1319
Journal of Cell Science 113, 1319-1334 (2000)
Printed in Great Britain © The Company of Biologists Limited 2000
JCS0834
COMMENTARY
The p120 catenin family: complex roles in adhesion, signaling and cancer
Panos Z. Anastasiadis and Albert B. Reynolds*
Department of Cell Biology, Vanderbilt University, MCN #C-2310, 1161 21st Ave. South, Nashville, TN 37232-2175, USA
*Author for correspondence (e-mail: [email protected])
Published on WWW 21 March 2000
SUMMARY
p120 catenin (p120) is the prototypic member of a growing
subfamily of Armadillo-domain proteins found at cellcell junctions and in nuclei. In contrast to the functions
of the classical catenins (α-catenin, β-catenin, and γcatenin/plakoglobin), which have been studied extensively,
the first clues to p120’s biological function have only
recently emerged, and its role remains controversial.
Nonetheless, it is now clear that p120 affects cell-cell
adhesion through its interaction with the highly conserved
juxtamembrane domain of classical cadherins, and is likely
to have additional roles in the nucleus. Here, we summarize
INTRODUCTION
p120 (p120ctn, hereafter p120) was originally identified as a
prominent substrate of the Src oncoprotein (Reynolds et al.,
1989). cDNA cloning revealed that it contains an Armadillorepeat domain (Arm domain) that shares 22% identity with that
of the catenin Armadillo/β-catenin (Reynolds et al., 1992;
Peifer et al., 1994) and led to experiments that demonstrated
its direct interaction with cadherins (Reynolds et al., 1994;
Daniel and Reynolds, 1995; Staddon et al., 1995; Shibamoto
et al., 1995; see Fig. 1). Cadherins comprise a superfamily of
transmembrane cell-cell adhesion receptors that link adjacent
cells via calcium-dependent homophillic interactions between
the cadherin extracellular domains. They regulate a variety of
biological processes, including development, morphogenesis,
and tumor metastasis (for review see Takeichi, 1995; Yap,
1998). During tumor progression to malignancy, the aberrant
loss of expression of epithelial cadherin (E-cadherin), the
major cell-cell adhesion molecule in epithelial cells, is widely
believed to mediate the transition to metastasis (Perl et al.,
1998; reviewed by Yap, 1998). Cadherin function is modulated
by a group of cytoplasmic proteins called catenins (i.e. αcatenin, β-catenin, plakoglobin and p120), which interact
with the cadherin intracellular domain. Defects in catenin
expression or function have also been linked to metastasis. A
major role of catenins is to anchor the cadherin complex to the
actin cytoskeleton. β-Catenin and plakoglobin act as bridges
connecting E-cadherin to α-catenin, which in turn associates
with actin filaments either directly (Herrenknecht et al., 1991;
the data on the potential involvement of p120 both in
promotion of and in prevension of adhesion, and propose
models that attempt to reconcile some of the disparities in
the literature. We also discuss the structural relationships
and functions of several known p120 family members, as
well as the potential roles of p120 in signaling and cancer.
Key words: Cell adhesion, p120ctn, ARVCF,
δ-catenin/NPRAP/neurojungin, p0071, Plakophilin, Cadherin,
Clustering, RhoA, Kaiso, Presenilin, Armadillo/β-catenin
Nagafuchi et al., 1991; Rimm et al., 1995) or indirectly
(Knudsen et al., 1995; Nieset et al., 1997). β-Catenin also has
signaling roles in the cytoplasm and nucleus that are important
in development and cancer. For example, β-catenin/armadillo
is a key player in the Wnt/Wg signaling pathway, directly
mediating downstream events through transactivation of
transcription factors of the Lef1/TCF family (Molenaar et al.,
1996; Behrens et al., 1996; van de Wetering et al., 1997). In
addition, β-catenin interacts directly with the tumor suppressor
adenomatous polyposis coli (APC; Su et al., 1993; Rubinfeld
et al., 1993). Inactivating mutations in APC, or activating
mutations in β-catenin, cause the accumulation of β-catenin in
the cytoplasm and nucleus, leading to constitutive signaling
through interaction with Lef1/TCF (Munemitsu et al., 1995;
Korinek et al., 1997; Rubinfeld et al., 1997). Collectively,
defects in APC or β-catenin function are thought to account
for initiation of the majority of human colon cancer (Powell et
al., 1992; Morin et al., 1997) and a smaller percentage of
melanoma (Rubinfeld et al., 1997). The well-characterized
dual roles of β-catenin in adhesion and signaling establish an
important paradigm for other Arm proteins, many of which are
known to function as adhesion molecules (e.g. p120).
