 ]. As will be described later, these are important components in the regulation of the actin cytoskeleton leading to the migration response of cells.


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RHO FAMILY PROTEINS
 
Small GTPases of the Rho family are pivotal regulators of signaling networks that are activated by chemokine and cytokine receptors as well as other receptor types [39 ]. An introduction to these proteins is provided below, but for those who wish to see more detail, many excellent reviews exist and the reader is referred to recent examples [40 ].

The Rho family is part of the Ras superfamily of small (around 21 kDa) GTP-binding proteins. To date, 15 mammalian members of the Rho family have been identified: Rho (A, B, C, D, E, G), Rac (1, 2, 3), Cdc42 (two alternatively spliced variants of the same gene with different carboxy-terminal sequences), Rnd1/Rnd6, Rnd2/Rho7, TC10, and TTF. Of the mammalian proteins, the best characterized for their ability to regulate actin organization are RhoA, Rac1, and Cdc42. Rho was the first member of this family to be cloned in 1985, followed a few years later by Rac and Cdc42. The most frequently used tool for studying Rho function is C3 transferase, an exoenzyme from Clostridium botulinum, which ADP-ribosylates and inactivates Rho [41 ]. Treatment of many cell types with C3 transferase induces loss of stress fibers, and this was the first indication that Rho influences the actin cytoskeleton. Subsequently, Rac was also shown to regulate actin organization, and at the same time was independently purified as an essential cofactor for the NADPH oxidase in phagocytic cells [42 ].


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RHO FAMILY PROTEINS AND THE ACTIN CYTOSKELETON
 
The roles of Rho, Rac, and Cdc42 in regulating actin organization were first characterized in detail in Swiss 3T3 fibroblasts. These cells have proven to be a good model system for analyzing rapid changes in the actin cytoskeleton, because when confluent and serum-starved they lose practically all of the two most prominent actin filament-containing structures found in fibroblasts: stress fibers and lamellipodia. Stress fibers are bundles of actin filaments associated with myosin II filaments and other proteins, forming contractile fibers. They terminate at the plasma membrane in focal adhesions, where transmembrane integrins are clustered and associate both with extracellular matrix proteins outside the cell and with a large number of proteins inside the cell [43 ]. Lamellipodia are broad, highly dynamic membrane protrusions that extend and retract through a combination of actin polymerization at the plasma membrane, depolymerization within the cytoplasm, and myosin-mediated rearward movement of the actin fibers [2 ].

Constitutively active mutants of Rho and Rac induce the formation of stress fibers and lamellipodia, respectively, when microinjected into quiescent Swiss 3T3 cells. Conversely, microinjection of C3 transferase to inhibit Rho or of a dominant-negative Rac mutant to inhibit Rac inhibits growth factor-induced formation of these structures [41 ]. Activated Cdc42 protein induces the extension of filopodia [44 ], finger-like plasma membrane protrusions containing actin filament bundles, which actively protrude and retract. Under appropriate conditions, Cdc42, Rac, and Rho can activate each other sequentially in a cascade: Cdc42 can induce Rac-mediated lamellipodium formation, and Rac can induce Rho-mediated stress fiber formation [45 ].

Rho, Rac, and Cdc42 also regulate the assembly of adhesion sites to the extracellular matrix in fibroblasts. Rho mediates the formation of focal adhesions, whereas Rac and Cdc42 induce the formation of smaller adhesion sites (focal complexes) to the extracellular matrix, located in lamellipodia and at the bases of filopodia [41 ]. To determine how Rho, Rac, and Cdc42 act in cell types other than fibroblasts, we used a mouse macrophage cell line, BAC1.2F5, that resembles primary macrophages in being dependent upon CSF-1 for survival and proliferation as well as exhibiting many of the markers of normal activated macrophages [29 ].

