Protein which participates in cell movement

In eukaryotes, there are three types of protein fibers in the cytoskeleton: microfilaments , intermediate filaments , and microtubules. Intermediate filaments are not associated with motor proteins. Double helical structure of microfilament, composed of two intertwined strands of actin subunits. Microtubules are hollow structures composed of polymerized dimers of tubulin right image.

The left image shows the molecular structure of the tube. Image credit: OpenStax Biology. ATP, dynein motor proteins, and microtubule tracks are essential for movement of eukaryotic cilia and flagella. Flagella singular, flagellum are long, hair-like structures that extend from the cell surface and are used to move an entire cell, such as a sperm.

If a cell has any flagella, it usually has one or just a few. Note that, while they carry out the same function, the eukaryotic flagella discussed here has a fundamentally different structure from the prokaryotic flagella. Motile cilia singular, cilium are similar, but are shorter and usually appear in large numbers on the cell surface.

When cells with motile cilia form tissues, the beating helps move materials across the surface of the tissue. For example, the cilia of cells in your upper respiratory system help move dust and particles out towards your nostrils. Despite their difference in length and number, flagella and motile cilia share a common structural pattern and mechanism driving movement:.

The information below was adapted from OpenStax Biology ATP, motor motor proteins, and actin microfiliament tracks are essential for contraction of eukaryotic muscle. Muscles allow for motions such as walking, and they also facilitate bodily processes such as respiration and digestion.

The vertebrate body contains three types of muscle tissue: skeletal muscle, cardiac muscle, and smooth muscle:. The body contains three types of muscle tissue: skeletal muscle, smooth muscle, and cardiac muscle, visualized here using light microscopy. Smooth muscle cells are short, tapered at each end, and have only one plump nucleus in each.

Cardiac muscle cells are branched and striated, but short. The cytoplasm may branch, and they have one nucleus in the center of the cell. Muscles are composed of structures that enable contraction to promote organsimal movement. Each skeletal muscle fiber is a single skeletal muscle cell. Within each muscle fiber are myofibrils: long cylindrical structures that lie parallel to the muscle fiber. Myofibrils run the entire length of the muscle fiber, and because they are only approximately 1.

Sarcomeres give muscle its striated or banded appearance, due to the alternating bands of actin and myosin that allow sarcomeres to contract. A skeletal muscle cell muscle fiber is surrounded by a plasma membrane called the sarcolemma with a cytoplasm called the sarcoplasm. Collectively our results suggest that AbpG may participate in modulating actin dynamics to optimize cell locomotion.

In various physiological and pathological events, such as embryonic development, inflammatory and immune responses, and cancer metastasis, cell migration responding to environmental cues is a pivotal mechanism Bravo-Cordero et al. The migration process requires the coordination of signaling pathways and the motility machinery Insall, , and the complex underlying molecular network remains to be fully elucidated. Eukaryotic cell migration generally involves drastic cell shape changes driven by the rearrangement of cytoskeleton.

In the crawling movement of cells, continuous reorganization and turnover of the actin cytoskeleton occur Pollard and Borisy, At the cell front, rapid actin polymerization drives the extension of membrane protrusions such as lamellipodia and filopodia Bisi et al.

The new cellular protrusions adhere to the substratum through proteins that can engage the extracellular matrix to provide anchor points. For optimal migratory movement, a cell needs the contraction ability to drive the translocation of the trailing cell body; this ability depends on the interaction between actin filaments and myosin Cramer, The cell rear is detached from the original adhesion to allow the cell to advance a step.

These events proceed in a cyclical manner and are spatially and temporally coordinated Lauffenburger and Horwitz, ; Maruthamuthu et al. Dynamic reorganization of the actin cytoskeleton is intricately controlled by a myriad of actin-binding proteins ABPs; Winder and Ayscough, Two forms of actin—globular monomeric G-actin and filamentous polymeric F-actin—coexist in cells in a dynamic equilibrium; ATP—G-actin monomers add to the barbed end, and ADP—G-actin subunits dissociate from the pointed end of F-actin.

