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Regulation of Cell Motility by Abl Family Kinases

and *.

* Corresponding Author: Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, SP231, La Jolla, California, 92037, U.S.A. Email: lemke@scripps.edu.

Cell migration is a highly dynamic process that involves regulation of actin-mediated protrusion of a leading lamellipodia and its adhesion to the extracellular matrix, followed by translocation of the cell body and tail retraction at the rear. The migration machinery is regulated in a highly temporal and spatial manner through sophisticated sensing mechanisms that interpret external gradients of chemokines and adhesive proteins present in the extracellular environment. These directional cues are transmitted to the interior of the cell where they couple to the cytoskeletal network. In the following section, we highlight the role of the Abl family of nonreceptor tyrosine kinases, which transmit signals from growth factor and adhesion receptors to the actin and microtubule cytoskeleton of motile cells. These recent findings suggest that Abl kinases may contribute to cell migration processes, including development, wound healing, and immune function, as well as pathological conditions associated with cancer metastasis and inflammation.

Introduction

Cell migration is essential for normal development, immune function, and wound healing. However, when deregulated, cell migration contributes to autoimmune disease, inflammation, tumor-induced angiogenesis, and cancer cell metastasis. Regulation of cell movement is a complex process that involves cell adhesion to extracellular matrix proteins and gradients of growth factors present in the extracellular environment, which serve to guide cell movement through complex tissues. Cell migration is an integrated process that involves sensing directional cues from the extracellular environment, regulation of actin-mediated protrusion of a dominant leading lamellipodium at the front, tail retraction at the rear, and turnover of cell-matrix adhesions to the underlying substratum.1,2 All these events are coordinately controlled by complex signaling networks that operate in a temporal and spatial manner within the cell.2

Much of our knowledge of cell migration has been obtained from cultured cell lines and 2-dimensional in vitro assays, which do not fully recapitulate true 3-dimensional cell translocation that occurs in living organisms. Disruption of normal tissue architecture and establishment of cells in culture leads to reactivation of dormant migration mechanisms that would normally be suppressed since most cells in the adult body do not migrate except under special circumstances associated with immune function and wound healing.1,2 However, significant progress has been made in understanding the fundamental process of cell movement and a detailed understanding of the molecular events that transform a stationary cell into fully functioning migratory cell is beginning to take shape. Progress is also being made in extending these findings into 3-dimensional systems in vitro and in vivo.3,4 Here we highlight the importance of the Abelson family of non receptor tyrosine kinases (c-Abl and the c-Abl-related gene, Arg), which have recently emerged as key regulators of cell migration through their ability to relay signals from growth factor and integrin adhesion receptors to the actin and microtubule cytoskeleton that controls the migration machinery of the cell (fig. 1).

Figure 1. Schematic of a migrating cell and proposed regulation by Abl kinases.

Figure 1

Schematic of a migrating cell and proposed regulation by Abl kinases. Growth factors and adhesion proteins in the extracellular environment regulate cell migration through stimulation of integrins and growth factor receptors. Cell migration is a dynamic (more...)

Domain Structure and Developmental Function of Abl Family Kinases

The Abl family kinases are evolutionarily conserved non receptor tyrosine kinases that include the normal cellular c-Abl (Abl) and Arg, and the oncogenic forms v-Abl, Bcr-Abl, Tel-Arg.5-10 While a large body of literature describes the importance of the oncogenic forms in human health and disease, we will focus on the emerging role of endogenous Abl and Arg in regulation of cell movement in mammalian cells. Abl and Arg are ubiquitously expressed proteins that share high homology, comprised of SH2, SH3, actin binding, polyproline, and tyrosine kinase domains.5,7-9 Not surprisingly they share a significant level of functional redundancy and utilize similar effector proteins.7 However, a notable difference in these proteins is the ability of c-Abl to shuttle between the nucleus and cytoplasm due to nuclear localization signals (NLS), which are missing from the Arg gene product.8,10 Also, while approximately 75% of abl-/- animals die postpartum, the surviving mice show thymic atrophy, lymphopenia, osteoporosis, improper eye development, and spermatogenesis.11-14 In contrast, arg-/- mice are viable, but show behavioral defects. When both abl and arg genes are deleted, animals die early in development (E9-11) from neurological defects, indicating the necessity of both enzymes for proper embryonic development and that they can compensate for each other during normal development.12 Since proper cell migration is necessary for normal development, it is likely that the early lethality observed in the abl-/-arg-/- cells is at least in part due to deregulated migration events, especially during neural tube formation, in which Abl/Arg play a key role.12 This may also explain the high level of apoptosis seen in the Abl/Arg null embryos since defective migratory cells that incorrectly colonize developing tissues during pattern formation are readily eliminated by apoptosis.