Constitutively active and dominant-negative mutants of Rho, Rac, and Cdc42 were injected into BAC1 macrophages and assessed for their effects on the actin cytoskeleton and on adhesion sites [5 ]. As in fibroblasts, Rac induces the formation of lamellipodia and membrane ruffles and is required for the formation of these structures in response to CSF-1. Cdc42 induces rapid formation of filopodia and again is required for CSF-1-induced filopodium extension. These cells do not possess stress fibers, but have very fine actin cables within the cytoplasm, running parallel to the plasma membrane and around the nucleus. These cables are not detectable in cytokine-starved cells, but re-appear upon stimulation with CSF-1 after 15–30 min. Rho is required for this response and is activated downstream of Rac. The ability of Rac to activate Rho is thus conserved between fibroblasts and macrophages. Activated Rho also stimulates the formation of these cables in cytokine-starved cells, and induces cell contraction (Fig. 3 ). It is interesting that BAC1 macrophages have focal complexes that are regulated by Cdc42 acting upstream of Rac [5 ]. Again, the link between Cdc42 and Rac is present in these cells, as in fibroblasts. These focal complexes contain proteins normally associated with fibroblast focal adhesions, including ß1-integrin, vinculin, a focal adhesion kinase, and paxillin. In BAC1 cells, Rho does not regulate the formation of focal complexes, suggesting that it does not directly modulate cell adhesion, at least via integrin-containing complexes. Unfortunately, these macrophages only rarely develop podosomes in culture so it has not been possible to examine the regulation of these structures by Rho proteins through the use of this model.



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  		Figure 3. Model of the actions of Cdc42, Rac, and Rho in BAC1.2F5 macrophages. The cytokine CSF-1 independently activates Cdc42 and Rac, leading to the formation of filopodia and lamellipodia, respectively. Cdc42 also acts upstream of Rac to regulate the assembly of focal complexes. Rac activation leads to the Rho-mediated assembly of actin cables. It is suggested that filopodia regulate cell polarization toward a source of chemoattractant, whereas Rac and Rho together regulate cell migration.


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PROTEINS CONTROLLING RHO GTPASE ACTIVITY
 
All Rho family proteins bind GTP, and the majority have been shown to act as GTPases and cycle between an active, GTP-bound form and an inactive, GDP-bound form. Three different types of protein have been found to regulate the cycling of Rho family proteins.

Nucleotide exchange factors (GEFs) stimulate the release of nucleotide allowing GTP, which is at a higher concentration than GDP in cells, to bind and thereby activate the protein. Well over 30 potential exchange factors for Rho family proteins have been identified [46 ]; all contain a homologous Dbl domain that is sufficient to stimulate exchange, adjacent to a PH domain. Several mechanisms have been suggested for how GEF activity might be regulated in cells, one favored hypothesis being that PIP3 binds to their PH domains (Fig. 4 ). In the case of Vav, a GEF expressed only in hematopoietic cells, there is good evidence for this hypothesis [47 ] because Vav is activated by tyrosine phosphorylation in response to extracellular signals, and binding of PIP3 enhances this phosphorylation [48 ].



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  		Figure 4. Early signaling events in chemotaxis. On binding a chemoattractant, the activated receptor, be it a serpentine or tyrosine kinase receptor, signals through specific PI 3-kinase subunits to generate lipid signals such as PIP3. Proteins with pleckstrin homology (PH) domains, such as Vav GEF, bind the lipid signaling elements. GEFs are then activated, leading to activation of the Rho family of GTPases.

The intrinsic GTPase activity of the Rho proteins is enhanced by GTPase-activating proteins (GAPs). GAPs for Rho family proteins all share a related 140-amino-acid domain, the RhoGAP domain, which is sufficient to confer GAP activity. So far, little is known about how GAPs are regulated in cells, although changes in subcellular localization will probably be important. Finally, Rho, Rac, and Cdc42 have all been shown to complex with proteins known as GDIs (guanine nucleotide dissociation inhibitors), which prevent their interaction with other regulatory proteins and keep them sequestered in the cytoplasm [49 , 50 ]. Once an appropriate stimulus induces dissociation of the complex, binding of the Rho protein to the membrane is possible, consistent with GDIs acting as negative regulators of Rho signaling. Of the three mammalian GDIs specific for the Rho family, only RhoGDI has a high affinity for RhoA, Rac1, and Cdc42 [51 ]. In addition to keeping Rho family proteins in an inactive complex in the cytoplasm, RhoGDI interacts with ERM (ezrin/radixin/moesin) proteins, which in turn interact with transmembrane proteins such as CD44 and ICAM-1, and also with actin [52 ]. Because ERM proteins can adopt either a closed or open conformation, stimuli that induce unfolding of ERM proteins could lead to release of Rho proteins from RhoGDI and their subsequent availability for activation via GEFs. ERM proteins can also bind to the Rho GEF, Dbl [53 ], suggesting that they may coordinate the release of Rho proteins from GDIs and enhance exchange of GDP for GTP.