Many ABPs have been identified and categorized into a few major families based on the actin-binding domains, including the actin-depolymerizing factor homology ADF-H domain, the gelsolin homology domain, the Wiskott—Aldrich syndrome protein WASP homology-2 WH2 domain, the calponin homology CH domain, and the myosin motor domain Paunola et al.

Other activities of ABPs include filament capping, debranching, monomer binding, bundling, and cross-linking Winder and Ayscough, The repertoire of actin regulators is still expanding, and the cellular roles of many ABPs are still elusive. Dictyostelium discoideum is a simple eukaryote that exhibits chemotactic migration in multiple stages of its life cycle. During growth, Dictyostelium amoebae migrate toward bacteria and consume them by phagocytosis as their food. Under nutrient depletion, Dictyostelium cells enter a developmental program in which single cells collectively move toward the cAMP signals released from designated central cells, forming aggregates that later undergo differentiation and morphogenesis to turn into multicellular structures Kay, ; Weijer, With the many available molecular genetics tools and the haploid state ideal for genetic screening, Dictyostelium has been extensively exploited in studying cell migration and actin regulation Egelhoff and Spudich, ; Noegel and Schleicher, To uncover novel molecular players in the pathways underlying chemotactic cell migration, we previously performed a screen for Dictyostelium mutants defective in chemotactic responses to cAMP Pang et al.

In the present study, we analyzed a mutant collected in the screen and identified a novel actin-binding protein involved in modulating cell migration. T6 16 was a restriction enzyme—mediated integration REMI —generated mutant that showed defective chemotactic movement. Through standard REMI plasmid recovery procedures and sequencing analysis, we identified DDB, a previously uncharacterized open reading frame located at coordinates — of chromosome 4, as the gene disrupted in T6 We named this gene abpG and its —amino acid aa product actin-binding protein G AbpG see later discussion.

We examined the expression of abpG during development and found that AbpG protein levels peaked at the aggregation stage Figure 1C , which is consistent with a possible role of AbpG in supporting chemotactic migration. A, B Developmental phenotype. Cells developed on bacterial lawns and non-nutrient agar were photographed 5—7 d and 24—36 h, respectively, after plating.

C AbpG expression during development. Cells were developed on non-nutrient agar and harvested at different time points. Total lysates were analyzed by Western blotting with antibodies against AbpG and actin. Relative AbpG levels normalized to actin and relative to the value in V are shown at the bottom. We examined the chemotactic response of cells lacking AbpG in semiquantitative small-drop chemotaxis assays.

Cells were developed for 5—6 h with cAMP pulsing to become aggregation competent. A Small-drop chemotaxis assay. Developed cells in small drops were placed adjacent to cAMP drops on agar and examined after 20 min.

Drops showing more cells on the cAMP side were scored positive for chemotaxis. B, C Micropipette chemotaxis assay. Cells were stimulated with cAMP released from a Femtotip.

Images were captured every 10 s for a period of 20 min. Shown are micrographs taken before 0 min and after 20 min cAMP stimulation. Migration tracks of 10 cell centroids are shown on the right; black dot, the position of the Femtotip.

D Morphology of migrating cells. Red asterisk, the position of Femtotip. We further performed micropipette chemotaxis assays and recorded the migratory behavior of cells in cAMP gradients by time-lapse video microscopy.

Together our data suggest that AbpG functions to support optimal cell migration. Migration speed, migration distance per unit time. Directional persistence, net to total path length. Chemotaxis index, the cosine value of the angle between the direction of cell movement and the direction toward the chemoattractant source. Data presented are means with SDs from three independent experiments; n , total number of cells traced. A direction-sensing mechanism in Dictyostelium involves the asymmetrical activation of phosphatidylinositide 3-kinase to generate a local surge of phosphatidylinositol 3,4,5 -triphosphate PtdIns 3,4,5 P 3 ; Funamoto et al.

Results of Western blot analysis on detergent-soluble and -insoluble fractions of cell lysates showed that a significant amount of AbpG existed in the pellet fraction, consistent with the notion that AbpG can associate with cytoskeletal components Figure 3A. We investigated the subcellular localization of AbpG by immunofluorescence cell staining.