Unlike β-catenin, p120 does not interact with α-catenin or
with APC (Daniel and Reynolds, 1995), which implies that
p120 has a novel function in cadherin complexes. p120
apparently has both positive and negative affects on cadherinmediated adhesion, depending on signaling cues that remain
unspecified. Tyrosine and serine/threonine kinases are reemerging as important candidates for the regulaton of p120
1320 P. Z. Anastasiadis and A. B. Reynolds
Fig. 1. The role of p120 in
cell-cell adhesion and
signaling. The catenins
JMD
(p120ctn, β-catenin,
CBD
Plasma Membrane
plakoglobin and α-catenin)
bind to the cytoplasmic tails
Extracellular
of classical cadherins. βcatenin and plakoglobin
Wnt
compete for binding to the soE-cadherin
called catenin-binding
Ca++
domain (CBD) and mediate
the attachment of cadherins to
the actin cytoskeleton via αFz
catenin. In contrast, p120
p120ctn or
β-catenin or
(including isoforms and
family members
plakoglobin
probably other p120
subfamily members)
α-catenin
DSH
?
associates with the cadherin
vinculin
α-actinin
juxtamembrane domain
(JMD) and does not bind to
α-catenin. p120 may act as a
GSK3β
F-actin
Kaiso
switch, either promoting or
inhibiting cadherin-mediated
adhesion in response to
p120ctn
APC
unspecified signaling cues.
p120, like β-catenin, exhibits
dual localization both at the
β-catenin
Axin
membrane and in the nucleus.
Wnt/Wg signaling during
?
development, or APC
mutations in human cancer,
stabilize a normally transient
cytoplasmic pool of β-catenin
Cytoplasm
that translocates to the
nucleus, where it participates
in transcriptional regulation
LEF/TCF
(?)
through interactions with
Nucleus
transcription factors of the
Lef1/TCF family. Kaiso is a
novel transcription factor that interacts with p120. Although the biological significance of the p120-Kaiso interaction is not known, p120 may
affect nuclear signaling by transactivating Kaiso, which is postulated to act as a transcriptional repressor. In contrast to β-catenin signaling,
there is no mechanism to promote the degradation of p120 in metastatic cells that have downregulated cadherins. Thus, cadherin binding may
be an in important factor in regulating the putative role of p120 in transcription through its sequestration at the cell membrane.
activity, which suggests that the story will eventually come full
circle back to Src. In addition, given the β-catenin paradigm, it
is perhaps not surprising that p120 also enters the nucleus (Van
Hengel et al., 1999, and, in this issue, Mariner et al., 2000),
where it interacts with a novel transcription factor, Kaiso
(Daniel and Reynolds, 1999; Fig. 1). In fact, p120 is the
prototypic member of a growing gene family, whose protein
products localize both at junctions and in the nucleus.
Elucidation of the potential signaling pathways implied by these
observations promises to reveal important new information
about cell-cell communication, differentiation and cancer.
p120 ISOFORMS AND NOMENCLATURE
Initially designated p120CAS (for cadherin-associated Src
substrate), p120 was renamed p120ctn (catenin; Reynolds and
Daniel, 1997) to avoid confusion with a different Src substrate,
p130CAS (Crk-associated substrate; Sakai et al., 1994). In
addition, it is now evident that most cell types express multiple
isoforms of p120, which are derived by alternative splicing of
a single gene (Reynolds et al., 1994; Staddon et al., 1995; Mo
and Reynolds, 1996; Keirsebilck et al., 1998). Thus, the
nomenclature has been further refined to account for these
multiple forms (Fig. 2). N-terminal splicing events lead to the
use of four different ATGs (Keirsebilck et al., 1998), resulting
in the expression of p120 isoform type 1, 2, 3 or 4, according
to the respective ATG used as the translation start site.