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ACTIVATION OF CDC42, RAC, AND RHO
 
It is generally assumed that the major form of activation of Rho GTPases is via activation of GEFs, although this assumption must be considered in light of the complex pattern of controls outlined above. The GTPases are relatively small molecules acting as switches, whereas GEFs are usually large in size and contain many domains that allow them to interact with different regulatory cellular components and thus integrate various signals. Rac is activated by a wide variety of tyrosine kinase receptors including the CSF-1R [5 ] and serpentine receptors [54 ]. Data from a number of studies suggest that PI 3-kinase is a crucial component in this pathway but the details are not yet clear. Several studies have demonstrated that lamellipodia formation and membrane ruffling induced by activated Rac is not inhibited by pharmacological inhibitors of PI 3-kinase, and the ruffling induced by PI 3-kinase is blocked by dominant-negative versions of Rac [55 ]. These data all suggest that PI 3-kinase is acting upstream of Rac. For signaling via serpentine receptor, the Gß{gamma} heterodimer is likely to be the conduit to the p110{gamma} isoform of PI 3-kinase that leads to Rac activation via PIP3 production [56 ]. Ma and colleagues reported that a dominant-negative variant of Cdc42 failed to block PI 3-kinase-dependent effects, thus implying that the pathway between PI 3-kinase and the actin cytoskeleton is dependent on Rac but not on Cdc42. On the other hand, Benard and co-workers [54 ] demonstrated a clear activation of Cdc42 in addition to Rac. Our own work on CSF-1R in macrophages supports a similar pathway for signaling via receptor tyrosine kinases [36 ], although evidence for a specific Rac and/or Cdc42-mediated pathway has not yet been presented.

PIP3 binds to the PH domain of at least three GEFs, Tiam1, Sos, and the leukocyte-specific Vav [57 ]. In the latter study on Vav, PIP3 binding was found to enhance GDP-to-GTP exchange on Rac and Cdc42 as well as Rho, lending support to earlier findings that Vav activates Rho, Rac, and Cdc42, and not just Rac [58 ]. An attractive hypothesis is one that predicts that PIP3 binding to the PH domain of Vav elicits a conformational change, which then activates this GEF (Fig. 4) . It should not be forgotten that many other possibilities exist. It has been shown that N-formyl-methionyl-leucyl-phenylalanine (fMLP) receptor stimulation will also cause activation of the src-related kinase, Lyn [59 ], directly indicating the involvement of tyrosine kinase activity leading to Rac and Cdc42 activation through serpentine receptor activation. Activation of Rho itself can also be stimulated through G-proteins, with both G{alpha}12 and G{alpha}13 being implicated [60 ]. However, the exact mechanism by which G-protein {alpha} subunits lead to activation of Rho is yet to be fully elucidated, although a candidate GEF in this pathway has been identified as p115RhoGEF [61 ]. Although G{alpha} subunits can activate Rho through this GEF, additional signaling events must also be involved, the complexities of which are discussed in a recent review [62 ].