The AbpG-specific antiserum we generated could barely detect endogenous AbpG in immunofluorescence experiments; therefore we used AbpG-overexpressing cells to examine the localization of AbpG.

We next checked whether AbpG exhibits dynamic spatial distributions in actively migrating cells. Analysis of fluorescence signals in micrographs revealed that the appearance of mRFP-AbpG and the assembly of F-actin at the leading edge during migration shared similar kinetics Figure 3C. Note that AbpG could localize to locations other than the leading edge.

Together our data highlight the spatial and temporal colocalization of AbpG with F-actin in migrating cells. A Localization of AbpG in the detergent-insoluble cytoskeleton. Triton X—soluble S and —insoluble P fractions were prepared from aggregative cells and analyzed by Western blotting using antibodies against AbpG and actin.

B Colocalization of AbpG and F-actin in fixed cells. Cells were observed under a confocal microscope, and images were taken every 4 s. Two sets of consecutive micrographs are shown. On the basis of this predicted domain structure, we prepared plasmids to express a series of AbpG fragments that are fused with mRFP at their N-termini Figure 4A and assessed the cellular distribution of these mRFP-AbpG fragments in vegetative wild-type cells Figure 4B. These results indicate that the aa — region contains the required element for directing AbpG localization.

A Schematic representation of AbpG protein structure and different AbpG fragments used in domain mapping. B Cellular distribution of different AbpG fragments. C Colocalization of AbpG fragments and F-actin. Images were taken under a confocal microscope.

Western analysis on the precipitated proteins demonstrated specific, although not very robust, coimmunoprecipitation of actin with Flag-AbpG Figure 5A , indicating that AbpG can associate with actin in the context of cells.

To map the AbpG region required for interacting with actin, we expressed glutathione S -transferase GST —fused AbpG aa 1—, —, —, and — fragments in wild-type Dictyostelium cells; lysates were prepared from aggregation-stage cells and subjected to GST pull-down procedures. Western analysis on the pulled-down proteins showed that only the aa — AbpG fragment could interact with actin Figure 5B.

Furthermore, we expressed GST fusions to the four aa AbpG fragments within the aa — region in Escherichia coli. These four GST-AbpG fragments were purified and mixed with lysates of aggregative wild-type Dictyostelium cells and tested for actin interaction in GST pull-down assays. We checked whether the association of GST-AbpG with actin could still occur when the F-actin organization is disrupted.

The results showed that GST-AbpG failed to pull down a detectable amount of actin in lysates prepared from cells that were pretreated with latrunculin B which is a disruptor of microfilament organization; Figure 5D , consistent with the finding from the mRFP-AbpG studies that AbpG colocalized with cortical F-actin. We next used in vitro F-actin sedimentation assays using purified recombinant AbpG fragments to test for direct interaction with F-actin.

In addition, we tested AbpG fragments for G-actin—binding activity by an in vitro G-actin—sequestering assay; G-actin monomers were preincubated with purified recombinant GST-AbpG before initiating the polymerization reaction.

A Coimmunoprecipitation assay. B—D GST pull-down assay. Dictyostelium lysates were from untreated developed cells C or developed cells pretreated with dimethyl sulfoxide or latrunculin B D. E In vitro F-actin sedimentation assay.

Reaction mixtures were subsequently centrifuged to sediment F-actin. We further investigated the functional importance of the actin-binding aa — region of AbpG. A In vitro F-actin sedimentation assay.

Recombinant GST-AbpG fragments purified from bacteria were added in the actin polymerization reactions. After sedimentation of F-actin by centrifugation, proteins in supernatant and pellet fractions were analyzed using SDS—PAGE, followed by Coomassie blue staining top or Western blotting bottom. B Live-cell images.

Live vegetative wild-type cells expressing different mRFP-AbpG fragments were observed under a confocal microscope. C Developmental phenotype. Cells were developed on bacterial lawns.