Negative Regulation of Cell Migration by Abl Kinases through Uncoupling of CAS/Crk Complexes

Signal transduction by Abl kinases plays a key role during cell migration by virtue of their ability to integrate a diverse repertoire of signals that emanate from the extracellular environment, including extracellular matrix proteins (ECM) and growth factors.9,15,16 Upon integrin ligation during cell adhesion to ECM proteins and/or exposure to cytokines, Abl and Arg are reported to be activated and localized to focal adhesions and actin-rich membrane ruffles.17-19 These early reports were the first hint that Abl members may regulate the cytoskeleton and cell migration processes. Subsequently, Abl was shown to negatively regulate cell migration by disrupting the formation of a macromolecular signaling complex between the adaptor protein c-CrkII (Crk) and the docking protein p130CAS (Crk-associated substrate, CAS) and its effector proteins DOCK180 and the small GTPase Rac, which control the actin cytoskeleton and lamellipodium formation (refs. 20-22, fig. 2, fig. 3). Abl and Arg directly interact with the SH3 domain of Crk via their conserved proline-rich region (PXXP, fig. 2) and promote tyrosine phosphorylation of Crk at Y221.21-25 Y221 phosphorylation causes an intramolecular folding in which Crk's own SH2 domain binds to Y221 preventing interaction with phosphotyrosine residues present in the substrate domain of CAS as well as interactions with effector proteins that bind to the amino terminal SH3 domain of Crk. Thus, the binding of Abl to Crk is expected to inhibit cell migration by both phosphorylation of Y221 and displacement of effectors that bind to Crk's SH3 domain, including DOCK180.20-22

Figure 2. Proposed mechanism of Abl regulation of CAS/Crk coupling and membrane protrusion.

Figure 2

Proposed mechanism of Abl regulation of CAS/Crk coupling and membrane protrusion. Step 1) Growth factor and integrin receptor activation facilitates the assembly of a CAS/Crk/DOCK180/Rac signaling scaffold that promotes actin-mediated lamellipodium protrusion. (more...)

Figure 3. Functional connection map of Abl kinases showing prospective upstream and downstream effectors that mediate cytoskeletal remodeling during cell migration.

Figure 3

Functional connection map of Abl kinases showing prospective upstream and downstream effectors that mediate cytoskeletal remodeling during cell migration. See references in schematic for details. Heregulin (HRG), EGF receptor family members ErbB2 and (more...)

Consistent with this idea, expression of a kinase dead form of Abl or exposure of cells to the Abl kinase inhibitor STI57121,22,26 enhanced CAS/Crk coupling and cell migration by decreasing phosphorylation of CrkY221.22 Conversely, expression of a constitutively activated form of Abl inhibited cell migration and the assembly of CAS/Crk complexes, and this depended on a functional Abl PXXP domain and phosphorylation of CrkY221.22,24,25 Furthermore, embryonic fibroblast cells (MEF) isolated from abl-/-arg-/- deficient mice showed a complete loss of basal CrkY221 phosphorylation that led to increased CAS/Crk assembly and cell migration. As expected, reconstitution of these cells with Abl reversed this phenotype.22 Interestingly, abl-/-arg+/+ MEF cells show increased CrkY221 phosphorylation, indicating that Arg can also promote phosphorylation of endogenous Crk. Collectively, these studies demonstrated that Abl and Arg kinases function as negative regulators of CAS/Crk coupling and cell migration. This also strongly implicates endogenous Abl/Arg kinases as the primary regulators of Crk phosphorylation in cells and points to an important “housekeeping” role to monitor Crk phosphorylation levels in cells. The highly conserved CAS/Crk/DOCK180/Rac signaling module has been shown to regulate growth factor and integrin mediated cell migration in various cell types and in cell migration processes in vivo and, when deregulated, may contribute to cancer progression.21,27,28

Abl activation by integrins and growth factor receptors may serve as a negative feedback pathway to control the level of CAS/Crk coupling by reducing the pool of active unphosphorylated Crk available to interact with CAS following integrin activation. In migrating cells, this negative feedback signal would be expected to operate transiently downstream of integrin ligation events occurring at the leading front of the advancing lamellipodium in order to bring about steady-state levels of CAS/Crk complexes in this structure.4,21 Also, as indicated above, the increased association of Abl with the SH3 domain of Crk may displace positive effectors like DOCK180 to further reinforce the inhibition of cell migration by Abl. Interestingly, Abl phosphorylation and molecular folding of Crk has been shown to unmask a polyproline sequence (PPP) motif in Crk that can further interact with the SH3 domain of Abl, (ref. 29, fig. 2). The increased molecular stability of this protein complex may provide a mechanism to compete with positive effectors for binding to the SH3 domain of Crk, which could further potentiate the negative regulation of cell migration by Abl.29,30

