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1 Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0693; 2 3rd Division, Department of Medicine, Kobe University School of Medicine, Chuo-ku, Kobe 650-0017, Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
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Ischemic epithelial cells are
characterized by disruption of intercellular junctions and loss of
apical-basolateral protein polarity, which are normally dependent on
the integrity of the adherens junction (AJ). Biochemical
analysis of both whole ischemic kidneys and ATP-depleted Madin-Darby
canine kidney (MDCK) cells demonstrated a striking loss of E-cadherin
(the transmembrane protein of the AJ) with the appearance and
accumulation of an ~80-kDa fragment reactive with anti-E-cadherin
antibodies on Western blots of ATP-depleted MDCK cells. This apparent
ischemia-induced degradation of E-cadherin was not blocked by
either inhibitors of the major proteolytic pathways (i.e., proteasome,
lysosome, or calpain), or by chelation of intracellular calcium,
suggesting the involvement of a protease capable of functioning at low
ATP and low calcium levels. Immunocytochemistry revealed the
movement of several proteins normally comprising the AJ, including
E-cadherin and 
-catenin, away from lateral portions of the plasma
membrane to intracellular sites. Moreover, rate-zonal centrifugation
and immunoprecipitation with anti-E-cadherin and anti--catenin
antibodies indicated that ATP depletion disrupted normal
E-cadherin-catenin interactions, resulting in the dissociation of 
-
and 
-catenin from E-cadherin and -catenin-containing complexes.
Because the generation and maintenance of polarized epithelial cells
are dependent upon E-cadherin-mediated cell-cell adhesion and normal AJ
function, we propose that the rapid degradation of E-cadherin and
dissolution of the AJ is a key step in the development of the
ischemic epithelial cell phenotype. Furthermore, we hypothesize that
the reassembly of the AJ after ischemia/ATP depletion may require a
novel bioassembly mechanism involving recombination of newly
synthesized and sorted E-cadherin with preexisting pools of catenins
that have (temporally) redistributed intracellularly.
Madin-Darby canine kidney; adenosine 5'-triphosphate; adherens junction; polyacrylamide gel electrophoresis; adenosine 5'-triphosphate depletion; antimycin A; 2-deoxyglucose; plakoglobin; cell adhesion
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
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TO FUNCTION PROPERLY, EPITHELIAL cells depend on the integrity of intercellular junctions [e.g., adherens (AJ), tight, gap, desmosomes] and arrangement of plasma membrane lipids and proteins into strictly maintained apical and basolateral domains. Ischemia and subsequent reperfusion/reoxygenation perturb epithelial function by disrupting intercellular junctions (11, 19, 21, 30, 31), protein polarization (11, 19, 21), the actin-based cytoskeleton (1, 11), and folding mechanisms in the endoplasmic reticulum (17, 18). Although much of this dysfunction can ultimately be traced back to rapid and severe alterations in ATP, free radicals, intracellular pH, and calcium, the precise mechanisms involved in the generation of the ischemic epithelial cell phenotype remain poorly understood.
In models of polarized epithelial biogenesis, the generation and
maintenance of apical/basolateral polarity has been shown to be linked
to AJ assembly. In particular, calcium-dependent cell-cell adhesion via
homophilic interactions of the extracellular domain of E-cadherin (the
transmembrane protein of the AJ) between adjacent cells has been found
to be critically important in the formation of tight polarized
epithelia (12, 13, 29). For example, the addition of either calcium
chelators or anti-E-cadherin antibodies to the culture medium has been
shown to block the formation of intercellular junctions and the
development of apical-basolateral polarity in kidney-derived
Madin-Darby canine kidney (MDCK) epithelial cells (12). Furthermore,
transfection of nonpolarized fibroblasts with E-cadherin has been found
to induce the movement of Na-K-ATPase from a uniform distribution on
the plasma membrane to sites of cell-cell contact, in a manner
reminiscent of polarizing epithelial cells (20). Along with several
similar studies, these findings indicate that E-cadherin-mediated
cell-cell contact initiates a cascade of events leading to the
formation of polarized epithelial cells (10, 13, 23, 29). E-cadherin
also interacts with several cytoplasmic proteins (-,-, and
-catenin) and the cytoskeleton to form the AJ. Together, these
intra- and extracellular interactions provide the basis for many
properties characteristic of the AJ (6, 9, 14, 22, 25, 32, 33).
