Regulation of the actin cytoskeleton in Helicobacter pylori-induced migration and invasive growth of gastric epithelial cells
Cell Communication and Signaling
Regulation of the actin cytoskeleton in Helicobacter pylori-induced migration and invasive growth of gastric epithelial cells
Silja Wessler 0
Mario Gimona 1
Gabriele Rieder 0
0 Division of Molecular Biology, Department of Microbiology, University of Salzburg , Salzburg , Austria
1 University Clinic for Blood Group Serology and Transfusion Medicine, PMU, General Hospital Salzburg, SALK , Salzburg , Austria
Dynamic rearrangement of the actin cytoskeleton is a significant hallmark of Helicobacter pylori (H. pylori) infected gastric epithelial cells leading to cell migration and invasive growth. Considering the cellular mechanisms, the type IV secretion system (T4SS) and the effector protein cytotoxin-associated gene A (CagA) of H. pylori are well-studied initiators of distinct signal transduction pathways in host cells targeting kinases, adaptor proteins, GTPases, actin binding and other proteins involved in the regulation of the actin lattice. In this review, we summarize recent findings of how H. pylori functionally interacts with the complex signaling network that controls the actin cytoskeleton of motile and invasive gastric epithelial cells.
Helicobacter pylori; type IV secretion system; CagA; actin cytoskeleton
The continuous reorganization and turnover of the actin
cytoskeleton is a fundamental process in the regulation of
cell adhesion to neighboring cells and extracellular matrix
(ECM), phagocytosis, cell shape or migration. Generally,
actin exists in cells as monomeric globular actin (G-actin)
and filamentous actin (F-actin), which are formed upon
polymerization of G-actin monomers in a defined
directionality. A wide range of upstream signaling molecules
including the cell adhesion molecule E-cadherin, integrins,
components of the ECM, or stimuli such as tumor
necrosis factor alpha (TNF-a) and lysophosphatidic acid (LPA)
are known in the transmission of extracellular signals to
the actin cytoskeleton allowing rapid reactions to a
changing environment (Figure 1A). Hence, remodeling of the
actin cytoskeleton architecture depends on a large group
of signaling molecules that bind to actin and modulate the
assembly of the actin network (see  for a comprehensive
Among actin-dependent cellular processes, efficient cell
migration requires a coordinated rearrangement of the
actin lattice in motile cells. Polymerization of F-actin at
cell protrusions triggers the formation of sheet-like
lamellipodia and rod-like filopodia pushing migrating
cells [2,3]. Additionally, formation of contractile
structures through interaction of actin with myosin II pulls
the cell body across the ECM. Those processes involve a
wide range of actin binding proteins (e.g. cortactin,
aactinin, fascin, profilin, filamin, etc.) that contribute to
actin stabilization, bundling and branching, forming a
complex network. Signaling pathways modulating actin
rearrangement are complex and have been covered in
several excellent reviews [4-6]. Summarizing the most
important findings in a simplistic model (Figure 1A),
signaling pathways initiated at cell surface receptors to
promote distinct membrane protrusions converge on Rho
family GTPases as the key elements of signal
transduction. One of the best characterized Rho GTPase family
members is RhoA regulating the formation of stress
fibers and focal adhesion assembly, while Rac and Cdc42
are mainly involved in membrane ruffling and formation
of filopodia, respectively . Rac1 and Cdc42 can induce
actin polymerization through members of the
WiskottAldrich syndrome protein (WASP) family and
WASPinteracting proteins (WIPs). The WASP family of actin
nucleation promoting factors (NPFs) includes WASP,
NWASP and four forms of WASP verprolin homologous
protein (WAVE). Through a conserved C-terminal
Figure 1 Signal transduction pathways involved in the regulation of the actin cytoskeleton. (A) The formation of actin-dependent
structures, such as stress fibers, focal adhesions, lamellipodia, and filopodia is controlled by cell surface molecules ranging from E-cadherin and
integrins to receptors for small components (e.g. TNF-a or LPA) allowing the transmission of extracellular stimuli to the actin cytoskeleton. The
Rho GTPases RhoA, Rac1, and Cdc42 are key elements in the regulation of actin filaments. Rac1 and Cdc42 induce actin polymerization through
WASP/WAVE family members and WIPs stimulating the Arp2/3 complex. RhoA regulates Dia1/profilin and the ROCK/MLC pathways to promote
polymerization of F-actin. (B) Focal adhesions are important structures in linking the ECM to the intracellular actin cytoskeleton via a and b
integrin heterodimers. The extracellular part of integrins binds to proteins of the ECM, while the intracellular domain recruits a wide range of
intracellular signaling (FAK, Src, etc.) and adaptor proteins (talin, paxillin, vinculin, or p130CAS, etc.) to connect the actin cytoskeleton.