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REGULATION OF THE CYTOSKELETON
 
Once activated, Rho family proteins can interact with downstream target (effector) proteins, stimulating signaling pathways that lead to the observed cellular responses. For example, many observations on Rho function are consistent with its ability to regulate cell contractility [63 ]. This is seen clearly in macrophages, where microinjection of activated Rho protein rapidly leads to cell contraction [5 ]. As well as stimulating actomyosin-based contractility, Rho can also stimulate actin polymerization in a more cell type-restricted manner [64 ]. Many targets for Rho family proteins have recently been identified, including protein kinases, phosphoinositide kinases, and adaptor proteins, which have no enzymatic function but have the ability to interact with one or more other proteins [65 ]. A number of targets have the potential to link Rho, Rac, or Cdc42 directly with the actin cytoskeleton. For example, IQGAP1, which is abundant in lamellipodia, binds to actin filaments and also to Rac and Cdc42 [66 ]. Cdc42 directly stimulates actin polymerization in leukocyte extracts in a manner that seems independent of either PIP2 or PIP3 [67 ]. A Cdc42-interacting protein, CIP4, shows sequence homology to a small region of ERM proteins and may act as a transducer to the actin cytoskeleton [68 ]. In addition, Rho-kinase/ROK can induce the phosphorylation of myosin II light chain kinase [69 ], whereas the Rac/Cdc42-specific PAK family of kinases can phosphorylate myosin I heavy chain, although it is debatable whether this occurs in mammalian cells [70 ].

Indirect mechanisms linking Rho proteins to the actin cytoskeleton are more common. One member of the PAK family, the Cdc42-specific PAK4, induces the formation of filopodia [71 ]. PAKs also promotes turnover of focal complexes under the influence of Cdc42 or Rac [72 ], suggesting a role in the breakdown of attachments to the substratum that may be critical for macrophage locomotion. Finally, the Rho target p140mDia can bind to profilin [73 ], an actin-binding protein with the potential to enhance actin polymerization at the leading edge of migrating cells. The precise mechanisms whereby these targets, and undoubtedly others, act to regulate actin reorganization, have yet to be fully elucidated [69 ].


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WAS AND WASP
 
For leukocytes in general and macrophages in particular, interest has recently focused on Wiskott-Aldrich Syndrome protein (WASP). The Wiskott-Aldrich Syndrome (WAS) is a rare inherited X-linked recessive disease characterized by immune disregulation and microthrombocytophenia [74 , 75 ]. The clinical phenotype of the immune disorder includes susceptibility to pyrogenic, viral, and opportunistic infections [76 ]. Several lines of evidence suggest a role for this hematopoietic cell-restricted protein as a mediator of Cdc42, and to a much lesser extent Rac, effects on the cytoskeleton. Three groups have demonstrated that WASP interacts directly with Cdc42 in a GTP-dependent manner [77 78 79 ]. Overexpression of WASP induced the formation of actin filament clusters in several cell types and this clustering could be inhibited with dominant-negative Cdc42 [79 ]. More recently, inducible targeting of WASP to the plasma membrane has been shown to induce filopodia formation in the presence of activated Cdc42 [80 ]. This same group also demonstrated that WASP acts downstream of Cdc42 in membrane protrusion formation.

In recent months, a fuller picture of WASP and related family proteins (N-WASP and SCAR proteins) has emerged [81 ]. It was found that members of the WASP family all share a conserved amino-terminal portion called the EVH1 domain, which shares some similarities with PH domains. As well as binding phosphoinositides, it seems that EVH1 domains perform a unique function, interacting with proline-rich target sequences [82 ]. For WASP, the most likely candidate is the WASP-interacting protein WIP [83 ]. Just carboxy-terminal to the EVH1 domain of WASP is the CRIB motif, which confers interaction with Cdc42, and more centrally there are proline-rich sequences that can interact with SH3-containing proteins such as the adaptor proteins Nck and Grb2, protein tyrosine kinases of the c-Src family such as Fyn, and the actin-binding protein profilin [84 ]. The carboxy terminus of WASP family proteins is made up of two regions. One is an actin-binding motif [85 ] known as the WH2 motif. The second is the A motif, which includes a cluster of acidic residues that mediate binding to the Arp2/3 complex [85 ]. Interest in the Arp2/3 complex has been intense because it proved essential for the reconstitution of actin-based motility and polymerization on the surface of the intracellular parasite Listeria monocytogenes [86 ]. The complex, which was first discovered in 1994, localizes to the leading edge of motile cells [87 ] including macrophages [G. Jones, unpublished data], where it is also found in WASP-enriched podosomes. The Arp2/3 complex caps the slow-growing (pointed) ends of actin filaments [88 ], and also binds to the sides of filaments, allowing cross-linking and branching of the actin cytoskeleton [89 ].