The ability of Abl to both phosphorylate and tightly bind to Crk as well as its ability to translocate within the cell suggests that this enzyme could also serve as a shuttle protein to deliver phosphorylated Crk to the membrane and/or focal adhesions (fig. 2).17,18,31,32 In this case, integrin-induced signals would induce formation of Abl/Crk complexes and their translocation to the membrane and/or focal contacts. In this way, integrin-mediated activation of Abl would provide a sensitive mechanism to modulate the pool of active/inactive Crk available to bind to effectors in distinct compartments of the cell. Further studies will be necessary to determine whether Crk retains the ability to translocate to the membrane and/or focal contacts in abl-/-arg-/- cells and whether integrin-mediated Rac activation is compromised in cells without functional Abl family kinases. Also, it will be important to identify the upstream components responsible for integrin activation of Abl family kinases during cell spreading and migration. Src would be a good candidate for this role, as it is activated by integrins and can in turn activate Abl and regulate cell migration.33,34

Abl Regulation of HGF-Induced Cell Migration

Inhibition of Abl kinase activity by STI571 has also been shown to enhance Hepatocyte Growth Factor (HGF)-induced motility in a panel of thyroid cancer cell lines.28 In this study, treatment of cells with clinically relevant doses of STI571 increased HGF-induced cell migration in 10 of 13 independently derived cell lines and induced strong branching morphogenesis and cell invasion in Matrigel. Inhibition of basal Abl kinase activity with STI571 in the absence of HGF also increased cell migration in 9 of 13 cancer cell lines and induced a moderate increase in branching and cell invasion. Interestingly, STI571 had no effect on primary thyroid cell lines, suggesting Abl kinase activity specifically and negatively regulates cell migration and invasion in malignant thyroid cancer cells.

Although the mechanism of STI571-induced cell migration is not fully understood, it appears that inhibition of Abl kinase activity promotes increased tyrosine phosphorylation of Met, which is the receptor for HGF. Met phosphorylation was associated with increased activity of downstream targets, including ERK and Akt, and the response was specific to the Met receptor since there were no changes in phosphorylation of the PDGF receptor in response to STI571.28 Localization studies revealed that Met and Abl are enriched in the leading pseudopodium of migrating cells, suggesting that their spatial regulation contributes to lamellipodia formation.28 Although the mechanism is not defined, the results suggest that enhanced phosphorylation of Met promotes increased activation of ERK and Akt at the front of the migrating cell to regulate lamellipodial dynamics. ERK and the PI3K/Akt pathways have been shown to regulate cell migration2,35,36 and ERK activity is highly localized to the leading pseudopodium where it regulates the actin-myosin system.35

Abl activation may also be part of a negative feedback loop that controls the level of Met and Crk phosphorylation and their downstream signals to suppress cell migration.37 Consistent with this idea, HGF-induced Abl activity is significantly enhanced in spreading cells that are actively engaging the ECM.28 Crk also transduces signals downstream of the Met receptor that are important for HGF-directed epithelial migration. Together these findings suggest that the Met receptor, integrins, and CAS/Crk cooperate to regulate cell spreading and migration. If this is the case, then inactivation of negative feedback signals from Abl would promote increased CAS/Crk/Rac signaling leading to increased lamellipodium protrusion as discussed above. This in turn would facilitate integrin ligation and membrane spreading over the ECM and enhanced Met activation through cross-talk with integrin receptors. Growth factor receptors are known to associate with integrins and cosignal to the interior of the cell.38 While CAS/Crk coupling can regulate lamellipodium dynamics, the picture is likely to be more complex than this, as Crk can also couple to the focal adhesion protein paxillin which regulates HGF-induced cell migration through interactions with GIT2/PKL, β-PIX/Cool and Rac.39 It will be interesting in the future to further define the role of Abl in regulation of Met-induced cell migration and identify the key effectors in this process.