However, despite its importance in the generation and maintenance of
the tight polarized epithelial cell, much remains to be understood
about the effects of ischemia on the AJ and the proteins that
comprise it.
Here we show that ischemia and/or ATP depletion induces distinct biochemical lesions in the AJ. Analysis of ischemic whole kidney and ATP-depleted cultured MDCK cells demonstrates that an ischemic insult results in the selective degradation of E-cadherin and the disruption of the protein-protein interactions between E-cadherin and the catenins that comprise the AJ. These findings suggest that alterations in E-cadherin, as well as its interactions with the cytoplasmic components of the adherens junction, constitute a key lesion in epithelial ischemia. Moreover, because the maintenance of polarized epithelial cells is critically dependent on E-cadherin-mediated cell-cell contact, the results also provide a potential unifying mechanism for generation of the ischemic epithelial cell phenotype, including the loss of polarity and the disruption of other intercellular junctions.
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EXPERIMENTAL PROCEDURES |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
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Reagents and chemicals.
Antibodies against E-cadherin were either isolated from hybridoma cells
(rr-1) kindly provided by Barry Gumbiner (Univ. of California-San
Francisco) or purchased from Sigma Chemical (St. Louis, MO) and
Transduction Laboratories (Lexington, KY). Antibodies against -,
-, and -catenin were from either Transduction Laboratories or
Sigma. Antimycin A and 2-deoxyglucose were also from Sigma.
Renal ischemia and ATP depletion. For the in vivo studies of epithelial ischemic injury, adult Sprague-Dawley rats were subjected to 0-3 h of renal ischemia without reperfusion as previously described (17). For the in vitro analysis of epithelial ischemia, confluent monolayers of MDCK cells (~106 cells/100-mm2 dish) growing in Dulbecco's modified minimal essential medium (supplemented with 5% FCS and antibiotics) were depleted of ATP for 0-6 h by incubation in PBS (supplemented with 1.5 mM CaCl2 and 2 mM MgCl2) containing 2 mM deoxy-D-glucose and 10 µM antimycin A (30, 31).
Confocal immunofluorescent microscopy. Confluent MDCK cell monolayers growing on coverslips subjected to ATP depletion were fixed in methanol, permeabilized with saponin, reacted with antibodies against components of the AJ, and examined with a Bio-Rad confocal microscope as described (30, 31).
Immunoprecipitation.
Control and ATP-depleted monolayers of MDCK cells were rinsed gently
with PBS, lysed for 30 min at 4°C in 1 ml of immunoprecipitation buffer (27), and subjected to immunoprecipitation with anti-E-cadherin antibodies (rr-1) and anti--catenin antibodies by using methods previously described (5, 17, 30, 31).
Rate-zonal centrifugation. Monolayers of MDCK cells were grown in 6-well cluster plates and subjected to 0-4 h of ATP depletion as described above. The cells were rinsed twice in PBS, solubilized for 30 min at 4°C in 1 ml immunoprecipitation buffer (27), and cleared of insoluble matter. The supernatant was then layered on top of 5-20% linear sucrose gradients created in the immunoprecipitation buffer without detergents and subjected to rate-zonal centrifugation (17, 30, 31).
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RESULTS AND DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
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To investigate the effects of ischemia on E-cadherin and the AJ, we employed an ischemic whole kidney preparation as well as ATP depletion of MDCK cells, a well-characterized cell culture model of epithelial cell ischemia that reproduces many of the lesions seen in epithelial ischemic injury but has the advantage of being amenable to detailed biochemical analysis (4, 8, 11, 17, 19, 30, 31, 34).
ATP depletion and whole tissue ischemia induces selective
degradation of E-cadherin.
Western blot analysis of ATP-depleted MDCK cell lysates revealed the
highly reproducible loss of the 120-kDa band of E-cadherin and the
appearance of an ~80-kDa fragment that was also recognized by the
anti-E-cadherin antibody (rr-1) (Fig.
