Departments of 1 Pediatrics, 2 Ophthalmology and Visual Sciences, and 3 Pharmacology, University of Wisconsin-Madison, Madison, Wisconsin 53792
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ABSTRACT |
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Protein tyrosine phosphorylation is a
dynamic reversible process in which the level of phosphorylation, at
any time, is the result of phosphatase and/or kinase activity. This
balance is critical for control of growth and differentiation. The role
of tyrosine phosphatases during nephrogenesis and in kidney disease requires delineation. Appropriate regulation of focal adhesion proteins
such as focal adhesion kinase (FAK) and paxillin are important in
cell adhesion, migration, and differentiation. We have previously shown
that B cell lymphoma/leukemia-2 (bcl-2) /
mice develop cystic
kidneys and exhibit sustained phosphorylation of FAK and paxillin. We
have examined the expression and activity of focal adhesion tyrosine
phosphatases [Src homology-2 domain phosphatase (SHP-2), protein
tyrosine phosphatase (PTP 1B), and PTP-proline, glutamate, serine, and
threonine sequences (PEST)] during normal nephrogenesis and in cystic
kidneys from bcl-2
/
mice. Cystic kidneys from postnatal day
20 bcl-2
/
mice demonstrate a reduced expression,
sixfold decrease in activity, and altered distribution of SHP-2 and PTP
1B. PTP-PEST expression and distribution were similar in both bcl-2 +/+
and bcl-2
/
mice. The altered regulation of PTP 1B and SHP-2 in
kidneys from bcl-2
/
mice correlates with sustained phosphorylation
of FAK and paxillin. Thus renal cyst formation in the bcl-2
/
mice may be the result of an inability of complete
differentiation due to continued activation of growth processes,
including activation of FAK and paxillin.
focal adhesion kinase; paxillin; renal cysts; focal adhesion tyrosine phosphatases; protein tyrosine phosphatase-proline, glutamate, serine, and threonine sequences; Src homology-2 domain phosphatase; B-cell lymphoma/leukemia-2
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INTRODUCTION |
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RENAL
HYPOPLASIA/DYSPLASIA/APLASIA
are the second leading causes for renal transplantation in children.
These renal diseases are the result of abnormal development caused by
altered growth, differentiation, and/or organogenesis
(29). The death repressor B cell lymphoma/leukemia-2
(bcl-2) plays an important role during nephrogenesis. Mice deficient in
bcl-2 (bcl-2 /
) develop renal hypoplasia/cystic dysplasia. Renal
cyst formation in bcl-2
/
mice, as well as other renal cystic
diseases, is characterized by increases in apoptosis and
proliferation, altered tubular morphology, and epithelial cells that do
not fully differentiate (3, 4, 13, 23, 30, 31). Gross cyst
formation in bcl-2
/
mice occurs at multiple sites along the
nephron at postnatal day 20 (P20)
(25). We have observed nuclear localization of
-catenin, loss of apical brush-border actin staining, and sustained
phosphorylation of focal adhesion kinase (FAK) and paxillin in cystic
kidneys from bcl-2
/
mice, suggesting that altered cell adhesive
mechanisms occur (24, 26). Interestingly, renal cyst
formation in these mice occurs at a time when bcl-2 expression normally
has declined significantly. This suggests that early loss of bcl-2
during nephrogenesis may affect the ability of these kidneys to
differentiate/mature at later times.
Tyrosine phosphatases play an important role during growth and
differentiation. Altered regulation of tyrosine phosphatases may
contribute to aberrant protein phosphorylation that leads to disease.
The role these phosphatases play during nephrogenesis and renal cyst
formation is unknown. We have recently demonstrated that FAK and
paxillin are highly expressed and phosphorylated during normal
nephrogenesis and decline to very low levels after renal
maturation (P20) (26). In contrast, sustained
phosphorylation of FAK and paxillin was observed in cystic kidneys from
P20 bcl-2 /
mice. The overexpression of phosphorylated
FAK or paxillin, in myoblasts, causes these cells to remain
proliferative and inhibits their ability to initiate terminal
differentiation (20); thus it is tempting to speculate
that this occurs in cystic kidneys from bcl-2
/
mice.
