Stem Cells, Vol. 15, No. 4, 259-267,
July 1997
© 1997 AlphaMed Press
Signaling Mechanisms in Growth Factor-Stimulated Cell Motility
Bela Anand-Aptea,
Bruce Zetterb
a Department of Cell Biology, Cleveland Clinic Research Institute, Cleveland, Ohio, USA;
b Department of Surgical Research, Children's Hospital, Boston, Massachusetts, USA
Key Words. Chemotaxis • Platelet-derived growth factor • Signaling
Dr. Bela Anand-Apte, Department of Cell Biology, Cleveland Clinic Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
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Abstract
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Most mammalian cells have the capacity to migrate. When placed into culture, cells will generally display a set rate of basal, unstimulated locomotion. The cells will begin to move in one direction and, after some time, change directions resulting in a random walk. External stimuli can influence cell motility in several ways to either enhance or retard the rate of migration (chemokinesis), to change the average amount of cell migration observed before the cell turns (persistence), or to increase the directionality of movement by limiting the number of turns made by the cells. Several factors have been identified that stimulate cell movement, but the signaling mechanisms that mediate this induced cell movement have only recently begun to be studied. In this review, we discuss the signals that support the directional movement of fibroblasts and epithelial cells in response to chemoattractant gradients. The work will emphasize studies carried out by our laboratory and others on the stimulation of cell motility by the PDGF. These results indicate that at least two sets of signaling molecules cooperate to regulate cell motility in vivo. These include phospholipase C-gamma, phosphoinositide-3' kinase and the Ras-GTPase activating protein Ras-GAP. The first set are those which bind to the intracellular domain of the receptor tyrosine kinase and bring about the phosphorylation and/or activation of intracellular effectors proximal to the receptor. The second is a set of downstream effectors that regulate either the rate of cell movement or the directionality of that movement depending on the cell type. These include Ras and the Ras-related GTPase Rac along with free phosphoinositides and calcium ions that regulate the actin polymerization machinery. Signals that mediate nuclear changes leading to cell proliferation, such as elements of the MAP kinase pathway, do not appear to play a role in PDGF-stimulated cell migration. Current work thus suggests that a coordinated spatial regulation of signaling elements that interact with the cell membrane and cytoskeleton but not necessarily with nuclear elements is the controlling mediator of directional cell motility.
Cell motility influences a number of physiological and pathological processes. During embryogenesis, invasion of the uterine wall by migrating cells of the mammalian zygote results in the development of the placenta. In addition, the movement of cells during gastrulation contributes to the establishment of the form of the developing organism. Wound healing requires the migration of fibroblasts and epithelial cells while bone remodeling is characterized by crawling of osteoblasts and osteoclasts. The ability of white blood cells to crawl to infected tissues is critical for the body's defenses against infection. A number of disease states are a consequence of altered cell motility. The migration of arterial vascular smooth muscle cells from the media to the intima is believed to play an important role in atherogenesis and restenosis. Tumor metastasis is a result of migrating tumor cells which invade and destroy normal tissue architecture and function at distant sites. This is the major contributor to the lethality of cancer. Knowledge of the basic mechanisms underlying cell migratory behavior is critical to understanding a variety of physiological and pathological processes.
Factors which induce cell motility (motility factors) include as a subset polypeptide growth factors, such as PDGF, basic fibroblast growth factor (FGF), hepatocyte growth factor (scatter factor), vascular endothelial growth factor and epidermal growth factor [1-3] and lysophosphatidic acid [4, 5]. These factors bind to their receptors on the cell surface and induce migration stimulatory signals which result in the reorganization of the cellular cytoskeletal architecture and stimulation of the motility machinery of the cell resulting in cell migration.
Cell migration induced by growth factors is believed to be regulated through classical signal transduction pathways similar to those described previously for mitogenesis. These include activation of tyrosine kinases [6], protein kinase C [7] and GTP-binding proteins [8]. The signaling pathways that result in DNA synthesis and mitogenesis have been studied extensively and determine a defined sequence of stimulation as well as inhibition of the expression of specific genes. It can be speculated that the signaling pathways utilized for the migration response by growth factors may result in the modulation of cell surface receptors, extracellular matrix (ECM) and cytoskeletal elements, probably in a specifically defined hierarchical sequence of events, which are critical and necessary for the motility response of cells.