1A). This smaller band was either
not present in control cells or apparent only as a faint band; however,
as ATP depletion proceeded, this band progressively increased, whereas
the 120-kDa band diminished (Fig. 1, A and B). More
than one-half of the 120-kDa form of E-cadherin was reproducibly
degraded by 2 h and, by 4 h of ATP depletion, the 80-kDa fragment
represented the predominant band detectable on the blots with the
anti-E-cadherin antibody (Fig. 1B). In contrast, there was no
similar striking loss of the cytosolic catenins detectable even after 6 h of ATP depletion, a point at which little or no 120-kDa form of
E-cadherin is detectable (Fig. 1C). Thus ATP depletion of
cultured MDCK cells induced a rapid and selective loss of E-cadherin under conditions when ATP levels are extremely low (<10% of control) (4, 17, 31).
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-catenin detectable on
Western blots was only slightly altered by whole tissue
ischemia (Fig. 1D). Thus the observed loss of
E-cadherin (under conditions of ATP depletion or ischemia)
appears to be a highly selective event occurring in both cultured cells
and in vivo.
It is important to note that the 80-kDa band that we have identified is
likely different from the soluble 80-kDa fragment of E-cadherin that is
either released into the media of cultured human carcinoma cells,
generated by trypsinization of epithelial cells in the presence of
calcium (7), or found circulating in the serum of cancer patients (15).
Because this fragment is cleaved from the cell surface and is lost into
the extracellular media or serum, one would not expect to detect it on
Western blots of cell lysates, as is the case with the 80-kDa fragment
described here. In addition, this extracellular cleavage fragment of
E-cadherin would not be able to interact with the cytosolic catenins,
whereas the 80-kDa fragment described in this study can be
immunoprecipitated with -catenin (see below) and is also
coimmunoprecipitated with anti--catenin antibodies (see below).
Moreover, taken together with the fact that ~95% of
surface-accessible E-cadherin is internalized within the first 60 min
of ATP depletion of MDCK cells (19), the 80-kDa fragment described here
is probably the result of an intracellular degradation event,
rather than an extracellular cleavage that gives rise to the 80-kDa
fragment found in the media or serum.
The single and highly reproducible 80-kDa fragment observed after the
ATP depletion of MDCK cells suggests that a highly specific cleavage of
E-cadherin is occurring. However, relatively high concentrations of a
number of proteolytic inhibitors that block degradation via different
proteolytic pathways, including proteasomal, lysosomal, and
calpain-mediated mechanisms, had no apparent effect on the loss or
cleavage of E-cadherin, or the generation of the 80-kDa fragment (Fig.
2, lanes 1-8). These data
raise the possibility that an intracellular, potentially novel,
protease capable of operating at low ATP levels (or
independent of ATP) is involved in the degradation of
E-cadherin. Moreover, because treatment with cell-permeant calcium
chelators 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM
(BAPTA-AM; 200 µM) and dimethyl-BAPTA-AM (100 µM-data not shown),
concentrations more than twice as high as those found to reduce
intracellular calcium concentration
[Ca2+]i in ATP-depleted MDCK cells
by >60%) (34) had little or no effect on the loss of E-cadherin
(Fig. 2, lanes 9-10), the candidate protease is also
unlikely to be dependent on increased levels of intracellular calcium.
(This is also consistent with the lack of inhibition with blockers of
calpain activity.)
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ATP depletion perturbs the cellular localization of components of
the adherens junction.
To further analyze the fate of the proteins comprising the AJ,
immunocytochemical analysis was performed. In control cells, E-cadherin
was localized to lateral aspects of the plasma membrane in a continuous
linear staining pattern with only a modest amount of apparent
intracellular staining (Fig. 3A).
Although there was some intracellular staining for each of the catenins
in control cells, these three proteins were also primarily found in a
linear pattern at the lateral portions of the plasma membrane (Fig. 3, C, E, and G). After 4 h of ATP depletion,
although there was little change in the localization of -catenin,
(Fig. 3H), the staining pattern for E-cadherin, and
-catenin, and to a lesser extent -catenin, was altered. For
example, the linear staining at the level of the plasma membrane for
E-cadherin appeared to be thinner and more discontinuous (Fig.