Photographs were taken 5—7 d after plating. It should be noted here that depletion of GMAP led to loss of the pericentrosomal Golgi localization and to an inhibition of directional cell migration [ 11 ]. Another question that is provoked by these findings is whether Golgi-originating MTs are qualitatively or functionally distinct from those that nucleate at the Golgi?

Importantly, MTs originating from the Golgi were radial as those emanating from the centrosome. Instead, Golgi-nucleated MTs preferentially oriented towards the leading edge in migrating cells, thus contributing to the asymmetry of the microtubule network [ 22 ].

This question was at least partially answered by the finding that the cis -Golgi protein GM is involved in MT formation [ 24 ]. Again, Golgi-emanating MTs were oriented towards the leading edge in migrating cells, and consequently, depletion of AKAP inhibited directional cell migration [ 24 ]. The studies discussed previously clearly establish that the Golgi is an MT-nucleating organelle.

However, they do not take the nature of the Golgi into account. Alternatively, if we assume that the cisternal maturation model is correct, MTs forming at the cis -Golgi in an AKAPdependent manner will move on as the cisterna is maturing. Alternatively, the MTs formed at the cis- Golgi are handed over as the cisterna matures. This scenario requires the existence of other factors at the medial to trans -Golgi that are required for the formation of MTs.

Whether these assumptions are true has to be determined in the future. ERKs transmit signals downstream of a plethora of receptors and thus they orchestrate a wide range of biological processes such as proliferation, differentiation, and cell movement. However, whether Golgi-localized active Ras has any direct role in cell migration remains to be determined.

This appears likely to be the case, because downstream targets of Ras in particular ERK have been shown to regulate directional cell movement. Intriguingly, serine is also phosphorylated by cdk1 during mitosis [ 28 ].

Mutation of serine to alanine led to an inhibition of Golgi and centrosome orientation towards the leading edge [ 14 ]. In conventional light microscopy, treatment of cells with mitogens does not change Golgi morphology [ 14 ], our unpublished observations. Whether there is a mild rearrangement of Golgi structure which facilitates its orientation towards the leading edge remains to be determined.

Importantly, these cells also display a fragmented Golgi, which most likely accounts for the observed inhibition of migration [ 29 ]. These data can be interpreted as follows: the excessive Ras and in consequence ERK activation in pRasGAP depleted cells results in fragmentation of the Golgi which in consequence inhibits directional cell migration. Whether an analogous effect for a Ras GEF exists in epithelial cells remains to be determined. The Raf kinase inhibitory protein 1 RKIP1 has been identified to act as a suppressor of metastasis in a variety of cancer types [ 31 , 32 ].

RKIP1 overexpression inhibits cell migration and reduces the invasive potential of cancer cells. On the other hand, RKIP1 expression is reduced in specimens derived from metastatic lesions, thus emphasizing its role as a prometastatic protein [ 33 ].

Loss of RKIP1 increases ERK signaling, and this is a condition that is thought to causally underlie the increase in cell migration and the elevated metastatic potential of the cell. It remains to be determined whether this is the case and whether this involves signaling to or from the Golgi. RKTG is a seven-transmembrane protein that localizes to the Golgi with its N-terminus facing the cytosol [ 34 ].

Despite the well known connections of Golgi and migration on one side and ERK signaling and migration on the other side, very little is known about whether RKTG interferes with ERK signaling to the Golgi in the context of cell motility. Thus, RKTG is involved in regulating tumor angiogenesis [ 35 ]. However, whether RKTG has a direct impact on the motility of epithelial cancer cells remains to be determined in the future.

JNKs have been shown to signal downstream of Rho family GTPases, which are well known regulators of cell migration see the following. Rho family GTPases are small G-proteins consisting of three main members, Rho, Rac, and Cdc42, which were shown to regulate a variety of cellular processes such as cell death, phagocytosis, and cell polarity.

In addition, while inactive Rho family GTPases are bound to Rho-GDI guanine-nucleotide dissociation inhibitor that functions as a chaperone preventing nonspecific, premature activation.