Furthermore, alternative splicing of the C-terminal end leads
to use of exon A, exon B, both exons A and B, or none of them.
On rare occasions, p120 contains a sequence encoded by an
additional exon (exon C), which is inserted within Arm repeat
6. Various combinations of these N- and C-terminal exons
generate the different p120 bands observed in various cell
types. The current, and definitive nomenclature, is shown in
Fig. 2 (for comparison with older ‘CAS’ nomenclature, see
Reynolds and Daniel, 1997).
The existence of cell-type-specific expression patterns
implies functional differences between the p120 isoforms. For
example, macrophages and fibroblasts make N-cadherin and
p120 catenin roles in adhesion and signaling 1321
Fig. 2. p120 nomenclature and alternative
splicing. p120 contains a central Armadillo
domain that has ten Arm repeats (depicted
by gray boxes) interrupted by short loops
in repeats 4, 6 and 9. Cell-type-specific
alternative splicing events result in
multiple isoforms. Four N-terminal ATG
start sites generate p120 isoforms 1, 2, 3,
and 4. p120 isoform 1 contains a putative
coiled-coil domain (yellow box), which is
absent from isoforms initiating at internal
ATGs 2-4 and is conserved among p120’s
close relatives (see Fig. 4). Additional
alternative splicing results in alternative
usage of exons in the C-terminal end.
Exons A and B are often used, whereas
exon C is used rarely. The splicing
complicates the nomenclature. Isoforms
are designated p120ctn 1-4, depending on
the N-terminal start site. The A, B, and/or
C designations are included if the exon is
present (e.g. p120ctn1A, p120ctn1BC). The
letter N (for none) is used if it is known
that none of the C-terminal exons is
present (e.g. p120ctn1N).
ATGs: 1
2 3
4
p120ctn1ABC
C
(352-394)
B
p120ctn2ABC
p120ctn3ABC
p120ctn4ABC
H1
R1
A
SLRKGMP
H2
PPSNWRQ
PELPEVIAMLGF RL
H3
DAVKSNAAAYLQHLC
Fig. 3. Sequence alignment and
R2 (395-436) YRNDKV
KTDVRKL
KGIPILVGLLDH PK
KEVHLGACGALKNIS
organization of the p120 Arm
repeats. The recently elucidated
R3 (437-480) FGRDQDN
KIAIKNC
DGVPALVRLLRK AR
DMDLTEVITGTLWNLS
crystal structure of the β-catenin
R4 (481-538) SHDSIK
MEIVD
HALHALTDEVII PH
SGWEREPNEDCKPRHIE WESVLTNTAGCLRNVS
Arm repeats (Huber et al., 1997)
makes it possible to realign the
R5 (539-587) SERSEAR
RKLRECD
GLVDALIFIVQA EIGQKDS
DSKLVENCVCLLRNLS
p120 Arm domain in the context
of structural data, and is
important for mutational
R6 (588-645) YQVH
REIPQA
ERYQEALPTVANS TGPH AASCFGAKKGKGKKP TEDPANDTVDFPKRTS
analysis. According to this
alignment, p120 has ten
contiguous Arm repeats, each of
which consists of three helices
R7 (646-686) PARG
YELLFQP
EVVRIYISLLKE SK
TPAILEASAGAIQNLC
(H1, H2 and H3). Repeats 4, 6
R8 (687-732) AGRWTYGRYI RSALRQE
KALSAIAELLTS EH
ERVVKAASGALRNLA
and 9 contain looped-out
structures located between
R9 (733-780) VDARN
KELIGK
HAIPNLVKNLPG GQ
QNSSWNF
SEDTVVSILNTINEVI
helices H2 and H3. The basic
motif (KKGKGKK) is thus
R10 (781-824) AENLEAA
KKLRET
QGIEKLVLINKS GN
RSEKEVRAAALVLQTIW
embedded within repeat 6.
Conserved residues are
highlighted in red. In the
Consensus
+. ...