domain, WASP proteins stimulate the actin-related
proteins 2/3 (Arp2/3) complex activity to nucleate actin
filaments and to elongate at their free barbed ends. Stress
fiber assembly and contraction are predominantly
induced by RhoA  as mentioned above, which controls
Dia1/profilin to promote polymerization of F-actin .
Another mechanism involves Rho-induced
Rho-associated serine/threonine kinase (ROCK) as an important
downstream effector to induce myosin light chain (MLC)
phosphorylation  (Figure 1A).
Commonly, contractile stress fibers attach to the plasma
membrane at nascent focal adhesions, which are stabilized
by a and b integrin heterodimeric receptors (Figure 1B).
Bridging the ECM to the actin cytoskeleton, the integrin
ectodomain directly binds to ECM proteins (e.g.
fibronectin), while the intracellular domain is connected to the
actin cytoskeleton via recruited adaptor and signaling
proteins including focal adhesion kinase (FAK), vinculin, talin
and paxillin . Upon activation, FAK recruits the
nonreceptor tyrosine kinase c-Src to the focal adhesion sites in
order to phosphorylate other focal adhesion proteins such
as paxillin and p130Cas leading to mature focal adhesions
(Figure 1B). The integrity and maturation of focal adhesion
complexes cycle between assembly at the protrusions and
disassembly at the trailing edge of migrating cells; however
the precise molecular mechanisms are not completely
understood. In this review, we summarize the current
findings on how the human carcinogen Helicobacter pylori
(H. pylori) controls the host cell actin cytoskeleton to form
stress fibers and deregulates adhesion complexes to induce
changes in cell shape, migration and invasive growth.
H. pylori induces migration and invasive growth
of gastric epithelial cells
H. pylori is one of the most successful human pathogen
that colonizes the gastric lining epithelium in the
stomach of approximately 50% of the worlds
population. Once acquired and not eradicated by antibiotics,
H. pylori normally persists throughout lifespan since the
host is unable to clear the infection. Only a minority of
10-15% of infected individuals develops severe gastric
diseases which mainly depend on bacterial expressed
pathogenic and virulence factors, environmental
determinants and individual genetic predispositions (e.g.
polymorphisms of host genes such as interleukin-1b (IL-1b),
IL-8, IL-10, runt-related gene 3 (RUNX3), etc.), which
can influence gastric atrophy and carcinogenesis [10-12].
Most severe complications are inflammatory disorders
involving acute and chronic gastritis or ulceration of the
stomach and duodenum, which can eventually result in
Mucosa Associated Lymphoid Tissue (MALT)
lymphoma and gastric cancer . According to its
capability to promote cancer, H. pylori was classified by the
World Health Organization as a class-I carcinogen .