In a wound scratch assay, activation of Cdc42 has been observed to occur within the first hour after wounding suggesting that Cdc42 activation is an early event in cell migration [ 38 ]. In agreement with this, depletion of Cdc42 inhibited directional cell migration.

However, although the involvement of Cdc42 in directional polarity is beyond any doubt, major evidence came from biochemical experiments that do not allow any conclusion about spatial aspects of this activity. Therefore, considerable efforts in the past 10 years were spent on the development of fluorescent sensors that allow visualization of Cdc42 and other Rho GTPase members activity in living cells.

These reporters are mostly based on FRET fluorescence resonance energy transfer , and a review on the various constructs that were designed to report spatiotemporal signaling of Rho family GTPase members has been published very recently elsewhere [ 39 ]. Using these fluorescent reporters, several groups reported on the existence of a pool of Cdc42 at the Golgi [ 40 , 41 ].

However, most of these experiments are based on overexpressed Cdc42, which might lead to oversaturation of Rho-GDI resulting in a higher basal activity of Cdc42 in these cells, and therefore, more work is needed to elucidate whether Cdc42 is truly active at the Golgi.

In addition, it has to be determined whether active Cdc42 that is observed at the Golgi is the result of local activation or whether Cdc42 was activated at another location and is then transported in its active form to the Golgi. A recent report suggested yet another role for the Golgi in controlling Cdc42 activity. There, Osmani et al. They showed that enrichment of Cdc42 was dependent on post-Golgi membrane trafficking.

This finding indicates that the role of the Golgi in controlling Cdc42 activity is mediated by directing secretory traffic towards the leading edge, supplying the plasma membrane with modulators of Cdc42 activity [ 42 ]. In support for a bona fide activity of Cdc42 at the Golgi was the discovery that the Golgi matrix protein GM interacts with Tuba and recruits it to the Golgi [ 43 ]. Tuba is an exchange factor for Cdc42, and therefore, this discovery would indicate that Cdc42 is activated locally at the Golgi.

This was further supported by the finding that knockdown of GM by siRNA reduced the steady-state level of active Cdc42 [ 43 ]. However, it should be noted here that cell migration is unlikely to be mediates by the steady-state levels of active Cdc42, but rather the result of induced Cdc42 activity and this was not tested for. In addition, the pool of Tuba observed on the Golgi in this report was very faint and most other findings including our own unpublished observations indicate that Tuba primarily localizes to locations other than the Golgi [ 44 ].

Therefore, more work is needed to determine whether Golgi membranes provide an environment where Cdc42 can be activated. This is important in order to support a primary role for the Golgi in directional cell migration where the Golgi not only responds to polarity signaling originating from the plasma membrane, but in fact initiates such polarity signaling.

Further attempts will also have to focus on whether active Cdc42 at the Golgi regulates other signaling pathways involved in cell migration.

This and many other questions will have to be answered in the future. Like Cdc42, also some of its downstream effectors have been shown to localize to the Golgi and to be involved in cell migration.

Early evidence suggested that this might be the case [ 48 ], and it was clearly proposed that WASPs would promote cell migration and invasion and therefore be prometastatic. WASP proteins have been shown to be regulated by signaling. Overexpression of a WAVE2 mutant that cannot be phosphorylated inhibits orientation of the Golgi towards the leading edge and in consequence also directional cell migration [ 49 ].

Therefore we might ask whether phosphorylation of GRASP65 and WAVE2 by ERK occurs simultaneously, and if yes, whether there is any dominance of one effect over the other and finally we have to determine whether these effects are cell-type specific in order to reach a generally applicable conclusion that would qualify these molecular events to be potential targets for antimetastatic cancer therapy.

Phosphorylation of WAVE2 in the context of cell migration has been shown by several kinases such as Cyclin-dependent kinase 5 [ 50 ] or Casein kinase-2 [ 51 ]. Whether these events occur on the Golgi remains to be determined. Targeting Rho signaling is important in light of the fact that upstream regulators as well as downstream signaling molecules of Rho GTPases were shown to determine the metastatic potential of several cancer types.