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CELL MIGRATION
 
The ability of Rho, Rac, and Cdc42 to regulate cell adhesion and actin organization suggests that they could be involved in cell migration and chemotactic responses. We have tested this hypothesis on BAC1 macrophages. Migration of microinjected cells can be directly measured in a Dunn chemotaxis chamber by time-lapse microscopy followed by computer-assisted analysis [31 ]. This allows the immediate effects of microinjecting proteins to be determined, avoiding the less direct approach of establishing cell lines that show altered migratory responses as a result of long-term changes in gene expression induced by the exogenously expressed GTPases.

We have observed that activated forms of Rho, Rac, and Cdc42 inhibit the migration of macrophages in response to CSF-1 [8 ]. This most likely reflects the fact that expression of these proteins dramatically reorganizes the cytoskeleton such that a cell can no longer be polarized sufficiently to allow migration [5 ]. Inhibition of Rho and Rac, by microinjection of C3 transferase and of the dominant-negative N17Rac1 protein, respectively, also prevents the migration of cells. The effect of N17Rac1 is expected, because lamellipodia are universally observed at the leading edge of migrating cells, and are required for forward protrusion of the membrane. The effect of inhibiting Rho suggests that the contractile actin cables regulated by Rho play an important role in mediating cell migration, probably pulling the body of the cell forward. In the absence of Rho, cells gradually extend dendritic processes, terminating in lamellipodia [5 ]. This suggests that the cell is still able to extend its leading edge, but the cell body does not follow and net translocation is not achieved.

Unlike inhibiting Rho and Rac, which completely abrogates cell migration, inhibiting Cdc42, and thus the formation of filopodia, does not prevent cells moving in response to CSF-1, but actually enhances their migration rate compared to control injected cells [8 ]. However, the dominant-negative N17Cdc42 protein does prevent cells recognizing a chemotactic gradient of CSF-1, and the cells migrate in random directions. This effect of N17Cdc42 resembles the response of BAC1 cells to tumor necrosis factor {alpha} (TNF-{alpha}), which abolishes their ability to detect a gradient of CSF-1 without altering their speed of locomotion [31 ]. Consistent with a role for Cdc42 in responding to the concentration gradient, TNF-{alpha} also inhibits CSF-1-induced filopodium formation without affecting lamellipodium formation or membrane ruffling [90 ].


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A ROLE FOR INTEGRINS
 
One explanation for why macrophages move faster when Cdc42 is inhibited is that the adhesions to the substratum are weaker, because the integrin-containing focal complexes are dispersed [5 ]. It has been shown that cell migration is maximal at a critical strength of interaction between the cell and the extracellular matrix, dependent on ligand concentration, integrin expression, and integrin-ligand affinity [91 ]. Possibly, by decreasing the clustering of integrins at focal complexes, the cells can move faster [1 ].

Using mouse knockouts for a series of Src-family tyrosine kinases, Lowell’s group have defined a signaling cascade leading from integrins involving the adapter protein c-Cbl and PI 3-kinase that is required for macrophage spreading upon a fibronectin substratum [92 ]. Thus it seems likely that PIP3 is once again implicated in signaling, this time from activated integrins, to the Rho proteins Cdc42 and Rac that regulate macrophage spreading via focal complexes. A similar conclusion can be drawn from the observation [16 , 17 ] that p110{gamma} knockout mice retain a greater number of leukocytes in the circulation, coupled with a marked inability to migrate into tissues. This observation may suggest that p110{gamma} is an important component of the signaling pathways that regulate leukocyte selectin and integrin molecules. A description of integrins is beyond the scope of this review, but a full discussion of integrin signal transduction in myeloid cells has recently been published [93 ], as have descriptions of the role of Rho proteins in cell adhesion [69 ].