Therefore, dephosphorylation of FAK and paxillin may play an important
role during differentiation and renal maturation.
Src homology-2 domain phosphatase (SHP-2), protein tyrosine phosphatase (PTP 1B), and/or PTP-proline, glutamate, serine, and threonine sequences (PEST) can dephosphorylate focal adhesion proteins, such as FAK and paxillin, affecting cell growth and differentiation. Cells that lack expression of these phosphatases have hyperphosphorylation of FAK and paxillin as well as altered adhesion and migratory properties (2, 34). Cultured fibroblasts lacking functional SHP-2 have a reduced ability to spread and migrate on fibronectin, an increased number of focal adhesions, condensed F-actin aggregation at the cell periphery, and a significant reduction in FAK dephosphorylation (34). Cytoskeletal organization is altered similarly to that of FAK-deficient cells in these SHP-2 mutant cells. Cells deficient in PTP-PEST also have a phenotype similar to that of FAK-deficient cells, with altered cell migration and decreased turnover of focal adhesions. PTP-PEST acts to potentiate the action of FAK rather than antagonize it (2). These data suggest tyrosine phosphatases such as SHP-2 and PTP-PEST may work together with FAK to control the dynamics of focal adhesions (2, 34). Overexpression of PTP 1B in fibroblasts decreases cell migration, increases the time for cell spreading, and leads to formation of large focal complexes scattered over the ventral surface, which is similar to the reaction observed in PTP-PEST-deficient cells. Therefore, it is thought that an intermediate level of tyrosine phosphatase activity is necessary for formation of normal focal adhesions and cell migration (2).
To gain insight into the role SHP-2, PTP 1B, and PTP-PEST play during
nephrogenesis and renal cyst formation, we have examined their
expression, distribution, and activity in normal and cystic kidneys.
Cystic kidneys from bcl-2 /
mice displayed reduced expression and
activity as well as an altered distribution of SHP-2 and PTP 1B. SHP-1
and PTP-PEST expression were not affected in these kidneys. Thus
inappropriate expression and activation of tyrosine phosphatases SHP-2
and PTP 1B may impede terminal differentiation of renal epithelial
cells, contributing to renal cyst formation.
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MATERIALS AND METHODS |
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Animal breeding. Bcl-2 heterozygote animals were interbred. The genotypes of the offspring were determined by PCR analysis, as previously described (26). To examine expression of SHP-2, SHP-1, PTP 1B, and PTP-PEST, normal mice were interbred and the kidneys were removed at the times noted. Embryos were removed from anesthetized pregnant female mice on day 15 of pregnancy. Kidneys were surgically dissected from embryos and postnatal mice. Samples from affected congenital polycystic kidney (cpk; cpk/cpk) mice and their normal littermates were generously supplied by Dr. James Calvet.
Protein lysate preparation and Western blot analysis. Kidneys or metanephroi were homogenized and sonicated in a modified radioimmunoprecipitation assay buffer containing (in mM) 142.5 KCl, 5 MgCl2, 10 HEPES, pH 7.4, orthovanadate, and 2 sodium fluoride, as well as 1% Nonidet P-40 (NP-40) and a complete protease inhibitor cocktail (Boehringer Mannheim, Indianapolis, IN). The protein concentration was determined utilizing a Bio-Rad DC protein assay. Total protein lysate (20 µg) was electrophoresed on a 4-20% polyacrylamide gel and transferred to a Hybond enchanced chemiluminescence nitrocellulose membrane (Amersham, Arlington Heights, IL). The membranes were blocked for 1 h at room temperature in Tris-based saline buffer containing 20 mM Tris, pH 7.6, 137 mM NaCl, and 0.05% Tween (TBST), 3% bovine serum albumin, and 3% nondairy creamer. The membranes were then incubated overnight at 4°C with rabbit polyclonal antibodies to PTP 1B, which recognize both p50 and p42 PTP 1B (1:1,000; Dr. Terry Woodford-Thomas, Washington University, St. Louis, MO) (30), rabbit polyclonal antibodies to PTP-PEST (amino acids 470-775: noncatalytic portion; 1:2,500; Dr. Michael Schaller, University of North Carolina, Chapel Hill, NC), or rabbit polyclonal antibodies to SHP-2 (syp; 1:1,500; Upstate Biotechnology, Lake Placid, NY). The membranes were then washed with TBST, incubated with the appropriate secondary antibody (Pierce, Rockford, IL), washed with TBST, and developed with enhanced chemiluminescence (Amersham).