.G ..LV. L.. ..
.. ..A . L+.LS
consensus motif (bottom), +
A
T
A
denotes basic residues (H,K,R),
yellow boxes denote small hydrophobic residues (A,C,P,V,T), green boxes denote large hydrophobic residues (F,I,L,M,W), whereas orange
boxes denote general hydrophobic residues (A,C,F,I,L,M,P,T,V, or W).
preferentially express p120ctn1A isoforms, whereas epithelial
cells make E-cadherin and preferentially express smaller
isoforms, such as p120ctn3A. Because alternative splicing
usually affects only the N- and C-terminal domains, the Arm
domain is left intact and free to interact with cadherins.
Different isoforms may affect cadherin function by recruiting
distinct binding partners to the cadherin complex. Other
members of the p120 family are also expressed as multiple
isoforms, which for the most part have not been characterized.
The regulated expression of multiple p120 family members and
their isoforms, might provide an important mechanism for finetuning the activities of the various cadherins in different cells.
THE p120 FAMILY
Two groups with different functions
Members of the p120 family share a characteristic structural
1322 P. Z. Anastasiadis and A. B. Reynolds
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
1
1
1 M F A R K P P G A A P L G A M P V P D Q P S S A S E K T S S L S P G L N T S N
1
M P A P E Q A S - L V E E G Q P Q T R Q E A A S T
1
1
1
M
M
G
G
D
E
D
P
D
D
G
G
S
C
S
M
E
N
E
E
V
V
T
P
E
H
E
E
S
S
T
T
T
A
T
T
A
A
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A
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A
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I
I
I
I
L
L
L
L
A
A
A
A
S
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V
V
V
V
K
K
K
K
E
E
E
E
Q
Q
Q
Q
E
E
E
E
M A A P G A P A E
M Q E G N
N-term coiled-coil region
20
20
59
45
0
9
5
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
21
21
60
46
1
10
6
A
A
L
L
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
69
54
116
104
1
50
41
F
E
R
V
M
L
V
G
G
T
S
D
S
T
D
A
G
G
A
D
Q
L
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D
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C
L
I
I
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M
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A
L
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F
W
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L
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I
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N
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L
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L
L
G
N
S
S
Q
R
S
S
A
S
L
A
L
T
L
S
Q
Q
Y
L
L
M
M
T V K S L R I Q - - - - - E Q V Q Q T L A R K G R S S V G N G - - - - - - - - - - N L H R T
- L R A A R V Q - - - - - E Q V R A R L L Q L G Q Q S R H N G - - - - - - - - - - S A E L D
S
A
N
N
N
S
G
T
T
S
S