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A ROLE FOR WASP
 
The generation of regulated immune responses is dependent on the ability of cells to migrate in response to integrated chemical signals [94 ]. In addition to the influx of neutrophils and macrophages to sites of inflammation, these processes are responsible for the relocation of dendritic cells from their surveillance positions in non-lymphoid tissue to the secondary lymphoid organs, and migration of lymphocytes into their specialized B and T cell zones [95 ]. The cellular mechanisms that allow these trafficking processes to occur are, therefore, intimately related to the regulation of the cytoskeletal apparatus. Cells from WAS patients can thus provide natural models with which to answer some questions about cytoskeletal rearrangements and the migration of leukocytes [96 ].

To investigate the role of WASP in generating cell polarization induced by chemoattractants, we analyzed the chemotactic responses of WAS macrophages to linear concentration gradients of CSF-1. Chemotaxis of WAS macrophages to CSF-1 was found to be abolished, whereas normal human macrophages show a strong chemotactic response to this cytokine [97 ]. However, the speed of cell motility was indistinguishable from normal human cells. This result is reminiscent of the findings for BAC1 cells exposed to gradient of CSF-1 in the presence of TNF-{alpha} [31 ] where the loss of filopodia is linked to a failure to sense gradients of chemoattractant. Furthermore, polymerization of actin on the ventral surfaces of WAS macrophages and extension of filopodia and lamellipodia were severely compromised, adding further support for the role of WASP as a physiological effector for Cdc42 in hematopoietic cells [97 ]. Similar disturbances of WAS cell motility and cell polarization have been reported from other laboratories [98 ]. Because WASP is expressed in all hematopoietic cells, similar abnormalities of cell polarization and chemotaxis-driven trafficking may be apparent in other hematopoietic lineages such as T lymphocytes [99 ] and dendritic cells [100 ].


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A POSSIBLE MODEL FOR MIGRATION AND CHEMOTAXIS
 
These data all suggest a pathway through which multiple signaling cascades activated by both serpentine and tyrosine kinase receptors could activate the actin polymerization required for cell migration and chemotaxis. From model systems [18 ] it seems that proteins with phosphoinositide-binding PH domains are selectively recruited to the leading edge of chemotaxing cells. This intracellular asymmetric distribution generates a much sharper gradient than the causative gradient of chemoattractant. The mechanism of recruitment of PH-containing proteins involves the production and degradation of phosphoinositides, especially PIP3. Additional support for this view comes from mice deficient in SHIP (SH2-containing inositol-5-phosphatase), an enzyme that hydrolyzes PIP3. These mice suffer from a lethal infiltration of the lungs by macrophages and neutrophils, suggesting that abnormal persistence of the PIP3 signal leads to excessive leukocyte recruitment and inflammation [101 ].

Polarized aggregation of serpentine chemotactic receptors to the leading edge of migrating cells was previously thought to be the mechanism by which the directional signaling to cells was maintained [102 ], but the application of more advanced imaging techniques have discounted this otherwise attractive hypothesis [103 ] and it is now accepted that chemokine receptors remain diffusely distributed over the cell surface [104 ]. These findings show that the continued sensing of a gradient does not require an asymmetric localization or redistribution of serpentine receptors, or indeed of the G-proteins linked to these receptors [19 ], but does involve localized recruitment of PH domain-containing proteins [18 ].

