Department of Internal Medicine I, University of Ulm, 89070 Ulm, Germany
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ABSTRACT |
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The
initial pathophysiological events that characterize
CCK-hyperstimulation pancreatitis include the breakdown of the actin filament system and disruption of cadherin-catenin protein complexes. Cadherins and catenins are part of adherens junctions, which may act as
anchor for the cellular actin filament system. We examined the
composition and regulation of adherens junctions during CCK-induced acinar cell damage. Freshly isolated CCK-stimulated rat pancreatic acini were examined for actin filaments and functional adherens junctions by immunocytology and laser confocal scanning microscopy or
by coprecipitation and immunoblotting for E-cadherin, - and
-catenin, p120ctn, and phosphotyrosine. In addition to
E-cadherin and
-catenin, acinar cells express the
cadherin-regulatory protein p120ctn and the attachment
protein
-catenin. Both colocalize and coimmunoprecipitate with
E-cadherin in one complex, and all colocalize with the terminal actin
web. Supramaximal secretory CCK concentrations (10 nM) initiated tyrosine phosphorylation of p120ctn but not of
-catenin
within 2 min, preceding the breakdown of the terminal actin web by
several minutes. Under these conditions, the cadherin-catenin
association within the adherens junction complex remained intact. We
describe for the first time supramaximal CCK-dependent tyrosine
phosphorylation of the adherens junction protein p120ctn
and demonstrate the presence of an intact adherens junction protein complex in acinar cells. p120ctn may participate in the
actin filament breakdown during experimental conditions mimicking pancreatitis.
cadherin; catenin; pancreatitis; tyrosine phosphorylation
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INTRODUCTION |
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ACUTE PANCREATITIS is an inflammatory
disorder that is initiated through damage of acinar cells (18). Its
initial morphological hallmarks are intracellular disruption of the
apical actin web, disturbance of regulated apical secretion that
results in the intracellular colocalizaton of digestive and lysosomal
enzymes within cytoplasmatic vacuoles, and rapid distension of the
extracellular space with accumulation of activated digestive enzymes
(16). Premature activation of proteases within the intracellular
vacuoles can explain part of the cellular damage and may be sufficient for subsequent degradation of intracellular proteins, including cytoskeletal structures (12, 14). Other potential mechanisms responsible for actin disassembly include the regulation of
actin-binding proteins such as gelsolin or -thymosin (20) or the
disruption of membrane-bound actin anchoring systems.
One of the known actin anchoring protein complexes are the adherens
junctions that physically connect neighboring cells. In polarized
epithelial cells, the cell-cell contacts of adjacent cells via adherens
junctions are mediated by Ca2+-dependent homophilic
interaction of the transmembrane protein E-cadherin, a member of the
cadherin protein family, which also includes R-cadherin, N-cadherin,
LI-cadherin, and neural cell adhesion molecule (1).
E-cadherin contains a single transmembrane domain, five extracellular
domain repeats with highly conserved Ca2+ binding motifs,
and an intracellular actin microfilament connecting domain (21). The
intracellular domain of E-cadherin serves as anchor for the epithelial
cell cytoskeleton through interaction with several proteins, most of
them part of the catenin protein family. -Catenin and
-catenin
interact directly with E-cadherin, whereas
-catenin mediates
attachment of this complex to the microfilament system (1). Another
catenin, p120ctn, binds to the cytoplasmatic juxtamembrane
region of E-cadherin in close proximity to the binding site for
-
and
-catenin (22). p120ctn was originally identified in
fibroblasts as the putative substrate of the activated tyrosine kinase
Src (3), and this phosphorylation, together with the tyrosine
phosphorylation of
- and
-catenin, may be the key event for the
disruption of adherens junctions (2, 25). p120ctn is also
phosphorylated in response to mitogenic stimulation of breast cancer
cells with epidermal growth factor (11). Binding of p120ctn
promotes lateral clustering of cadherin molecules and thus strengthens cell-cell adhesion (27), an effect that may be blocked by
hyperphosphorylation during mitosis (11).
Recently, we (17) examined for the first time the expression of
E-cadherin and -catenin in the adult pancreas and demonstrated their
restriction to acinar and duct cells, in which they were colocalized at
adherens junctions. Induction of pancreatitis by supramaximal secretory
concentrations of caerulein, a well-characterized experimental model of
acute edematous pancreatitis, led to dissociation, internalization, and
degradation of both proteins within 2 h. Reassembly of E-cadherin and
-catenin occurred within 12 h after the start of supramaximal
caerulein infusion. The regulation of the E-cadherin-
-catenin
assembly was not addressed.