H. pylori pathogenesis is dependent on the expression
of bacterial virulence factors , which might involve
complex cellular responses of gastric epithelial cells
[15,16]. The vacuolating cytotoxin A (VacA) is secreted
by many, if not all, H. pylori isolates and might enhance
the H. pylori virulence though its pleiotropic functions in
vivo. VacA binds to many surface factors, including the
receptor-like protein tyrosine phosphatase alpha and beta
(RPTPa and RPTPb) presented on host cells and, after
uptake, induces membrane anion-selective channels and
pore formation, apoptosis and gigantic vacuoles in host
cells . VacA is further associated with the inhibition
of T-cell function through binding to the b2 integrin
receptor [18,19]. Another important pathogenic factor is
the cytotoxin-associated gene A (CagA), which has
attracted much attention since its expression is closely
associated with the development of severe diseases in
vivo [20,21]. The cagA gene is located within the cag
pathogenicity island (cagPAI) region on the bacterial
chromosome, which encodes proteins important for
structure and function of a specialized type IV secretion
system (T4SS) [22,23]. Importantly, it has been
demonstrated that the cagPAI protein CagL represents a
T4SSpilus associated adhesin for a5b1 integrin expressed on
the epithelial host cell surface. Binding of the
fibronectinmimicking Arg-Gly-Asp (RGD) motif in the CagL
molecule to b1 integrin is necessary to translocate CagA into
the host cytoplasm [24,25]. Many studies described that
CagA-positive H. pylori strains are closely connected
with the development of acute gastritis, pre-neoplastic
and neoplastic lesion [26-29]. Causative associations
between CagA and the formation of neoplasia were
demonstrated in Mongolian gerbils [30,31] and in a
transgenic mouse model in which CagA induced
neoplastic transformations in vivo .
In healthy individuals, the gastric epithelium represents
effective first barriers against pathogens, which is tightly
sealed by coordinated regulation of epithelial cell shape,
polarity, cell-to-cell and cell-to-matrix adhesions.
Concomitantly with colonization of the gastric mucus, H. pylori
dismantles the epithelial barrier function to induce
inflammatory responses and neoplastic changes
dependent on H. pylori virulence factors . This might be
facilitated by a rearrangement of the actin cytoskeleton
as a central mechanism in those processes. Supporting
this suggestion, H. pylori induces the formation of
protrusions and massive stress fibers in cultured gastric
epithelial cells accompanied by the loss of epithelial
morphology and cell-to-cell adhesions leading to a
mitogenic-invasive scattering phenotype in vitro [33,34]
reminiscent of growth factor-induced Epithelial-Mesenchymal
Transition (EMT). The EMT phenotype requires a
complex morphogenetic program initiated by alteration of
gene expression, the loss of typical epithelial properties
and the increase of mesenchymal characteristics ,
which could be detected in H. pylori-colonized cells .
During EMT, cells lose their polar, epithelial nature
and acquire a highly motile, mesenchymal morphology.
Principally, EMT is defined by the (i) disassembly of
intercellular junctions, (ii) reorganization of the actin
cytoskeleton from cell-cell and cell-matrix junctions into
protrusive and invasive pseudopodial structures such as
actin stress fibers and actin-dependent protrusion of cell
pseudopodia, (iii) and an increase of cell motility. In
general, these processes occur in synchronous fashion, but
independently from each other . Accordingly,
efficient H. pylori-mediated cell migration is an extremely
complex coordinated process which is initiated by the
extension of lamellipodia at the leading edge of the cell,
assembly of new focal adhesion complexes, secretion of
proteases to degrade contacts to the ECM supporting the
formation of invadopodia, development of contractile
forces and finally disassembly of focal adhesions leading
to tail detachment (Figure 2) [34,37].
Actin-dependent protrusion of pseudopodial surface
extensions is a key element during EMT-related
migration of H. pylori-colonized cells. Pathogenic H. pylori
strains induce a morphogenetic program in different
gastric epithelial cell lines that closely resembles the features
of EMT . CagA-transfected cells invade through the
extracellular matrix via the formation of invasive
pseudopodia  indicating that CagA might induce EMT in
gastric cancer cells. Functionally these structures mimic
invasive podosomes or invadopodia, and show a similar
dependence on matrix metalloproteases (MMPs) for
invasion. In support of this concept non-invasive
podosomes have been shown to become gradually replaced by
invasive invadopodia in EMT (Figure 2) .