H
S
S
I
M
K
Y
S
V
A
P
P
P
S
P
P
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R
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D
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G
S
A
S
G
R
M
F
Y
L
G
Q
E
Q
Q
K
E
M
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A
Y
E
T
Y
P
P
P
P
A
A
V
R
G
D
A
G
L
Y
G
Q
V
S
S
A
N
Q
I
L
Y
F
Y
L
Y
108
90
172
163
12
90
84
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
109
91
173
164
13
91
85
V
E
H
H
E
H
H
E
E
S
N
C
L
T
T
T
N
S
F
V
M
Y
V
Q
Q
Q
E
Q
T
T
T
N
D
N
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V
L
V
Q
D
G
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F
F
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T
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L
T
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N
G
F
N
R
H
-
V
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N
-
A
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A
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A
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Q
Y
L
T
T
G
S
K
S
T
T
T
P
S
S
S
C
E
V
S
P
P
-
A
S
-
P
R
-
P
A
-
P
Q
-
P
S
-
P
P
-
S
-
150
133
224
223
54
132
130
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
151
134
225
224
55
133
131
Y
-
V
-
I
-
S
-
T
-
G
-
V
-
S
-
P
P
-
P
S
Q
-
R
R
R
R
K
K
R
T
T
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G
S
S
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V
V
P
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S
V
L
Q
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F
L
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Q
A
R
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E
S
V
V
P
T
S
R
A
A
P
S
S
T
S
H
M
V
L
L
L
L
N
G
G
G
G
S
R
G
P
P
S
S
H
H
G
D
D
A
G
S
P
S
F
F
L
-
G
G
H
G
N
R
A
L
L
L
S
R
R
F
P
P
P
P
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L
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V
L
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S
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A
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M
I
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A
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A
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P
A
P
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S
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V
L
A
L
A
P
Q
S
G
A
N
D
E
P
N
P
A
P
N
R
T
N
F
L
S
Y
A
P
Y
A
Y
A
N
H
P
I
D
Y
Y
Y
Y
M
Q
G
S
S
G
T
P
T
A
S
S
T
H
T
L
L
S
T
T
S
R
G
D
T
T
S
D
P
R
R
L
L
R
Y
V
D
H
P
P
S
Q
S
F
F
A
A
S
Y
F
R
L
P
A
Y
S
H
K
L
P
Y
Q
E
N
R
R
R
S
R
R
G
G
G
A
K
S
G
N
F
-
G
G
G
A
Q
Q
G
G
G
S
S
A
A
A
P
P
P
P
G
G
A
G
L
Y
-
P
A
S
-
Y
A
Q
-
V
P
-
G
Q
R
-
Q
G
P
-
A
G
A
-
197
174
275
280
95
175
171
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
198
175
276
281
96
176
172
G
S
S
-
T
V
P
P
H
S
A
A
T
T
N
T
R
T