How do macrophages respond to a gradient of CSF-1? Previous work on BAC1 cells has shown that uniformly distributed CSF-1R is rapidly endocytosed after stimulation with CSF-1 [30 ] and that no detectable CSF-1R re-appears on the surface for at least 20–30 min [105 ]. This makes it most unlikely that the cells are continuously sensing and responding to the gradient, as would be the case with serpentine receptors. This hypothesis is supported by the observation that a cell which initially lies directly downgradient to another macrophage, thus sensing a distorted diffusion gradient, appears to move persistently away from a source of CSF-1 even after entering an area in which the normal gradient has been retained [31 ]. This observation suggests that initial receptor activation is sufficient to generate cell polarization, which is retained in the absence of further receptor availability. A possible model for how macrophages polarize in response to gradients of CSF-1 is considered here (Fig. 5 ). The earliest response of rounded, cytokine-starved macrophages to CSF-1 is rapid extension of filopodia and lamellipodia all around the free margin of the cell, a response that is seen whether the CSF-1 is presented as an isotropic [30 ] or gradient [31 ] stimulus. This initial response is followed by cell spreading, reaching a maximum spread cell area within 5 min of addition of CSF-1. It is likely that the gradient is detected during this initial stage, and that the extension of filopodia is necessary for this. The filopodia may act as sensing devices because they have a high surface area with the potential to carry large numbers of CSF-1 receptors. When they later retract back into the cell as the spreading process ensues, they may create a concentrated "hot spot" of activated receptor that is subsequently endocytosed but still actively signaling [106 ]. The cell then senses the difference in signal intensity between the up- and down-gradient ends of the cell, and polarizes its actin cytoskeleton accordingly. Possibly, the sites of filopodium retraction act as centers to drive the polarization, recruiting further PH-domain containing proteins and actin-associated proteins to the up-gradient hot spot. This asymmetric recruitment will favor the formation of a dominant lamellipodia on the up-gradient face of the spreading cell, which subsequently results in directed movement up the cytokine gradient [107 ]. Cdc42, in stimulating the formation of filopodia, thereby initiates the process of gradient detection. In the absence of Cdc42, the cells still migrate, but not in response to the gradient of chemoattractant. The extent of cell polarization is far less and the cells remain quite rounded [8 ]. It is likely that this latter behavior is due to a stochastic process of lamellipodial extension [1 ].



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  		Figure 5. A model for the roles of Rho GTPases in macrophage migration and chemotaxis. In the absence of CSF-1, BAC1 cells have a rounded morphology. Upon addition of CSF-1, macrophages extend filopodia and subsequently spread via the extension of lamellipodia, forming new focal complex adhesions to the substratum. In a gradient of CSF-1, the cell polarizes its actin cytoskeleton such that lamellipodium extension becomes restricted to the up-gradient face of the cell. Macrophage polarization requires Cdc42 activity, and cell migration is mediated through the actions of Rac, which extends the lamellipodia, and Rho, which causes retraction of the cell body so as to detach the rear of the cell.


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FUTURE DIRECTIONS
 
Clearly there is still a long way to go before we have a comprehensive description of cell polarization, motility, migration, and chemotaxis. Although the identification of Rho family proteins as key regulators of the actin cytoskeleton was a stunning breakthrough, the precise means by which Rho proteins control the formation and breakdown of filopodia, lamellipodia, and cell adhesion to the substratum is far from well understood. Similarly, although many examples in the literature support a generalized role for Cdc42 in generating cell polarization [108 ], precisely how this is achieved is currently only a subject of active research rather than detailed modeling. As far as chemotaxis is concerned, the recent evidence pointing to a critical role for lipid signaling and PH domain-containing proteins in creating the asymmetric response after ligand binding to both serpentine and tyrosine kinase surface receptors serves as the foundation for work to identify the cellular targets that actually generate asymmetric cellular extensions. Finally, it would be facile to assume that the signal transduction pathways discussed in this review act in isolation: any suggestion that separate linear pathways lead to the biological response under investigation is an oversimplification. Instead, complex interdependent signaling networks must be involved and the untangling of these networks must be the focus of future work. The genetic tools that allow us to visualize the chemotaxis-induced redistribution of PH domain-containing proteins and cytoskeleton-associated proteins in living cells are now being developed. Together with the use of mutant cells with defects in chemotaxis this approach will undoubtedly contribute dramatically to our future understanding of cell polarization and chemotaxis.


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ACKNOWLEDGEMENTS
 
This work was supported by grants from the UK Medical Research Council, The Wellcome Trust, and the Arthritis Research Campaign. I thank Graham Dunn (Randall Centre, London), Anne Ridley (Ludwig Institute, London), and Adrian Thrasher (Institute of Child Health, London) for numerous stimulating discussions.


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