We have now identified the additional adherens junction proteins
-catenin and p120ctn in pancreatic acinar cells and can
confirm their colocalization with E-cadherin and the terminal actin
web. Stimulation of isolated acinar cells with CCK, a well-established
system to examine secretagogue effects on acinar cell integrity (10),
led to increased tyrosine phosphorylation of p120ctn
without changing the integrity of the adherens junction protein complex. Our data indicate that CCK may regulate actin assembly through
adhesion protein phosphorylation.
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METHODS |
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Materials and animals.
Soybean trypsin inhibitor was from Boehringer (Mannheim, Germany), and
collagenase was from Worthington (Cell Systems, Hamburg, Germany).
Polyclonal antibodies against -catenin and
-catenin were from
Sigma (St. Louis, MO). Monoclonal antibodies against E-cadherin,
-catenin, and p120ctn were purchased from Transduction
Laboratories (Lexington, KY). Oregon Green 488 phalloidin was from
Molecular Probes (Eugene, OR). Peroxidase-conjugated affinity-purified
rabbit anti-mouse IgG and peroxidase-conjugated affinity-purified goat
anti-rabbit IgG were from Dianova (Hamburg, Germany). Enhanced
chemiluminescence reagents were obtained from Pierce (Rockford, IL).
Sulfated CCK-8 was from Bachem (Bubendorf, Switzerland). Essential and
nonessential amino acids were purchased from GIBCO (Gaithersburg, MD).
Male Wistar rats (150-200 g) were bred at the animal care and
treatment facility of the University of Ulm.
Preparation of isolated rat pancreatic acini.
The preparation of isolated rat pancreatic acini was performed
essentially as described previously (19). Isolated acini were washed
twice in oxygenated Krebs-Ringer-HEPES buffer consisting of 104 mM
NaCl, 5 mM KCl, 1 mM KH2PO4, 1.2 mM
MgSO4, 2 mM CaCl2, 0.2% (wt/vol) BSA, 0.01%
(wt/vol) soybean trypsin inhibitor, 10 mM glucose, and 25 mM HEPES, pH
7.4 with NaOH, supplemented with minimal essential amino acid solution
and glutamine. Cell viability, as assessed by trypan blue exclusion,
exceeded 95%. To verify the responsiveness and physiological integrity
of the preparation, isolated acini were stimulated with CCK as
described previously. The secretion of amylase was <5% of total
cellular amylase under basal conditions, with a biphasic dose-response
curve and maximum secretion of >25% of the total between
1010 and 3 × 10
10
M CCK after 30 min. All preincubation and incubation steps were carried
out at 37°C.
Immunocytochemistry. Acini were stimulated with the indicated concentrations of CCK or buffer control. After an excess volume of ice-cold Krebs-Ringer-HEPES buffer was added, cells were pelleted at 100 g for 2 min, were placed on SuperFrost microscope slides, were allowed to adhere to the slides for 5 min, and were then fixed using 4% formaldehyde for 10 min on ice. The slides were washed once in PBS, permeabilized with 0.5% Triton X-100 in PBS, and then washed three times in PBS. Blocking of nonspecific binding with PBS-3% BSA was performed for 40 min at room temperature. Primary antibodies were added for 60 min in PBS-0.1% BSA. The slides were washed three times in PBS and incubated with Alexa488-coupled goat anti-mouse IgG together with Cy3-coupled goat anti-rabbit IgG and/or with Oregon Green 488 phalloidin (0.2 µM) for 1 h in the dark. Cells were embedded in Mowiol (Calbiochem, Bad Soden, Germany) and coverslipped. Signal distribution was analyzed using a confocal laser scanning microscope (TCS 4D, Leica, Heidelberg, Germany).
Isolation of E-cadherin-catenin complexes. To examine the integrity of E-cadherin-catenin complexes, isolated pancreatic acini were equilibrated for 20 min at 37°C. CCK was added for indicated time periods, and the incubation was terminated by suspending the acini in an excess volume of ice-cold Krebs-Ringer-HEPES buffer. The acini were then pelleted by centrifugation at 300 g (4°C). Cellular protein was extracted by trituration in lysis buffer consisting of 50 mM Tris · HCl, pH 7.5, 150 mM NaCl, 50 mM CaCl2, 1 mM MgCl2, 0.5% NP-40, and 0.1% Triton X-100, supplemented with protease inhibitors (0.5 mM phenylmethylsulfonyl fluoride, 1 mg/ml soybean trypsin inhibitor, 10 µg/ml leupeptin, 10 µg/ml aprotinin) and 0.5 mM sodium orthovanadate. The lysate was cleared by centrifugation at 10,000 g at 4°C, and the protein content of the supernatant was measured using the Bradford method (Biorad, Munich, Germany). Two hundred micrograms of protein extract were incubated with five micrograms of E-cadherin antibody in lysis buffer for 1 h. Complexes were pelleted after additional incubation with affinity-purified rabbit anti-mouse IgG precoupled to protein A agarose. After three washes in lysis buffer, precipitates were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Gel-resolved proteins were electrophoretically transferred to polyvinylidene difluoride membranes (Immobilon P, Millipore, Bedford, MA). Membranes were incubated overnight in blocking buffer [50 mM Tris · HCl, pH 7.8, 100 mM NaCl, 0.5% Tween 20, 2% (wt/vol) BSA]. The membranes were then incubated for 1 h with primary antibodies in blocking buffer. After three washes with Tris-buffered saline-0.1% Tween 20, antigen-antibody complexes were visualized using peroxidase-conjugated secondary antibody and the enhanced chemiluminescence system by exposure to Kodak X-OMAT AR films for 30 s to 2 min. Quantitation was performed densitometrically using Phoretix 1D gel analysis software (Phoretix, Newcastle upon Tyne, UK).