Figure 2 Model of migrating epithelial cells. For efficient migration, epithelial cells develop new actin-dependent protrusions which are
connected to the ECM via newly assembled focal adhesions (red) at the leading edge. Secretion of proteases to degrade ECM is required to
extend the protrusion into the ECM to form invadopodia. At the tail, matured focal adhesions (grey) disassemble to facilitate the movement of
the cell body in a defined direction.
Adhesion based spatio-temporal orchestration of
actinpolymerization-driven invasive structures  is a feature
of many physiological and pathological events. The players
in this scenario are mechano-sensitive molecules that also
depend on integrin-mediated outside-in signaling cascades
and involve many of the same players (such as ezrin, Abl,
Src, etc.) that are required for H. pylori-induced cell
invasion into neighboring tissues [38,41,42]. A significant
element that separates invadopodia from focal adhesions is
the modulation of the cells secretory machinery and the
focal secretion of ECM-degrading matrix metalloproteases
(MMPs) that ultimately allow the breach of tissue
boundaries . The ultrastructural features and intracellular
dynamics of H. pylori-induced pseudopods are still poorly
defined, but a future identification of these structures as
invadopodia-related cellular protrusions would not be a
As infection with cagA-positive strains of H. pylori is
tightly associated with the induction of gastric
adenocarcinoma the targets highjacked by injected CagA likely
controls pseudopod formation and invasion of infected motile
cells. Indeed, in vitro studies have shown that CagA binds
the adapter molecule growth factor receptor bound
protein 2 (Grb2) , which can link Abl and Src kinase
signaling cascades to MMP expression and invadopodium
formation  and can thus contribute to the site-specific
formation of signaling complexes required for cell
migration and invasive growth. Interestingly, H. pylori induces
expression of MMP-7 at the lamellipodia of motile cells,
which was also triggered by activated RhoA and Rac ,
suggesting a close connection between ECM degradation,
invasive growth and efficient cell motility. The cortical
cytoskeleton serves as a nexus between the extracellular
environment and the cytoplasm, and is positioned to
coordinate cellular signal relays. It comes thus as no surprise
that cytoskeleton-associated cortical proteins have key
roles in H. pylori-induced cell modulation. The mucin-like
transmembrane glycoprotein podoplanin can also induce
EMT, cell migration and invasive growth by recruiting the
ERM (Ezrin, Radixin, Moesin)-family protein ezrin, an
organizer of the cortical cytoskeleton, to the plasma
membrane. This interaction is essential for the activation of the
RhoA/ROCK pathway by podoplanin [47,48]. In H.
pyloriinfected gastric epithelial cells, ezrin becomes
dephosphorylated which could be involved in the development
and metastasis of H. pylori-induced gastric cancer .
Ezrins dual role as an actin binding and GTPase
scaffolding protein further identifies this molecular complex as a
key target for understanding the cytoskeletal
rearrangements that lead to migration and invasive growth of
infected epithelial cells [49,50].
In fact, the EMT-like phenotype of H. pylori-infected
epithelial host cells implies the formation of protrusions
and elongation. Rather unfortunate, terms like scattering
phenotype or hummingbird phenotype in connection
with H. pylori infection has been widely become
synonymous with cell elongation or cell migration.
Interestingly, data are accumulating indicating that cellular
elongation and motility are differentially regulated by
H. pylori via independent signal transduction pathways
. Consistently observed, the drastic elongation of host
cells is strictly dependent on CagA injection [52-54], while
H. pylori-induced cell motility is cagPAI-dependent, but
largely CagA-independent [42,51,55]. Making those
observations more complex, data are accumulating that CagA
and VacA functions are antagonizing each other in some
assays. In accordance with a study showing that specific
VacA variants inhibited CagA-dependent cell elongation,
CagA reduced VacA-mediated apoptosis and vice versa,
underscoring the interfering functions of pathogenic
factors expressed by H. pylori [56,57]. Furthermore,
H. pylori-expressed pathogenic factors might differentially
interact with host cells leading to the disruption of the
gastric epithelium and determining the outcome of gastric
disorders. Rapid host cell elongation and migration are
particular evident in human gastric cancer cells (e.g. AGS
cells) [53,58,59], breast cancer cells (e.g. MCF-7 cells)
[42,60], and a subtype of the canine kidney cell line
MDCK [55,61]. Milder and less pronounced development
of this typical phenotype was observed in gastric MKN-1,
MKN-28 and Hs-746T cells within early phases of
H. pylori infections . In terms of cell morphological
and junctional changes, only few reports on primary
gastric epithelial cells are available [62,63]. Importantly,
Krger et al. demonstrated H. pylori-induced motility and
growth of ex vivo isolated gastric cells . Access to
primary cells is limited; hence it is important to investigate
observed cellular molecular mechanisms in vivo as well.