For instance, PAK1, which signals downstream of Cdc42 and Rac, was shown to be overexpressed in hepatocellular carcinoma and expression of PAK1 was furthermore shown to correlate with the metastatic potential of this cancer type [ 52 ].

For other proteins linked to Rho GTPases, the situation is less clear. Divergent findings have been made concerning the role of RhoGDI2 in cancer, which seems to depend on the type of cancer investigated. For instance, in ovarian cancer, RhoGDI2 was shown to be a suppressor of proliferation, invasion, and metastasis [ 53 ].

RhoGDI2 expression is elevated in gastric cancer [ 54 ] but downregulated in bladder cancer [ 55 ]. Upon entry into mitosis, the Golgi apparatus disassembles and reforms at the end of mitosis in the two new daughter cells [ 56 — 58 ]. Therefore, it is not surprising that Golgi proteins were shown to be phosphorylated by mitotic kinases such cyclin-dependent kinases Cdk.

Apart from mitotic effects, there are atypical Cdk family members that are activated by proteins other than cyclins and Cdk5 is one of these [ 59 ]. Cdk5 was shown to phosphorylate the Golgi protein GM and thereby to mediate Golgi fragmentation in apoptotic neurons [ 56 ].

Cdk5 has a well-documented role in cell migration where the majority of effects described are due to alterations of the actin cytoskeleton via modulating proteins like pRhoGAP, focal adhesion kinase, and ROCK [ 59 , 60 ].

All migration-related effects of Cdk5 were described for effects that are unrelated to the Golgi. However, Cdk5 has been shown to not only localize to the Golgi but also to interact with Cdc42 and to phosphorylate the Cdc42 effector PAK1, and this phosphorylation was suggested to play a role in formation of Golgi carriers [ 61 ]. This study has been performed in neurons, but it certainly tempts to speculate about a potential role of Golgi localized Cdk5 in the context of epithelial cell migration.

There are seven distinct phosphoinositide subspecies that are involved in a wide range of biological effects such as proliferation, differentiation, vesicle trafficking, and cell survival. Among the different phosphoinositides, phosphatidylinositolphosphate PI 4 P formed by different PIkinases PI4K is most important for the regulation of various biological functions of the Golgi. A possible explanation is that GOLPH3 interacts with VPS35, a component of the retromer complex which is known to regulate endocytic trafficking transmembrane receptors [ 66 ].

A direct link between PI 4 P at the Golgi and the role of this organelle in cell migration does not exist. In addition, GOLPH3 regulates endocytic trafficking of transmembrane receptors which have a role in cell migration.

Finally, GOLPH3 regulates budding of vesicles from the Golgi, and polarization of secretory trafficking is one of the major factors accounting to the role of the Golgi in directional polarity Figure 2.

However, at the current stage this remains speculative and future experiments will have to address the question whether GOLPH3 plays any role in cell migration. While a promigratory role of GOLPH3 remains speculation, in the next section we will discuss an example how a regulator of budding at the TGN was shown to be involved in cell migration. Protein kinases D PKD were initially classified as diacylglycerol-stimulated members of the protein kinase C family of serine-threonine kinases but, due to limited similarity, were reclassified as a novel group of the calmodulin-dependent kinase family [ 67 ].

As mentioned previously, one of the roles of the Golgi in directional cell migration is due to the polarization of secretory cargo towards the leading edge. In accordance with this, inhibition of PKD, by using a kinase-dead version, was shown to inhibit formation of lamellipodia at restricted areas of the cell surface and thus random cell motility was strongly affected [ 71 ].

This work provided the first evidence on a potential role of PKD in cell migration, but its role in directional migration was not tested. The inhibitory effect of PKD on cell migration is mediated in part by phosphorylation of cortactin [ 73 ], an actin-binding protein enriched in lamellipodia of motile cells and invadopodia of invasive cancer cells [ 74 ].