PDGF is a potent mitogen and chemoattractant [8, 9] whose signaling pathway leading to mitogenesis has been well characterized. In the interest of simplicity, this review will focus mainly on the signaling pathways that mediate PDGF-stimulated cell motility with appropriate comparisons to other growth factors that have been studied. Before we begin our discussion it is important for the sake of clarity to make distinctions between the different types of induced cell motility: chemokinesis (random motility), chemotaxis and haptotaxis. Chemokinesis is the induction of random, nondirectional motility in response to a ligand without any orienting cues. On the other hand, chemotaxis and haptotaxis represent a directional response of cells to a gradient of ligand. Chemotaxis describes the directed migration of cells towards a positive gradient of soluble chemoattractant whereas haptotaxis is the directed migration of cells along a gradient of anchored substrate such as ECM molecules.
It is as yet unclear whether these different types of motility responses utilize distinct signaling pathways. The motility responses to PDGF are complex as it stimulates chemotaxis in fibroblasts and epithelial cells [10], whereas smooth muscle cells respond by undergoing chemokinesis [11]. For chemotaxis to occur a cell must be able to distinguish a spatial difference in concentration of the ligand at its leading edge versus its trailing end, thus allowing it to become polarized and move up the gradient. It is important to note that both random and oriented migration will be inhibited by agents that disrupt the motile apparatus. In contrast, agents that act exclusively on directional cues will only block chemotaxis, not chemokinesis.
PDGF can exist in a homodimeric form AA, or BB and in a heterodimeric form AB [12]. The various isoforms of PDGF have differential effects on fibroblasts, monocytes, granulocytes and smooth muscle cells [13]. Recent reports suggest that the migratory response induced by ligand binding to the PDGF-ß receptor (PDGFR-ß) may be different from that induced by ligand binding to the PDGF-
receptor [14]. PDGF BB exerts its effect on cells by binding to its cell surface tyrosine kinase receptor, PDGFR-ß. As with the majority of the members of the receptor tyrosine kinase family, PDGFR-ß contains an extracellular domain consisting of immunoglobulin-like regions, a transmembrane domain and an intracellular region which contains a tyrosine kinase domain. Upon binding of its ligand, PDGF BB, the receptor dimerizes and activates the receptor tyrosine kinase which autophosphorylates the receptor [15]. A number of autophosphorylation sites have been identified in the intracellular domain, which allow for specific binding of downstream signaling molecules ([15], and references therein). As with mitogenesis, autophosphorylation of PDGFR-ß is essential for chemotaxis toward PDGF to occur [15-17]. The five potential signaling molecules, phospholipase C-gamma (PLC-gamma), phosphatidylinositol-3 (PI-3) kinase, Ras-GAP, Syp-phosphatase and Src have separate specific binding sites on the PDGF receptor. All these molecules contain a highly conserved stretch of 100 amino acids, Src-homology-2 (SH2) domains along which interactions with the receptor take place [12, 18]. These associations are highly specific and require the phosphorylation of tyrosine residues in the appropriate intracellular domain of the receptor [19]. The strategy of transfecting cells with PDGFR-ß subunits containing tyrosine to phenylalanine (Y
F) substitutions of specific tyrosines has allowed the identification of signaling molecules important in PDGF-mediated mitogenesis [19-24]. These mutations prevent the phosphorylation of that specific domain of the receptor and inhibit the binding of the signaling intermediate to be studied. One drawback of this approach is that it fails to ascertain if a specific signaling molecule is sufficient to elicit the response being tested. This problem was overcome by the analysis of "add back" mutants developed by Andrius Kazlauskas and coworkers [25]. PDGF receptors with YF mutations in all five tyrosines responsible for binding PLC-gamma, PI-3 kinase, GAP and Syp phosphatase were unable to transduce mitogenic or chemotactic signals in response to PDGF. Adding back of specific tyrosines was employed as a strategy to determine which, if any, signaling intermediate was sufficient by itself or in combination with others to induce a PDGF-mediated response, mitogenesis or chemotaxis.