So far, it is still speculative if changes in cell morphology
actually contribute to H. pylori-associated gastric diseases,
even these processes likely influence host responses during
decades of persistent H. pylori infections.
Helicobacter pylori induced signal transduction
pathways leading to a deregulated actin
cytoskeleton independently of CagA
While it is clear that H. pylori induces striking cytoskeletal
changes in epithelial cells, knowledge of the signal
transduction pathways is rare. In serum-starved cells, both
CagA-positive and CagA-negative H. pylori strains
mediated the formation of actin filaments and
lamellipodial structures  implying activation of Rho GTPases. In
fact, activation of Rac1 and Cdc42 has been demonstrated
in H. pylori-infected AGS cells . Microinjection of
inactive Rac prevented actin cytoskeleton rearrangements
in lamellipodial structures in H. pylori-colonized cells .
Through transfection of dominant-negative and
catalyticactive cDNA constructs or using well-characterized
GTPase-targeting toxins, Crk adapter proteins, Rac1 and
H-Ras, but not RhoA or Cdc42 were identified as crucial
components leading to H. pylori-induced cell elongation
. Consistent with actin polymerization in H.
pyloriinfected cells , activation of Rho GTPases occurs
independently of CagA injection, but obviously required the
T4SS apparatus . Since CagL was identified as an
adhesin for a5b1 integrins that is decorated at the tip of
the T4SS allowing CagA injection and b1 integrin
activation , it is tempting to speculate that CagL represents
a promising candidate for stimulating Rho GTPase
activation as well (Figure 3A). This hypothesis is currently
supported by the finding that CagL-coated latex beads
stimulated membrane ruffling via integrin-mediated
activation of FAK and Src . Another possible scenario
proposes is OipA as an inducing factor since oipA mutants
have been reported to less activate FAK presumably
independently of cagPAI or CagA ; however experiments
with recomplemented oipA mutants are pending.
The b1 integrin/FAK/Src pathway transmits signals to
the actin cytoskeleton via paxillin, an important
scaffolding protein located in focal adhesions . In H.
pyloriinfected cells activated FAK phosphorylates tyrosine 118
in the paxillin protein (paxillinY118) which was essential for
cell motility in response to H. pylori . Since
phosphorylated paxillinY118 binds the adaptor protein v-crk
sarcoma virus CT10 oncogene homolog (Crk) in response
to cell adhesion, platelet-derived growth factor (PDGF) or
angiotensin II , H. pylori-triggered paxillinY118
phosphorylation may also act upstream of the activation of
Crk/DOCK180 (dedicator of cytokinesis)/Rac1/WAVE/
Arp2/3 signal transduction pathway in H. pylori-infected
cells, which has been detected in another study (Figure
3A) . Alternatively, H. pylori-induced Src activity
could activate p130Cas leading to the recruitment of the
Crk complex; however an involvement of p130Cas in
H. pylori-mediated cytoskeletal rearrangement still needs
to be demonstrated (Figure 3A).