Immunoprecipitation and phosphatase assays. Kidneys were homogenized and sonicated in 150 mM NaCl, 50 mM Tris (pH 7.4), 1% NP-40, and protease inhibitors, but no phosphatase inhibitors. The protein concentration was determined, and 600 µg total protein were incubated with 3 µg anti-SHP-2, anti-PTP 1B, or IgG (as a negative control), followed by incubation with GammaBind Plus Sepharose (Pharmacia Biotech, Piscataway, NJ). The immunoprecipitates were then washed three times in buffer containing 0.2% NP-40. The immunoprecipitates were incubated with 0.2 mM phosphopeptide RRLIEDAEpYAARG (Upstate Biotechnology) for 15 min. The phosphate released was measured by using malachite green (Upstate Biotechnology) according to the manufacturer's instructions. The reactions were linear over the time assayed.
Processing of kidneys for histological studies and immunohistochemistry. Kidneys were surgically removed from mice, placed in an optimum cutting temperature compound (VWR Scientific, St. Louis, MO), and rapidly frozen. Sections of 7 µm each were placed on polylysine-coated slides (Sigma, St. Louis, MO). The sections were fixed in cold acetone (PTP 1B) or 3% paraformaldehyde (SHP-2 and PTP-PEST), washed in PBS, and incubated for 15 min in PBS blocking buffer (PBS containing 1% bovine serum albumin, 0.3% Triton X-100, and 0.2% skim milk powder). The sections were then incubated overnight at 4°C with rabbit polyclonal antibodies to PTP 1B (1:100; Upstate Biotechnology), SHP-2 (1:200; Upstate Biotechnology), or PTP-PEST (1:3,000; Dr. M. Schaller). The sections were incubated with indocarbocyanine (CY3)-labeled secondary antibody (Jackson ImmunoResearch, West Grove, PA). Nephron segments were identified by lectin staining and morphology. The sections were double stained with Lotus tetragonobolus agglutinin (Vector Laboratories, Burlingame, CA) to identify proximal tubules or Dolichos biflorus agglutinin (Vector Laboratories) to identify collecting duct. For these experiments, fluorescein-labeled lectins (1:40) were incubated overnight with the primary antibody and processed as previously described (25). The slides were then photographed.
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RESULTS |
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SHP-2 expression and activity are altered in cystic kidneys from
bcl-2 /
mice.
To understand the role tyrosine phosphatases have during
differentiation and renal maturation, we have examined the expression, activity, and distribution of SHP-2. SHP-2 is a cytosolic tyrosine phosphatase that positively regulates cell differentiation and plays a
role in growth factor- and integrin-signaling pathways. Phosphorylated
SHP-2 is a 70-kDa protein (p70), and the dephosphorylated form is a
64-kDa protein (p64). SHP-2 can dephosphorylate FAK and other focal
adhesion proteins, such as paxillin, thus modulating cell
adhesion and migration (18). We examined SHP-2 expression in kidneys from embryonic day 15 (E15),
P0, P10, and P20 mice to delineate
expression during normal nephrogenesis and after renal maturation (at
P20). In addition, we examined SHP-2 expression in cystic
kidneys from P20 in bcl-2
/
mice. At P20,
gross cyst formation occurs at multiple sites along the nephron
(25).