Abl Regulation of PDGF-BB-Induced Cell Migration

In contrast to HGF, Abl activity increases chemotaxis motility following activation of the platelet-derived growth factor receptor (PDGFR) with PDGF-BB.6,34,40 In an elegant set of experiments it was shown that full Abl and Arg activation by the PDGFR involves a molecular interplay with Src kinase, PLC-γ1, and the PDGFR.6,34,40 In this system, PDGFR activation decreases the intracellular level of phosphatidyl inositol bisphosphate (PIP2) through PLC-γ1 hydrolysis or by dephosphorylation of PIP2 by inositol polyphosphate 5-phosphatase. It is thought that the decrease in cellular PIP2 levels at specific sites in the membrane relieves the auto-inhibited state of Abl/Arg, the first step in the kinase activation cascade. However, full activation of Abl and Arg requires phosphorylation at several sites, including tyrosine 412 in Abl and 439 in Arg, which are in the activation “loop” of the kinase domain.40 Although the functional consequences are not fully defined, Abl/Arg and the PDGFR can form a molecular scaffold where they undergo reciprocal phosphorylation.40 This could provide additional sites for SH2 docking proteins that couple this complex to downstream effectors that mediate cell function or directly regulate tyrosine kinase activity and substrate phosphorylation. Interestingly, while it is not yet known how the PDGFR/Abl/Arg scaffold couples to the migration machinery of the cell, it appears that Abl is the primary player that mediates PDGFR-mediated chemotaxis since only Abl and not Arg reconstituted abl-/-arg-/- MEF cells showed increased migration in the presence of PDGF-BB.40 It appears then that Abl kinase activation plays a positive role downstream of the PDGFR to mediate cell migration.

The reasons why Abl negatively regulates HGF and Crk-mediated cell migration but positively regulates PDGFR-directed migration are not known. The simplest scenario is that PDGFR-mediated migration is a separate signaling pathway, which is uncoupled from the negative feedback constraints provided by integrin-mediated signaling events. In this case, Abl may provide an early signaling cue at the membrane that establishes the direction of cell migration in response to a gradient of PDGF-BB. In support of this notion, PLC-γ1 has been shown to play an important role in mediating directional cell migration in response to EGF.41 On the other hand, the negative feedback function of Abl may be a downstream step in the migration process that operates exclusively to monitor integrin-mediated CAS/Crk coupling after the cell is stimulated to migrate with PDGF-BB. This is consistent with the idea that Abl regulation of CAS/Crk coupling is important for maintaining proper lamellipodial extension and focal adhesion turnover, which is downstream of chemokine gradient sensing mechanisms that initiate and direct cell movement. It will be important to determine the interplay of PDGFR, Abl, and CAS/Crk signaling in the future and how the PDGFR/Abl scaffold couples to the migration machinery of the cell.

Future Prospects

While we have presented current evidence for the role of Abl/Arg in cell migration, future work will undoubtedly uncover additional Abl-mediated mechanisms that control cell migration. For example, Abl and Arg associate with and transmit signals to numerous F-actin structures and the microtubule (MT) network, giving rise to microspikes, filopodia, ruffle formation, neurite extension, and synaptic junctions (fig. 3).5,7-10,12,15,16 Arg can directly crosslink MT and F-actin where it may serve to insert MT into F-actin protrusive structures in the lamellipodium.9,15,42 Although this article can not give detailed consideration to this important topic due to space limitations, these direct interactions are likely to assemble key signaling scaffolds that mediate remodeling of the actin cytoskeleton and contribute to morphogenic processes necessary for cell movement. Indeed, a significant amount of evidence indicates that Abl/Arg regulate various effector proteins known to facilitate actin dynamics, including the Rho family of GTPases, Rac and Rho (fig. 3).5,7-9,12,15,16,18,22,23,32,43-51 Thus, Abl and Arg are in prime position to serve as cytoskeletal sensors that couple signals emanating from the extracellular environment to the migration machinery of the cell. The challenge will be to decipher the complex signaling cascades and molecular interactions that regulate Abl/Arg activity and their downstream effectors and determine whether these events contribute to physiologically relevant cell migration processes in vivo. Finally, although much is known about oncogenic Bcr-Abl and Tel-Arg26,52-54 and their role in human leukemia, little is known about whether c-Abl and c-Arg contribute to cancer progression or other unwanted cell migration processes that contribute to inflammation and tumor induced angiogenesis. However, given the central importance of Abl and Arg as monitors of cell shape and movement it seems that future work should consider these non receptor tyrosine kinases as possible contributors to human health and disease.

Acknowledgements

We thank R. Hanley and M. Holcomb and Drs. Y. Wang, O. Pertz and K. Stoletov for helpful comments on the manuscript. The work in the laboratory of R.L.K. is supported by National Institutes of Health Grants CA97022 and GM68487. This is manuscript number 17071-IMM from The Scripps Research Institute.

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