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PLC-Gamma
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Activation of PLC is an immediate response to stimulation by a number of growth factors, and results in the hydrolysis of phosphatidylinositol 4,5 bis phosphate, with the generation of inositol triphosphate and diacylglycerol (DAG). Increased levels of inositol triphosphate result in the release of Ca2+ from intracellular stores which acts in concert with DAG to activate protein kinase C (PKC) [26-28]. Products of PLC activation have been postulated to promote chemotaxis of certain cell types [29]. The gamma isoform of PLC contains an SH2 domain which binds to the phosphorylated tyrosine residue at position 1021 on the PDGF receptor [30]. PDGF-induced activation of PLC-gamma is not consistently required for DNA synthesis [23, 25, 31]. Cells expressing PDGFR-ß subunits with YF mutation at position 1021 fail to bind or activate PLC-gamma in response to PDGF. These cells show reduced migration toward PDGF, suggesting that the PLC-gamma binding site on the receptor is a positive regulator of chemotaxis [16]. Cells expressing dominant negative mutants which suppress by 60% the endogenous PLC activity normally observed after PDGF stimulation show reduced migration toward PDGF BB [16]. Several possible mechanisms can be postulated to explain the positive regulation of chemotaxis by PLC-gamma: A) DAG, a byproduct of PLC activation, has the potential to nucleate actin, which is a critical step in pseudopod extension [32]; B) phosphatidylinositol bis phosphate, the substrate for PLC-gamma, associates with profilin, gelsolin and myosin type I actin binding proteins which are implicated in actin reorganization and the motility response [33-35], and C) PKC activation (generated by an increase in intracellular Ca2+ and DAG associated with PLC activation) has been shown to positively regulate chemotaxis mediated by PDGF and other growth factors [29, 36, 37]. Interestingly, add-back experiments suggest that PLC-gamma is sufficient to induce the mitogenic response, but not sufficient by itself to mediate the chemotactic response to PDGF ([16, 25] and Kundra and Zetter, unpublished observations).
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PI-3 Kinase
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PI-3 kinase is a complex, composed of a regulatory subunit, p85, and a catalytic subunit, p110, which associates with a majority of tyrosine kinase growth factor receptors. The p85 subunit binds to phosphorylated tyrosine residues at positions 740 and 751 on the PDGF receptor [19, 21]. Cells expressing PDGF receptors with YF substitution at these two positions failed to migrate toward PDGF [16, 38]. This can be correlated with their inability to bind and activate PI-3 kinase. Cells containing the PDGF receptor in which the entire kinase insert domain was deleted also showed decreased chemotaxis toward PDGF [16]. These cells also fail to respond mitogenically to PDGF. The kinase insert domain of the PDGF receptor contains the binding site for PI-3 kinase, further suggesting that PI-3 kinase may be a positive regulator of chemotaxis. However, add-back experiments suggest that although PI-3 kinase is sufficient to induce the mitogenic response to PDGF, it cannot mediate the chemotactic response in the absence of activation of other signaling molecules ([25], Kundra, unpublished observations]. Double add-back mutants in which the mutated PDGF receptor can bind PLC-gamma and PI-3 kinase but not GAP and Syp can migrate toward PDGF, indicating that both PLC-gamma and PI-3 kinase are necessary and together sufficient to induce chemotaxis (Kundra and Zetter, unpublished observations). It should be noted, however, that these responses may be specific for only some chemotactic factors as the ability of FGF receptor to promote chemotaxis is not dependent on increased activation of PLC-gamma, increased hydrolysis of phosphatidylinositol, or increased mobilization of calcium [39].