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RESULTS |
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Adherens junctions in pancreatic acinar cells.
Adherens junctions are protein structures that connect neighboring
epithelial cells and act internally as one of the anchors for the actin
cytoskeleton (1). We previously demonstrated colocalization and
association of E-cadherin and -catenin in the intact pancreas, thus
defining two proteins of the adherens junction complex (17). Here we
examined the distribution of adherens junctions and defined additional
component proteins in isolated pancreatic acinar cells.
Immunoprecipitation of E-cadherin was used to demonstrate association
of
-catenin and
-catenin with E-cadherin (Fig.
1). Immunocytochemistry and
immunoprecipitation identified another catenin, p120ctn, as
part of this complex (Fig. 2). All four
proteins were localized to the lateral plasma membrane and were
colocalized by double-staining immunofluorescence, thus providing all
the necessary components of functional actin-binding adherens junctions
(Figs. 2A and 3). Similar to our
results in intact pancreatic tissue, E-cadherin and
-catenin were
colocalized with the terminal actin web at a well-defined region of the
lateral plasma membrane where the apical actin web terminates and where
it seems to attach to the plasma membrane and connect to the actin web
of the neighboring cell.
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CCK-dependent tyrosine phosphorylation of p120ctn.
One of the recognized regulatory mechanisms of adherens junction
composition and function is the phosphorylation of p120ctn
and - and
-catenin (2, 3, 11, 25). Treatment of acinar cells with
CCK stimulated rapid and reversible tyrosine phosphorylation of
p120ctn. Phosphorylation of p120ctn was
concentration dependent, with its maximum at 10
8 M
CCK. Maximal phosphorylation was observed within 5 min and decreased
thereafter to reach baseline levels after 10 min (Fig. 4A). Under the same conditions, we
did not detect phosphorylation of
-catenin or
-catenin either
under basal conditions or after stimulation with CCK (data not shown).
Preincubation with the tyrosine kinase inhibitor PP1 (15, 24) reduced
overall tyrosine phosphorylation, including phosphorylation of
p120ctn, and inhibited the CCK-induced breakdown of the
apical actin web (Fig. 4, B and C).
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Integrity of E-cadherin--catenin complexes after CCK
treatment.
E-cadherin-
-catenin complexes dissociate and both proteins
degrade during experimental acute hyperstimulation pancreatitis, and a
role for acinar cell damage was proposed (17). To examine whether this
indeed could be a direct effect of CCK or is secondary to other
cellular events, we stimulated isolated rat pancreatic acini with
concentrations of CCK known to induce cell injury. Stimulation with
10
8 M CCK did not change the cellular distribution
of E-cadherin, of the catenin p120ctn (Fig. 2A), or
of
- and
-catenin. Similarly, E-cadherin and p120ctn
remained colocalized during stimulation with cell-damaging
concentrations of CCK (10 nM). Coimmunoprecipitation was used to
confirm the integrity of adherent junction complexes during up to 2 h
of 10
8 M CCK treatment. As illustrated in Fig. 1,
10
8 M CCK had no effect on the association of
E-cadherin to either
-catenin or
-catenin. In control
experiments, which were designed to examine whether cadherin-catenin
complexes could be regulated in acinar cells, chelation of calcium in
the incubation medium was sufficient to inhibit
-catenin binding to
E-cadherin (Fig. 5).
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DISCUSSION |
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Supraphysiological doses of CCK or of its homologue caerulein initiate acute edematous pancreatitis in the rat (16). In isolated acinar cells, a similar cell injury is stimulated by supramaximal secretory concentrations of CCK (23). The cellular mechanisms that mediate these events are incompletely understood. One of the central events appears to be the breakdown of the apical actin filament system, which is required for regulated exocytosis (20). In fact, depolymerization of filamentous actin by actin monomer binding proteins or by cytochalasin D blocks regulated secretion (20) and inhibits CCK-induced tyrosine phosphorylation of the actin-associated proteins paxillin, p125FAK, and p130cas (7, 8). However, regulatory mechanisms for the balance of actin assembly and disassembly in vivo in acinar cells are largely unknown. They likely include actin cross-linking proteins or actin anchoring complexes at the plasma membrane resembling focal adhesion protein complexes or adherens junctions. At least some component proteins of both types of actin anchoring complexes are expressed in acinar cells and are capable of binding filamentous actin (17, 19).