Regulation of CagA-mediated host cell elongation
The H. pylori-induced changes in cell morphology are
dominated by the drastic elongation of epithelial cells
which involves active regulation of both the actin
cytoskeleton and focal adhesions. Single-cell analyses suggested
that H. pylori-dependent cell elongation might be
mediated by deregulated focal adhesions rather than actin
cytoskeleton rearrangement. Stabilized focal adhesions
cause a defect in cell retraction leading to the formation of
strong traction forces on motile H. pylori-infected cells
. CagA increases phosphorylation and subsequent
activation of myosin light chain (MLC) in a Drosophila model
. The concomitant mispatterning of MLC results in
cell elongation due to retraction failure and disruption of
epithelial morphology and integrity. Based on a
phosphoproteomic analysis the actin-binding protein
vasodilatorstimulated phosphoprotein (VASP) was identified, which
co-localized with focal adhesions of H. pylori-infected cells
. Down-regulation of VASP expression and inhibition
of VASP phosphorylation blocked cell elongation in
response to H. pylori, but it was not investigated whether
phosphorylated VASP disturbed the disassembly of focal
The significance of focal adhesions in promoting cell
elongation has been emphasized by the finding that b1
integrin-mediated injection of CagA is important in the
process of cell elongation . Upon translocation, CagA
localizes at the inner membrane of infected cells, where it
is rapidly phosphorylated by the non-receptor tyrosine
kinases c-Src, Fyn, Lyn and Yes of the Src family kinases
(SFK) [73,74]. Phosphorylation sites were localized in a
Figure 3 Schematic overview of CagL and CagA-mediated signal transduction pathways involved in H. pylori-induced cell motility and
elongation. (A) H. pylori expresses CagL at the tip of the T4SS that directly binds to b1 integrins presented on gastric epithelial cells. Activated
b1 integrin stimulates FAK and Src activity in early phases of H. pylori infections. FAK phosphorylates paxillin upon infection which might
contribute to c-Abl-phosphorylated Crk signaling, which could be influenced by SFK activity via paxillin or p130CAS. FAK, SFKs and Abl
kinasemediated activation of Crk proteins can regulate the actin cytoskeleton through the DOCK180/Rac1/WAVE/Arp2/3 pathway contributing to
epithelial cell migration. (B) CagL-integrin binding leads to the translocation of the H. pylori pathogenic factor CagA into the host cytoplasm.
CagA is rapidly phosphorylated by kinases of the Src family (SFK) and bind to a large number of host cells factors (X) in its phosphorylated and
non-phosphorylated form. Tyrosine phosphorylated CagA interacts with Shp-2 and Csk to inactivate FAK and Src in late phases of H. pylori
infection. While inactivated Src is replaced by activated Abl kinases to maintain CagA phosphorylation, inactive Src leads to tyrosine
dephosphorylation of Src target molecules ezrin, vinculin and cortactin. Cortactin is then serine phosphorylated by H. pylori-activated ERK1/2
kinases, which crucially contributes to cell elongation. Black arrows, H. pylori-induced direct signaling pathways. Dotted arrows, H. pylori-induced
or Src-mediated indirect signaling pathways. Grey arrows, inactivating signaling pathways. Red arrow, CagA injection as the central step in the
regulation of focal adhesions. P, phosphorylated proteins. X, host cell proteins.
Glu-Pro-Ile-Tyr-Ala sequence (EPIYA motif), which
exists as different 1-5 repeats, namely EPIYA-A,
EPIYAB, EPIYA-C in Western H. pylori isolates and EPIYA-A,
EPIYA-B, EPIYA-D in East-Asian strains [75,76]. The
Src-mediated CagA phosphorylation (CagAPY) is
followed by a rapid inactivation of Src kinase activity,
triggered by the binding of CagA to the C-terminal Src
kinase (Csk) (Figure 3B) [54,58]. Src kinase inactivation
then leads to the dephosphorylation of Src target proteins
such as vinculin, ezrin and cortactin [49,54,77]. In fact,
tyrosine phosphorylation of CagAPY together with the
dephosphorylation of SFKs and their target molecules are
important in the process of regulation of the actin
cytoskeleton and focal adhesions which contributes to the
drastic morphological changes of H. pylori-infected cells
Another key molecule in H. pylori-stimulated cell
elongation is Shp-2 (src homology 2 domain tyrosine
phosphatase) (Figure 3B). Analysis of ectopically expressed
CagA and isogenic phosphorylation-resistant mutants
revealed that CagAPY directly binds to Shp-2 which led
to an increase of phosphatase activity of Shp-2 [78,79].