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Ras-GAP
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The PDGF-ß receptor kinase insert domain also contains a binding site for the signaling intermediate Ras-GAP along with the PI-3 kinase binding site [19, 21]. Ras-GAP is an SH2 domain-containing protein which stimulates the GTPase activity of normal Ras. Ras is a guanine nucleotide-binding protein which is active in its GTP-bound state and inactive in its GDP-bound state [40]. Ras-GAP accelerates the rate of GTP to GDP conversion thus inactivating Ras [41]. The activated PDGF receptor binds and phosphorylates GAP resulting in a translocation of a fraction of the total cellular GAP pool to the plasma membrane. YF mutations at position 771 of the PDGF receptor result in the inability of the activated receptor to bind GAP. This mutation has no effect on the ability of cells to respond mitogenically to PDGF [19, 21]. However, these cells migrate toward PDGF somewhat better than cells containing the wild type receptor, suggesting that GAP may in fact be a negative regulator of chemotaxis [16]. One mechanism for this effect may be the activation of GAP enzymatic activity upon binding to the receptor, which prevents Ras from maintaining the activated GTP-bound state for long periods of time. The other possibility is that the association of GAP with the receptor may serve to dock some other protein to the receptor which may have a negative regulatory effect.
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Syp Phosphatase
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Tyrosine to phenylalanine substitutions at position 1009 of the PDGF receptor result in an inability of the receptor to bind and activate Syp phosphatase [42]. Cells expressing the PDGFR-ß with this mutation can respond mitogenically to PDGF. These cells demonstrate an increased chemotactic response to PDGF (Mootha and Anand-Apte, unpublished observations) suggesting that Syp phosphatase may be a negative regulator of chemotaxis.
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Src
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Mutations at the Src binding site on the PDGF receptor were found to have no effect on the immediate motility response of membrane ruffling [38], suggesting that Src may not play a role in regulating migration toward PDGF.
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Sphingosine-1-Phosphate (Sph-1-P)
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PDGF receptor activation induces the formation of Sph-1-P. Sph-1-P does not affect the activation of PDGF-induced mitogenic signaling pathways, such as MAP kinase, leading to DNA synthesis and proliferation of cells. Sph-1-P inhibits motility toward PDGF probably by interfering with the dynamics of actin filament polymerization and depolymerization [43].
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Calcium and Calcium-Dependent Kinases
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Transient increases in intracellular calcium, probably mediated by periodic releases from intracellular stores, are seen during migration of cells [44-46]. Intracellular calcium gradients are observed in polarized locomoting cells, and a change of direction results in the a rapid transient change in the gradient in the new direction of cell motion [47, 48]. Tyrosine kinase receptor-mediated chemotactic factors can induce rapid increases in Ca2+ [49-52]. The migration of vascular smooth muscle cells toward PDGF BB is mediated and regulated via activation of a number of calcium-dependent enzymes such as calcium/calmodulin dependent protein kinase II, calcineurin (calcium/calmodulin activated protein phosphatase) and PKC [51, 53]. These calcium gradients probably play a role in the spatial regulation of the dynamics of actin filament assembly and disassembly resulting in forward motion.
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Ras
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Ras has been shown to be a critical intermediate in the signaling cascade for mitogenesis [54-57]. Ras is a guanine nucleotide-binding protein which is active in its GTP-bound state and inactive in its GDP-bound state [40]. Ras has a low level of intrinsic GTPase activity which converts Ras-bound GTP to GDP. Ras-GAP accelerates Ras-mediated GTP hydrolysis and inactivates Ras [41]. In contrast, Ras guanine nucleotide releasing factors such as the Ras-guanine nucleotide releasing factor and Sos accelerate the rate of guanine nucleotide exchange and activate Ras protein [58].