3B) and was accompanied by the appearance of punctate
intracellular staining for this protein (Fig. 3B). Although a
portion of both - and -catenin remained localized at the lateral
portions of the plasma membrane, 4 h of ATP depletion resulted in an
increase in the intracellular staining of both of these proteins as
well (Fig. 3, D and F). Because E-cadherin is known to
be inaccessible to externally added biotin after 1 h of ATP depletion
in MDCK cells (19), these immunocytochemical data support the notion
that ATP depletion leads to internalization of E-cadherin as well as
other components of the AJ. If, as the data suggest, E-cadherin is
internalized and degraded in response to ATP depletion, this raises an
interesting question: how are the homophilic interactions of E-cadherin
disrupted in the presence of normal levels of extracellular calcium
(see EXPERIMENTAL PROCEDURES)? It is possible that
alteration of the phosphorylation state of the E-cadherin-catenin
complex during ATP depletion affects E-cadherin homophilic binding,
allowing for the internalization of the protein and its subsequent
degradation. This notion is not without precedent because the
phosphorylation states of -catenin, -catenin, p120, as well as
E-cadherin have been shown to be critical to maintenance of
cell-cell adhesion in v-SRC-transformed MDCK cells and in mitotic MDCK
cells (2, 3, 28).
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ATP depletion alters E-cadherin-catenin interactions of the AJ.
Under normal physiological conditions, the cytoplasmic domain of
E-cadherin associates directly with either -catenin or -catenin, which in turn associate with -catenin. -catenin, which can
interact with -actinin and actin filaments, mediates the interaction
between the cadherin-catenin complex and the actin cytoskeleton (16, 24, 26). To determine whether, as a result of E-cadherin degradation, this complex of E-cadherin with the other components of the AJ was
altered, sucrose density gradient analysis was performed. Western blot
analysis of the gradient fractions revealed that, in control cells,
E-cadherin was found in the medium density fractions of a 5-20%
sucrose gradient as a 120-kDa protein (Fig.
4A). However, after 4 h of ATP
depletion, the amount of the 120-kDa form of E-cadherin was markedly
reduced and was now found in the lower density fractions of the
gradient (Fig. 4A). The ~80-kDa form of E-cadherin was now
apparent and was also found in this same low-density region of the
gradient (Fig. 4A). This behavior of E-cadherin is very
different from certain tight junction proteins, which fractionate as a
high-density complex after ATP depletion (31), and suggests that the
normal protein-protein interactions involving E-cadherin are disrupted
in the face of ATP depletion.
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-, -, and -catenin were all detectable on Western blots of E-cadherin immunoprecipitates. However, after 1-2 h of ATP depletion, a time at which
the 120-kDa E-cadherin is still the major form present in MDCK cells,
-catenin was barely detectable on Western blots (Fig. 4B).
Continued ATP depletion resulted in the dissociation of -catenin,
whereas -catenin was still detectable on Western blots of E-cadherin
immunoprecipitates even after 6 h of ATP depletion (Fig. 4B).
Thus ATP depletion caused a rapid disruption of the protein-protein
interactions between E-cadherin and - and -catenin. ATP depletion
would thus appear to affect intracellular transduction mechanisms
between E-cadherin and the actin-based cytoskeleton by dissolving links mediated by the catenins, which are thought to be crucial to
apical-basolateral protein polarization. Interestingly however, the
linkages between E-cadherin and -catenin appear to remain intact. In
fact, immunoprecipitation with anti--catenin antibodies was able to
coimmunoprecipitate both full-length E-cadherin as well as the 80-kDa
fragment of E-cadherin (Fig. 4C). This finding not only shows
that the E-cadherin and -catenin remain associated but also provides
strong support for the notion that 80-kDa cleavage fragment is
different from the extracellular fragment of E-cadherin that is found
in the media of trypsinized epithelial cells (7), or that that is found
circulating in the serum of cancer patients (15).