The CagA/Shp-2 complex has also been detected in the
gastric mucosa of H. pylori-positive patients with gastritis
and early stages of gastric cancer . Activation of
Shp-2 phosphatase activity has consequently been
reported to inactivate FAK in cells that ectopically
express CagA . In contrast to activated FAK,
dephosphorylated FAK cannot be localized in focal adhesions,
which might support the development of the elongated
cell phenotype. Contrary to this observation, CagL and
OipA activate FAK in H. pylori-infected cells [24,67].
Recently, a new functional form of cortactin was reported,
further underscoring the importance of cortactin as a
critical mediator in signal transduction pathways in H.
pyloriinfected host cells (Figure 3B). After Src-mediated tyrosine
dephosphorylation, cortactin becomes phosphorylated at
serine 405 (cortactinS405). Phosphorylated cortactinS405
strongly binds to and activates FAK. CortactinS405
phosphorylation was mediated by ERK1/2 kinases and might
trap activated FAK leading to a disturbed turnover of focal
adhesions (Figure 3B) . This is one of the first
identified mechanisms explaining why activation of
mitogenicactivated protein (MAP) kinases via Rap1 GTPases  or
protein kinases C (PKCs)  in response to H. pylori
infections can contribute to cell elongation [61,70,82].
In contrast to dephosphorylated SFK target molecules,
phosphorylation of CagAPY is potently sustained by
activated Abl kinases after inactivation of Src [60,85]. Abl
kinases maintain CagAPY phosphorylation and
CagAPYdependent downstream effects, which are still not fully
understood. Interestingly, it was indicated that transfected
East Asian-type CagA induced significantly stronger
effects on rat cell growth than the Western CagA ,
which are obviously attributable to the different EPIYA
motifs and their binding affinities to Shp-2 . As it is
not clear if Src and Abl kinases prefer different EPIYA
motifs or exhibit similar phosphorylation affinities, further
analyses are necessary to investigate the SFK and Abl
kinase-mediated CagA phosphorylation.
Activated c-Abl consequently also phosphorylates Crk
adapter proteins [60,85], which has been reported to
interact with CagAPY  linking a large CagAPY recruited
protein complex with signal transduction pathways towards
the actin cytoskeleton (Figure 3B). Diverse, but
coordinated signal transduction pathways converge on CagAPY
as an important central key molecule in H.
pylorimediated cell migration . Beside Shp-2 as the first
identified binding partner of CagA , many more
binding partners for phosphorylated and non-phosphorylated
CagA have been identified during the last years including
Par1/MARK, c-Met, PLCg (Phospholipase C gamma),
ZO1 (Zonula occludens-1), Csk (c-Src tyrosine kinase), Gab1
(Grb-associated binder 1), Crk (CDC2-related protein
kinase) proteins, Grb2 and the cell adhesion protein
Ecadherin [10,33]. It is still unclear whether one CagA
molecule can bind to more than one interaction partner
simultaneously. But for most of these identified binding
proteins it could be shown that they play a role in the
induction of the H. pylori-dependent scatter phenotype.
Infection of gastric epithelial cells with H. pylori in vitro
induces a strong motility response; however, our current
understanding of the complex molecular mechanism
contributing to this phenotype is still rudimentary
understood. Although data are steadily increasing
indicating that a5b1 integrin/CagA signaling is involved in
stabilization of focal adhesion at the rear of the motile
cell, it is unclear how these processes can be
differentiated from the cellular mechanisms stimulating the
assembly of nascent focal adhesions and rearrangement
of the actin cytoskeleton at the leading edge. Hence,
further studies are necessary to investigate signal
transduction pathways controlling these locally demarcated
regions in H. pylori infected host cells in vitro as well as
in vivo, which might have consequences on the
physiological balance and integrity of the gastric epithelium in
We thank Steffen Backert for critical reading of the manuscript and
apologize to all colleagues whose important work could not be cited here.
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