Fibroblasts expressing dominant negative Ras protein [55], which show a 20-40-fold decreased affinity for GTP, are inhibited in their chemotactic response toward PDGF [59]. Overexpression of Ras-GAP causes a decrease in the amount of activated Ras and results in an inhibition of the chemotactic response toward PDGF [59]. Ras activation has also been shown to play a role in wound-stimulated motility in corneal and vascular endothelial cells [60, 61]. Neointimal thickening following balloon injury of the rat carotid artery was inhibited by dominant negative Ras [62]. Conflicting results have been reported for the role of Ras in epithelial cell scattering in response to scatter factor [63, 64]. Interestingly, Ras seems to be important in the signaling cascade for the lysophosphatidic acid-induced motility response but not the fibronectin response [59], suggesting that different motility-inducing factors might utilize unique signaling pathways. It is also important to note that downregulation of Ras does not cripple the motile machinery of the cell as the cells have the ability to move toward some ligands. Recent evidence seems to suggest that Ras by itself may be sufficient to generate cytoskeletal rearrangements but not actual cell movement [65].
Classically, chemotaxis is characterized by a bell-shaped response curve with either too much or too little ligand limiting chemotaxis. In order to orient itself, a cell should be able to sense a spatial differential in the concentration of the ligand between its frontal and distal ends. If the polarization of the cell is the result of differential receptor activation at either end of the cell, then it could be postulated that a spatial localization of secondary signaling molecules could be important in determining the direction of cell movement. Thus the leading front of the cell might have an increased concentration of the positive regulatory signaling intermediates while the trailing edge might exhibit a higher concentration of the negative regulatory molecules. In support of this hypothesis some indirect evidence has been obtained to suggest that upregulation of H-Ras and EJ Ras activity in cells results in an inhibition of chemotaxis toward PDGF [59]. Conflicting results on the effect of Ras overexpression on random unstimulated motility of cells [10, 59, 60] suggest that different isoforms of Ras might have varied effects on specific cell types. Similarly, overexpression of guanine nucleotide releasing factors in cells, which facilitate the maintenance of Ras in its active GTP-bound state, also has the same inhibitory effect [59]. In both these cases, it can be envisioned that overexpression of a signaling molecule may essentially flood a cell and prevent the recognition of subtle differences in concentrations of Ras by different regions of the cell.
Overexpression of a number of other potential signaling molecules (sis, src, fes and fems) also results in a decrease in the chemotactic response toward PDGF [66]. The loss of the chemotactic response in these cells cannot be ascribed to cellular transformation since, of the cells transformed by the serine/threonine kinase, most migrate efficiently toward PDGF [66].
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Raf and Map Kinase Pathway
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Raf has been reported to be downstream of Ras in a number of signal transduction systems including mitogenesis of fibroblasts. Raf is recruited by Ras to the plasma membrane where it is subsequently activated [67-69]. Raf kinase activity directly leads to activation of MAP kinase kinase (MEK-1) and subsequent activation of MAP kinase [67, 70-72]. Complexes containing MAP kinase, Raf and Ras-GTP have been isolated [73, 74]. Neointimal thickening following balloon injury of rat carotid artery was not inhibited by dominant negative Raf, suggesting that it may not be involved in the signaling cascade for smooth muscle cell migration in response to PDGF. Additional evidence suggests that MAP kinase activity by itself is not sufficient for epidermal growth factor or PDGF-induced cell motility [75]. Experiments using cells transfected with dominant negative MEK show no alteration in their chemotactic response to PDGF (Anand-Apte, submitted). In addition, insulin-like growth factor-1 has been shown to induce cell motility independent of MAP kinase activation [76]. Although Raf and MAP kinase appear to be along the pathway for PDGF BB-mediated mitogenesis, they may lie outside the cascade for PDGF-mediated chemotaxis. This might imply that signal transduction pathways leading from an activated tyrosine kinase receptor to the nucleus or membrane/cytoskeleton to induce mitogenesis or chemotaxis, respectively, might diverge at a point distal to Ras activation.
Ras can interact directly with the catalytic subunit of PI-3 kinase as well as additional newly identified proteins [77, 78]. The role, if any, of these other Ras-binding proteins in the regulation of chemotaxis has not yet been determined.