We argue here that the rapid disruption of the protein-protein
interactions of the components of the AJ, as well as the loss of
E-cadherin itself, constitute a key lesion in epithelial
ischemia. Because the integrity of intercellular junctions and
protein polarization in epithelial cells is critically dependent on
E-cadherin-mediated cell-cell contact, as well as E-cadherin's links
to the actin-based cytoskeleton mediated through the catenins, these
findings also suggest a unifying mechanistic explanation for much that
has been observed in the ischemic epithelial cell phenotype, including the disruption of tight junctions and the loss of apical-basolateral polarity. The combination of degradation of full-length E-cadherin and
the loss of E-cadherin-catenin interactions, together with the
internalization of E-cadherin and - and -catenin, could explain
the disruption of productive cell contacts which occurs in
ischemia. In a very broad sense, this model is something
of a reversal of that proposed for the role of E-cadherin and the AJ in
the development of polarized epithelial cells, in which the homophilic
binding of E-cadherin between adjacent cells initiates a cascade of
events that lead to the formation of other intercellular junctions and
the development of apical-basolateral polarity.
The centrality of E-cadherin to epithelial polarization and biogenesis
of the permeability barrier [two key features of the normal
polarized epithelia that are disrupted in ischemia (11, 19,
31)] suggests that our results also bear in important ways on the
recovery of epithelial function after ischemic injury. E-cadherin is
selectively and rapidly degraded after ATP depletion. Taken together
with the finding that ATP depletion disrupts the normal protein-protein
interactions that comprise the AJ, these data indicate that the
recovery of the tight polarized epithelial cell phenotype is dependent
on the reassembly of the AJ. However, it remains unclear how the AJ is
reassembled after ischemic injury. Under normal physiological
conditions, E-cadherin interacts with either -, or -catenin at
the level of the ER. Soon after the arrival of this complex at the
plasma membrane, -catenin is loaded onto this complex, allowing for
interaction with the actin cytoskeleton (13). In the cell recovering
from ATP depletion (and presumably nonlethal ischemic injury), it seems
reasonable to hypothesize that a preexisting cytosolic pool of catenins
(that had redistributed intracellularly after ATP depletion) is
recruited by newly synthesized and folded E-cadherin during recovery of
the AJ. However, it remains possible that the cell initially utilizes
preformed AJ proteins (catenins and any remaining 120-kDa
E-cadherin) to rapidly reestablish cell-cell adhesion, with
subsequent synthesis and assembly of new AJs. Nevertheless, new
synthesis of E-cadherin (and, after severe injury, possibly the
catenins as well) is likely to be necessary for the AJ and the
polarized epithelial cell to fully recover from ischemic injury.
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ACKNOWLEDGEMENTS |
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This work was supported in part by a RO1 grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (to S. K. Nigam) and by a Scientist Development Award from the American Heart Association (to K. T. Bush). This work was done during the tenure of an American Heart Association Established Investigatorship (to S. K. Nigam).
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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: S. K. Nigam, Univ. of California, San Diego, Dept. of Medicine (0693), 9500 Gilman Dr., La Jolla, CA 92093-0693. E-mail: snigam{at}ucsd.edu
Received 13 August 1999; accepted in final form 30 November 1999.