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Expression of a closely related tyrosine phosphatase, SHP-1, is not
affected.
SHP-1 is a nontransmembrane tyrosine phosphatase with significant
sequence identity to SHP-2 (16, 33). However, the two phosphatases have distinct biological roles (27). We have
examined the expression of SHP-1 during nephrogenesis and in cystic
kidneys from P20 bcl-2 /
mice. SHP-1 was expressed at
similar levels during nephrogenesis and in normal and cystic kidneys
(Fig. 4). Because SHP-1 is constitutively
expressed during nephrogenesis and SHP-2 expression increases after
renal maturation in the normal kidney, these tyrosine phosphatases may
have different functions during nephrogenesis.
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PTP 1B expression and activity are altered in cystic kidneys from
bcl-2 /
mice.
PTP 1B is a 50-kDa tyrosine phosphatase that can be cleaved by calpain
to a more catalytically active 42-kDa form (10). Both 42- and 50-kDa forms of PTP 1B are expressed in the kidney (Fig.
5). P50 PTP 1B was highly
expressed in kidneys from E15, P0, and
P10 normal mice. Only a low level of p42 PTP 1B expression was observed in these lysates (Fig. 5). In kidneys from bcl-2 +/+ mice,
expression of 50-kDa PTP 1B declined at renal maturation (P20), with a concomitant increase in 42-kDa PTP 1B
expression (Fig. 5). In contrast, in kidney lysates from P20
bcl-2
/
mice, expression of PTP 1B remained low, which is similar
to that observed in kidneys from normal P10 mice (Fig. 5).
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PTP-PEST expression is not affected in kidneys from bcl-2 /
mice.
PTP-PEST is a tyrosine phosphatase also involved in regulating tyrosine
phosphorylation of focal adhesion proteins. PTP-PEST binds signaling
molecules, including Csk (8), paxillin (22), Shc (5, 14), and Grb2 (6), in its
noncatalytic region. PTP-PEST is a 120-kDa protein that was highly
expressed in kidney lysates from E15 normal mice (Fig.
8). Expression of p120 PTP-PEST was
observed at P0 but declined to very low levels at later
postnatal times in these mice. The decline of p120 PTP-PEST occurred
together with an increase in a 73-kDa protein (p73 PTP-PEST) during
postnatal renal maturation. Expression of p120 and p73 PTP-PEST was
similar in kidneys from P20 bcl-2 +/+ and P20
bcl-2
/
mice (Fig. 8).
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SHP-2 and PTP 1B expression is altered in cystic kidneys from cpk
mice.
Affected cpk/cpk mice have polycystic kidney disease that is
similar to autosomal-recessive polycystic kidney disease in humans (11, 15). Proximal tubules begin to dilate in embryonic
and newborn animals, with the kidneys of the affected animals becoming grossly cystic during the first 3 wk of life. To determine whether the
decreased expression of SHP-2 and PTP 1B was unique to cystic kidneys
from bcl-2 /
mice, we examined their expression in cystic kidneys from the affected cpk/cpk mice and normal
littermates. We observed decreased expression of both these
phosphatases in cystic kidneys from P20 bcl-2
/
mice
(Figs. 1 and 5). Figure 10 demonstrates
Western analysis of protein lysates prepared from affected
P20 cpk/cpk (CY) mice and P20 normal
littermates (NL) blotted for SHP-2 (A) and PTP 1B
(B). We observed decreased expression of both SHP-2 and
42-kDa PTP 1B in lysates from the affected cpk/cpk mice
compared with the normal littermates. The blots were stripped and
reblotted with
-catenin to control for loading. We had previously observed that the expression of
-catenin is similar throughout nephrogenesis and in cystic kidneys (26). Similar
expression of
-catenin was observed in cpk/cpk mice and
normal littermates (data not shown).