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Ras Related GTPases—Rho Family
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The Rho GTPases are a subgroup of the Rho family of small GTP-binding proteins. Similar to Ras, these proteins toggle between an active GTP-bound state and an inactive GDP-bound state [79]. It has been demonstrated that members of the Rho family of GTPases (cdc-42, Rac-1 and Rho) are regulators of distinct components of the actin cytoskeleton. Rac-1 was found to regulate the formation of lamellipodia (membrane ruffling) [80]; Rho is important in the formation of stress fibers [81] and cdc-42 is responsible for the induction of filopodia [65, 82-86]. Other functions may also be attributed to these molecules.
Lamellipodia are flat pleat-shaped protrusions from the leading edge of the cell which are believed to be pathognomonic of the motile phenotype. Microinjection of activated Rac protein into cells induced the formation of lamellipodia [80]. The first hint of the mechanism by which Rac may regulate actin polymerization was the observation that activated Rac could uncap barbed ends of actin filaments [87]. This process of uncapping appears to be mediated by phosphoinositide synthesis. Cells expressing N17-dominant negative Rac protein, which has a reduced affinity for GTP, are inhibited in their membrane ruffling as well as chemotaxis response to PDGF (Anand-Apte, submitted).
Additional evidence that Rho GTPase can regulate actin polymerization has come from the recent finding that Wiscott Aldrich Associated Protein (WASP) is an effector of cdc-42 [88-90]. Cellular expression of WASP causes clusters of WASP which are highly enriched in polymerized actin [89]. In a number of systems, signaling cascades for cytoskeletal rearrangements have placed Ras upstream of cdc-42, which is an activator of Rac. Rac is capable of independently activating Rho and is believed to function upstream of Rho. However, it should be noted that the precise hierarchy of these molecules in various signaling cascades may depend on experimental conditions and cell type and should therefore be interpreted with caution [91].
It has recently been shown that Rac and Rho are essential for transformation by Ras [92-95]. However, the observation that dominant negative Rac can inhibit transformation by oncogenic Ras but not by constitutively active Raf suggests that the two pathways (Rac/Rho and MAP kinase) bifurcate at the level of Ras [92-94]. Molecules and effectors downstream of Rac which are important in the chemotaxis signaling pathway have yet to be ascertained.
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ECM and Integrins
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Migration of cells on ECM require functional integrins. Recent evidence indicates that cell migration may be mediated by crosstalk between signaling induced by integrins and tyrosine kinase receptors. Focal adhesion kinase (FAK) is a tyrosine kinase which is localized in focal contacts [96, 97]. Tyrosine phosphorylation of FAK has been observed in response to integrins [98-102] as well as growth factors such as PDGF [103, 104]. PDGF also stimulates the association of FAK with PI-3 kinase and a 200 kD tyrosine phosphorylated protein [103-106]. Hepatocyte growth factor-induced motility response includes the recruitment of p125FAK, CSK proteins and integrins to focal adhesions in a tyrosine kinase dependent manner [107]. FAK-deficient mice show decreased migration and increased focal adhesions indicating that FAK may be involved in the turnover of focal contacts during cell migration [108].
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Conclusions and Future Directions
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Migration of vascular smooth muscle cells from the tunica media to the tunica intima of the vessel wall is believed to play a significant role in many vascular diseases [109-112]. This phenomenon has been implicated in the formation of atherosclerotic plaques as well as restenosis following angioplasty. Cell migration has also been suggested to be critical in the development of plaque-associated neovascularization which may be a key factor in the development of intraplaque hemorrhage and thrombosis resulting in acute myocardial infarction.
The molecular basis for this migratory response of cells is not clearly understood. Although this review has focused on some of the signaling pathways utilized for this process, it is important to remember that the process in vivo is probably more complex. There is likely an interplay between receptors on cells, migration and proliferation-inducing factors, environmental factors, ECM regulation and autocrine and paracrine interactions, etc. Identification of these mechanisms will allow a better understanding of the pathogenesis of atherosclerosis and the development of refined tools in the future for therapeutic intervention in cardiovascular diseases.
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accepted for publication April 21, 1997.
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Abstract
PLC-Gamma