Similar to other epithelial cell types, neighboring acinar cells are
closely connected by adherens junctions, which we have shown
to be composed of E-cadherin and -catenin (6, 17). During the
course of acute rodent pancreatitis, these complexes rapidly
disassemble within <2 h and might be the permissive factor for
extracellular edema formation and/or intracellular actin disruption. The details of their regulation in acinar cells are unknown. In this
work, we identify p120ctn and
-catenin as additional
adherens junction proteins in acinar cells. Both proteins
coimmunoprecipitate in a complex with E-cadherin and
-catenin and
colocalize in intact cells with the actin filament system and with the
other components of adherens junctions. This not only establishes all
necessary components for functional adherens junctions but also
strongly indicates a potential regulatory function for actin assembly.
Adherens junctions of neighboring cells consist of a backbone of
cross-linked cadherins with intracellular binding sites for the Arm
domain-containing proteins -catenin,
-catenin, and
p120ctn (22). Interaction of the adherens junctions with
the actin cytoskeleton occurs through attachment of
-catenin or
-catenin to the multifunctional
-catenin and through its
connection to actin filaments (1). In contrast, p120ctn is
not directly involved in the chain of proteins that mediates physical
attachment of cadherins to the actin filaments but binds to cadherins
in close proximity of
- and
-catenin binding sites, where it may
function as an inhibitory protein for actin binding (4;26). In
mesodermal cells, overexpression of p120ctn1B modulates
cell motility and orientation, i.e., cellular functions that are linked
to an intact cellular cytoskeleton, yet was not sufficient to replace
-catenin function in Wnt signaling, a cellular signaling pathway
that is dependent on adherens junctions but independent from actin
binding (9). This negative regulatory role of p120ctn seems
to be achieved through its tyrosine phosphorylation (5, 11).
Phosphorylation on tyrosine has been observed on -catenin,
-catenin, and p120ctn in different cell systems and
seems to differentially affect their interaction with other proteins of
the adhesion complex. Whereas tyrosine phosphorylation of
- and
-catenin stabilizes the interaction of cadherin-catenin complexes
with the actin cytoskeleton, tyrosine phosphorylation of
p120ctn likely destabilizes actin binding (3, 5). In our
system, CCK stimulates maximum phosphorylation of p120ctn
at supramaximal secretory concentrations without affecting the phosphorylation state of
-catenin. This suggests that regulation of
p120ctn by CCK affects the interaction of filamentous actin
with adherens junctions. Furthermore, the tyrosine kinase inhibitor PP1
(15, 24) decreased overall tyrosine phosphorylation and reduced the CCK-induced disintegration of the apical actin web. Even though this
effect may not be directly related to phosphorylation of p120ctn because tyrosine kinase inhibitors likely are not
entirely specific, our data, together with experiments in breast cancer
cells in which Src phosphorylation of p120ctn initiated
destabilization of actin filaments (11, 13), support a negative
regulatory role for p120ctn.
Of note, under conditions in which CCK induced phosphorylation of
p120ctn and initiated the destabilization of the acinar
cell actin filament system, the backbone of adherens junctions, i.e.,
E-cadherin with the attached - and
-catenins, remained intact.
Therefore, the dissociation and internalization of cadherin-catenin
complexes during experimental CCK-induced acute pancreatitis within 2 h likely are not caused by a direct regulatory role of CCK but rather are
secondary, e.g., to mechanical disruption of cell-cell contacts after
edema formation, which is further supported by the temporal relationship of actin breakdown and p120ctn
phosphorylation, both of which occur within minutes after CCK stimulation.
In summary, we define for the first time a complete adherens junction
complex in pancreatic acinar cells with the components necessary for
actin binding, i.e., E-cadherin, -catenin, and
-catenin.
Supramaximal secretory CCK was able to regulate one additional
component of this complex, p120ctn, which likely is
responsible for the actin release from the plasma membrane observed
within minutes after secretagogue stimulation.
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ACKNOWLEDGEMENTS |
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Present address of O. A. Musa: University of Gezira, Faculty of Medicine, PO Box 20, Medani, Sudan.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. P. Lutz, Univ. of Ulm, Robert-Koch-Str. 8, 89070 Ulm, Germany (E-mail: manfred.lutz{at}medizin.uni-ulm.de).
Received 2 August 1999; accepted in final form 3 November 1999.
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