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DISCUSSION |
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Protein tyrosine phosphorylation is a dynamic reversible process
in which the level of phosphorylation, at any time, is the result of
kinase and/or phosphatase activity. Altered regulation of phosphatases
and/or kinases can lead to abnormal growth and differentiation. The
role of tyrosine phosphatases during nephrogenesis requires further
delineation. We have examined the expression and activity of focal
adhesion tyrosine phosphatases during normal nephrogenesis and in
cystic kidneys from bcl-2 /
mice. Our major findings are
1) cystic kidneys display decreased expression and activity
of SHP-2 and PTP 1B; 2) either loss or altered localization of SHP-2 and PTP 1B was observed in cystic kidneys; and 3)
SHP-2 and PTP 1B are expressed with a nephron segmental distribution similar to FAK and paxillin in normal mice (Figs. 1 and 5). Therefore, aberrant regulation of these phosphatases may impede terminal differentiation of renal epithelial cells during renal maturation and
thus facilitate renal cyst formation.
Cystic kidneys have increased amounts of apoptosis and
proliferation, which suggests that epithelial differentiation is not complete (3, 4, 9, 12, 25, 31). These changes occur in the
bcl-2 /
mouse at a time when bcl-2 expression is normally low,
suggesting that its loss early in development may alter signaling pathways, which ultimately results in the inability of these epithelial cells to terminally differentiate. In P20 bcl-2
/
mice,
renal cystic disease correlated with sustained phosphorylation of p125 FAK and p68 paxillin, although no changes in the levels of these proteins were observed (26). Because the overexpression of
phosphorylated FAK or paxillin in myoblasts causes these cells to
remain proliferative and inhibits their ability to initiate terminal
differentiation (20), it is tempting to speculate that
this occurs in cystic kidneys from the bcl-2
/
mice. Our previous
studies, as well as studies from others, indicate that downregulation
of FAK and paxillin phosphorylation is essential for stabilization of
focal adhesion complexes and promotion of a nonproliferative
differentiated phenotype (20, 26). This is perhaps
mediated, at least in part, through local recruitment and activation of
focal adhesion tyrosine phosphatases. Therefore, appropriate
dephosphorylation of these proteins may be required during nephrogenesis.
SHP-2 is a widely expressed cytosolic tyrosine phosphatase that plays a
role in growth factor and integrin-mediated signaling pathways. SHP-2
can interact with various signaling molecules through its SH2 domains.
It is recruited to focal adhesions and can modulate the activity of FAK
(18). The loss of functional SHP-2 is lethal midgestation,
with a phenotype similar to FAK- and fibronectin-deficient embryos
caused by important migratory defects (21). The SHP-2
mutation also suppresses erythroid and myeloid differentiation,
suggesting an important role during hematopoietic development
(19). In addition, loss of functional SHP-2 in embryonic stem cells inhibits epithelial and fibroblast differentiation in vitro
(19). Therefore, SHP-2 may positively mediate cell differentiation. In the studies presented here, expression and activity
of SHP-2 were reduced in kidneys from bcl-2 /
mice compared with
their wild-type littermates. SHP-2 expression was also reduced in
kidneys from the cpk/cpk mice. This would be consistent with
epithelial cells from kidneys of P20 bcl-2
/
and
cpk/cpk mice, which express substantially lower amounts of
SHP-2, being unable to fully differentiate. This altered expression
appears to be specific for SHP-2, because SHP-1, a nontransmembrane
tyrosine phosphatase with significant sequence identity to SHP-2
(16, 33), is not affected. These two phosphatases have
distinct biological roles (27), which are apparent in
these studies. Thus appropriate expression and activation of SHP-2 may
be essential during normal nephrogenesis.
PTP 1B is a 50-kDa protein that has an ubiquitous tissue distribution.