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TOP
ABSTRACT
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EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
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  S. Gopalakrishnan, M. A. Hallett, S. J. Atkinson, and J. A. Marrs aPKC-PAR complex dysfunction and tight junction disassembly in renal epithelial cells during ATP depletion Am J Physiol Cell Physiol, March 1, 2007; 292(3): C1094 - C1102. [Abstract] [Full Text] [PDF]
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 C. Baldwin, Z. W. Chen, A. Bedirian, N. Yokota, S. H. Nasr, H. Rabb, and S. Lemay Upregulation of EphA2 during in vivo and in vitro renal ischemia-reperfusion injury: role of Src kinases Am J Physiol Renal Physiol, November 1, 2006; 291(5): F960 - F971. [Abstract] [Full Text] [PDF]
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D. B. N. Lee, E. Huang, and H. J. Ward Tight junction biology and kidney dysfunction Am J Physiol Renal Physiol, January 1, 2006; 290(1): F20 - F34. [Abstract] [Full Text] [PDF]
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M. D. Covington, R. C. Burghardt, and A. R. Parrish Ischemia-induced cleavage of cadherins in NRK cells requires MT1-MMP (MMP-14) Am J Physiol Renal Physiol, January 1, 2006; 290(1): F43 - F51. [Abstract] [Full Text] [PDF]
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M. D. Covington, K. J. Bayless, R. C. Burghardt, G. E. Davis, and A. R. Parrish Ischemia-induced cleavage of cadherins in NRK cells: evidence for a role of metalloproteinases Am J Physiol Renal Physiol, August 1, 2005; 289(2): F280 - F288. [Abstract] [Full Text] [PDF]
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 J. Jiang, D. Dean, R. C. Burghardt, and A. R. Parrish Disruption of Cadherin/Catenin Expression, Localization, and Interactions During HgCl2-Induced Nephrotoxicity Toxicol. Sci., July 1, 2004; 80(1): 170 - 182. [Abstract] [Full Text] [PDF]
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 R. Kuefer, M. D. Hofer, J. E. Gschwend, K. J. Pienta, M. G. Sanda, A. M. Chinnaiyan, M. A. Rubin, and M. L. Day The Role of an 80 kDa Fragment of E-cadherin in the Metastatic Progression of Prostate Cancer Clin. Cancer Res., December 15, 2003; 9(17): 6447 - 6452. [Abstract] [Full Text] [PDF]
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 D. E. GOLL, V. F. THOMPSON, H. LI, W. WEI, and J. CONG The Calpain System Physiol Rev, July 1, 2003; 83(3): 731 - 801. [Abstract] [Full Text] [PDF]
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D. Sinha, Z. Wang, V. R. Price, J. H. Schwartz, and W. Lieberthal Chemical anoxia of tubular cells induces activation of c-Src and its translocation to the zonula adherens Am J Physiol Renal Physiol, March 1, 2003; 284(3): F488 - F497. [Abstract] [Full Text] [PDF]
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E. W. Kuehn, K. M. Park, S. Somlo, and J. V. Bonventre Kidney injury molecule-1 expression in murine polycystic kidney disease Am J Physiol Renal Physiol, December 1, 2002; 283(6): F1326 - F1336. [Abstract] [Full Text] [PDF]
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S. Gopalakrishnan, K. W. Dunn, and J. A. Marrs Rac1, but not RhoA, signaling protects epithelial adherens junction assembly during ATP depletion Am J Physiol Cell Physiol, July 1, 2002; 283(1): C261 - C272. [Abstract] [Full Text] [PDF]
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 V. R. Price, C. A. Reed, W. Lieberthal, and J. H. Schwartz ATP Depletion Of Tubular Cells Causes Dissociation of the Zonula Adherens and Nuclear Translocation of {beta}-Catenin and LEF-1 J. Am. Soc. Nephrol., May 1, 2002; 13(5): 1152 - 1161. [Abstract] [Full Text] [PDF]
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J. Yang and Y. Liu Blockage of Tubular Epithelial to Myofibroblast Transition by Hepatocyte Growth Factor Prevents Renal Interstitial Fibrosis J. Am. Soc. Nephrol., January 1, 2002; 13(1): 96 - 107. [Abstract] [Full Text] [PDF]
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 C. Bianchi, E. G. Araujo, K. Sato, and F. W. Sellke Biochemical and Structural Evidence for Pig Myocardium Adherens Junction Disruption by Cardiopulmonary Bypass Circulation, September 18, 2001; 104(90001): I-319 - 324. [Abstract] [Full Text] [PDF]
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Z.-X. Liu, C. H. Nickel, and L. G. Cantley HGF promotes adhesion of ATP-depleted renal tubular epithelial cells in a MAPK-dependent manner Am J Physiol Renal Physiol, July 1, 2001; 281(1): F62 - F70. [Abstract] [Full Text] [PDF]
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M. Schmelz, V. J. Schmid, and A. R. Parrish Selective Disruption of Cadherin/Catenin Complexes by Oxidative Stress in Precision-Cut Mouse Liver Slices Toxicol. Sci., June 1, 2001; 61(2): 389 - 394. [Abstract] [Full Text] [PDF]
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