Furthermore, PKD was shown to phosphorylate the slingshot homologue 1 SSH1 , which results in its cytosolic sequestration [ 75 , 76 ]. PKD-mediated phosphorylation of SSH1 blocks it from activation of the actin depolymerizing factor cofilin. As a consequence loss of PKD induces migration. Thus, PKD is an excellent drug target for antimetastatic cancer therapy, where activators of PKD are expected to act as suppressors of metastasis.

Such an approach is currently being tested using the macrolactone Bryostatin 1, which activates PKD1 [ 77 ] and is currently in phase-II clinical trials where its antineoplastic effects are being evaluated. Mammalian target of rapamycin mTOR is a serine-threonine kinase that belongs to the family of phosphatidylinositol kinase-related kinase PIKK family. Both mTOR complexes were shown to be involved in cell migration.

TORC1 has been shown to localize the actin arc at the leading edge in migrating cells, where it activates p70S6 kinase and thereby controls actin dynamics [ 83 ].

Inhibition of TORC1 by rapamycin resulted in an inhibition of cell migration [ 83 ]. It was shown that inhibition of TORC1 by rapamycin reduced the activity of 4eBP1 and reduced the expression of RhoA, Rac1, and Cdc42, which are all important migration regulators [ 85 ].

Also TORC2 has been shown to regulate cell migration, which was to be expected given that the first biological effect ascribed to TORC2 was the regulation of the actin cytoskeleton via activation of Rho GTPases in yeast and in human cells [ 86 , 87 ]. All these effects were mostly linked to events at the leading edge plasma membrane.

Upon infection of mammalian cells with Toxoplama gondii , the centrosome and the Golgi relocate into close proximity of the parasitophorous vacuole and this movement of the Golgi and the centrosome is dependent on mTORC2 [ 91 ]. Therefore, it seems worthwhile to investigate whether mTORC1 and mTORC2 signal from the Golgi and thereby regulate the machinery involved in directional cell migration. The secretory pathway and particularly the Golgi are increasingly being viewed as hubs for signaling molecules contributing to the spatial organization of several signal transduction pathways.

The Golgi apparatus plays a well-appreciated role in cell migration and invasion. As highlighted in this paper, there are several known as well as many potential signaling pathways that regulate the Golgi in the context of cell migration. Migration and invasion represent the cell biological basis for the metastatic dissemination of tumor cells, and therefore, any inhibitor of cell migration represents a potential antimetastatic drug.

However, we are only beginning to grasp the extent of the regulation of the secretory pathway by signaling. Research in the future has to concentrate on uncovering the full regulatory network that orchestrates the Golgi during cell migration. We have recently found 38 kinases and phosphatases that when depleted lead to Golgi fragmentation and inhibition of migration [ 12 ]. This approach can be used as a complementary strategy to previous work that screened siRNA libraries or chemical compound libraries for effects on migration and invasion [ 92 , 93 ] to uncover novel targets for antimetastatic cancer therapy.

This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Special Issues. Academic Editor: M. Received 20 Nov Accepted 18 Dec Published 01 May Abstract Migration and invasion are fundamental features of metastatic cancer cells.

Introduction The development of efficient therapies against cancer represents a continuous challenge for scientist across various disciplines.

The Golgi Apparatus In mammalian cells, the Golgi apparatus is a single-copy organelle, composed of a stack of flattened cisternae that are laterally linked to form the Golgi ribbon. Cell Migration Cell migration is a dynamic and highly orchestrated cellular process.

Polarization of Secretory Trafficking Despite the early evidence for the role of the Golgi and the MTOC in directional cell migration, it remained unclear why these organelles are important. Nucleation of Microtubules The structure and the positioning of the Golgi are dependent on the microtubule MT cytoskeleton, which was first demonstrated by showing that the Golgi fragmented into several ministacks upon treatment with MT-depolymerizing drug nocodazole [ 18 ].

Figure 1. Schematic illustration of the Golgi in a migrating cell. The Golgi is oriented towards the leading edge and the microtubules MTs that nucleate from the Golgi are also oriented towards the leading edge red , contrary to centrosomal MTs blue that are non-polarized. Figure 2. Schematic illustration of signaling events at the Golgi that regulate directional cell migration as explained in the main text.

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