PTP 1B is cleaved by calpain to a more catalytically active 42-kDa
protein (10). Introduction of wild-type PTP 1B into 3Y1
fibroblasts reduces phosphorylation of FAK and the rate of cell
spreading (17). In addition, expression of
dominant-negative PTP 1B results in a reduction of adhesion and
spreading on fibronectin (1). Esophageal cancers also
demonstrate a significant reduction of PTP 1B expression compared with
surrounding tissue (28). The data presented here
demonstrate a decrease in p42 PTP 1B expression and PTP 1B activity, as
well as an altered distribution in cystic kidneys from P20
bcl-2 /
mice compared with P20 bcl-2 +/+ mice, thus
suggesting a role for PTP 1B during renal maturation. We also observed
decreased expression of 42-kDa PTP 1B in cpk/cpk kidneys.
Together, these data indicate that altered expression of SHP-2 and PTP
1B may contribute to an immature cystic phenotype.
Tyrosine phosphatases localized to focal adhesion complexes are important in modulation of FAK activity during cell adhesion and migration. We believe that during the final stages of renal maturation, when downregulation of FAK and paxillin should occur, SHP-2 and PTP 1B are not properly recruited to focal adhesion complexes and/or activated. This hypothesis is supported by our data demonstrating decreased expression and activity and altered localization of PTP 1B in cystic kidneys. For example, in the normal kidney, PTP 1B localizes to the basolateral membrane where FAK and paxillin are expressed (26). However, in cystic distal tubules, PTP 1B is misdirected to the apical membrane; thus PTP 1B may not have access to FAK and paxillin to dephosphorylate the cystic distal tubules.
PTP-PEST is a cytoplasmic tyrosine phosphatase that can modulate focal
adhesion complexes. It has a NH2-terminal catalytic domain
and a COOH-terminal domain containing several PEST (8, 22). Fibroblasts lacking PTP-PEST have decreased migration, increased number of focal adhesions, and hyperphosphorylation of FAK
and paxillin (7). We observed similar levels and
distribution of PTP-PEST in kidneys from P20 bcl-2 /
and
P20 bcl-2 +/+ mice. At P20, p73 PTP-PEST is the
most abundant form, and is recognized by an antibody against the
noncatalytic domain. Thus PTP-PEST expression is similar in kidneys
from bcl-2 +/+ and bcl-2
/
mice.
In summary, the appropriate recruitment and activation of tyrosine
phosphatases to focal adhesion complexes are essential for
stabilization of cellular adhesive mechanisms and modulation of cell
adhesion and migration. The decreased activity and expression, as well
as an altered distribution of PTP 1B and SHP-2, are consistent with
sustained phosphorylation of FAK and paxillin and the
immature/undifferentiated cystic phenotype in bcl-2 /
mice. Our
data demonstrating that SHP-2 and PTP 1B expression is reduced in
cystic kidneys from the cpk mice suggest that these changes
are not unique to the bcl-2
/
mouse. Thus proper regulation of
tyrosine phosphatases, including SHP-2 and PTP 1B, may play an
important role during renal maturation.
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ACKNOWLEDGEMENTS |
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The authors thank Dr. Anna Huttenlocher for critically reviewing the manuscript and Drs. Terry Woodford-Thomas and Michael Schaller for generously supplying antibodies for PTP 1B and PTP-PEST, respectively. We greatly apppreciate the generosity of Dr. James Calvet for supplying us with samples from the affected cpk/cpk mice and their normal littermates.
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FOOTNOTES |
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This research (and C. M. Sorenson) was funded by a Scientist Development Grant from the American Heart Association and a Solomon Papper MD Young Investigator Grant from the National Kidney Foundation. N. Sheibani was funded by National Institutes of Health Grant AR-45599.
Address for reprint requests and other correspondence: C. M. Sorenson, Dept. of Pediatrics, Univ. of Wisconsin-Madison, H4/444 CSC, 600 Highland Ave., Madison, WI 53792-4108 (E-mail: cmsorenson{at}facstaff.wisc.edu).
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. Section 1734 solely to indicate this fact.
10.1152/ajprenal.00184.2001
Received 14 June 2001; accepted in final form 18 October 2001.
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