T
K
A
G
L
A
L
L
L
I
S
H
D
P
S
Q
R
H
Y
R
R
R
R
W
Q
D
N
A
G
I
G
E
T
F
Y
G
G
Y
S
L
H
L
S
S
P
R
S
Y
S
A
V
I
R
L
P
S
P
T
Y
A
P
P
G
E
S
N
A
S
D
G
G
R
G
L
L
G
G
A
Q
T
L
R
Y
F
T
T
L
V
L
S
P
Y
S
K
P
G
R
A
N
-
H
A
-
Y
P
P
-
E
E
R
N
R
-
D
G
G
G
E
-
G
P
S
-
Y
E
S
-
P
P
P
P
P
P
P
G
R
K
R
G
G
D
Q
D
Y
G
S
S
S
T
N
A
L
D
P
P
P
R
R
D
S
S
D
N
S
R
Q
R
E
R
Y
Y
L
Y
F
I
Y
G
G
A
Q
S
V
S
S
S
K
T
S
G
V
L
L
S
T
Y
V
V
S
S
Y
A
S
S
S
R
R
S
R
Q
R
E
G
T
V
-
S
G
-
S
S
-
P
P
-
I
L
-
N
T
-
V
L
I
L
-
T
G
V
T
A
-
R
M
V
D
G
Q
I
R
S
A
M
T
L
E
P
S
Q
E
T
E
E
P
A
T
N
S
P
G
-
L
-
S
-
P
-
I
-
R
R
R
R
W
R
A
Y
A
V
V
S
Q
A
R
G
T
A
R
R
A
P
P
S
S
H
H
S
S
L
P
P
Y
F
T
M
G
P
S
P
D
Y
245
219
335
329
131
215
210
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
246
220
336
330
132
216
211
E
P
T
Q
R
T
R
G
G
V
G
G
Y
A
P
Q
Q
-
G
S
-
D
-
G
T
V
S
-
C
I
G
C
-
Y
F
S
S
N
H
-
R
T
S
S
T
R
Y
A
L
S
S
T
Q
A
P
P
P
P
G
Y
Y
S
G
I
K
A
Q
K
R
H
H
R
G
H
R
Q
R
Q
S
S
G
Q
D
E
L
G
D
S
A
V
A
S
M
I
V
S
Y
F
S
T
C
S
S
P
T
A
-
I
V
-
G
P
-
T
Q
-
Y
H
-
V
A
L
-
G
G
T
G
-
P
P
L
P
-
Q
E
S
S
-
P
P
P
-
Q
T
L
-
V
G
K
Q
-
R
P
R
R
D
-
V
P
L
T
T
-
G
G
V
V
F
V
-
G
G
H
H
M
F
G
S
R
A
D
Q
D
S
S
S
S
M
K
S
S
V
L
E
E
I
I
R
D
P
Q
Q
K
P
A
L
Y
F
A
G
H
E
S
G
S
A
G
R
R
K
Q
R
N
L
F
F
H
Q
S
P
D
H
Q
S
Q
E
A
W
P
A
Q
Y
P
L
P
E
E
E
D
D
L
E
P
P
L
I
L
T
A
Y
Y
Y
Y
Y
Y
T
G
G
A
E
C
P
E
L
L
T
R
D
R
G
E
E
A
M
P
P
D
D
T
V
G
-
D
D
L
P
T
P
Q
T
Q
P
P
S
S
R
R
R
R
R
R
R
P
P
-
G
D
-
S
S
S
S
S
-
M
L
L
L
M
-
G
A
A
T
G
G
-
A
N
-
Y
A
G
G
T
L
T
291
270
394
385
166
255
242
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
292
271
395
386
167
256
243
D
D
S
L
L
L
I
D
D
R
R
R
E
R
L
E
A
S
K
K
A
D
G
S
S
G
E
P
Y
G
Y
Y
T
N
A
G
P
S
A
L
Y
M
E
S
S
G
L
R
M
L
Q
Q
S
T
T
M
E
H
H
K
A
L
S
P
G
S
G
G
Q
D
D
H
Q
Q
L
R
Y
Y
L
L
K
T
F
G
G
G
G
T
V
Q
T
T
P
Q
T
G
S
A
A
E
D
Q
Q
S
R
T
L
L
N
V
H
R
R
R
R
R
R
R
T
R
A
S
Y
P
S
G
L
A
S
-
Q
V
F
L
-
T
R
S
S
Y
V
R
P
P
P
P
S
P
G
S
E
E
D
T
L
G
D
C
H
L
C
Q
T
P
G
H
H
S
P
G
R
R
I
I
G
V
S
G
D
T
T
-
P
P
-
I
I
-
R
L
Y
Y
-
R
H
E
E
Q
Q
V
L
T
D
G
K
N
S
R
R
R
R
A
R
G
S
A
V
T
I
A
A
Y
Y
Y
Y
K
S
G
E
E
Q
Y
K
R
L
D
D
K
S
C
S
E
M
T
P
P
P
S
P
I
A
P
V
V
W
V
G
D
M
Y
R
H
A
D
R
R
P
Q
R
G
S
S
S
-
G
L
P
P
S
-
E
S
N
S
F
-
L
Q
H
H
-
A
S
G
S
-
Q
T
-
G
T
R
-
E
D
D
V
C
T
-
E
E
P
E
A
L
-
V
R
L
L
S
R
A
P
P
P
Q
K
E
P
S
A
P
G
Q
A
S
D
F
A
S
D
G
V
Q
P
H
Q
P
P
R
T
T
S
S
G
A
V
L
Y
M
T
L
V
A
S
Y
V
Y
Y
Y
V
L
W
T
R
R
I
D
S
336
322
454
444
215
311
287
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
337
323
455
445
216
312
288
A
A
T
T
P
S
L
P
P
S
G
P
S
A
L
L
T
V
I
G
D
A
A
A
S
S
R
S
P
-
S
-
S
-
P
-
G
G
-
V
I
-
D
G
-
S
-
V
-
P
N
-
L
L
-
Q
Q
-
R
R
-
T
T
-
G
S
-
S
S
R
-
Q
Q
Q
Q
C
A
G
H
P
H
R
N
H
H
G
-
P
-
Q
-
N
-
A
-
A
S
-
A
T
L
-
A
L
T
-
T
T
V
-
F
Y
G
-
E
E
Q
Q
K
Q
L
R
R
R
R
D
A
P
G
G
A
N
L
A
D
S
S
S
N
S
A
V
L
M
Y
Y
F
G
R
A
G
A
A
G
G
G
S
S
A
L
H
S
L
G
N
-
P
T
-
A
T
-
S
A
-
N
T
-
Y
Y
-
A
A
-
D
E
-
P
P
-
Y
Y
-
R
R
-
Q
P
-
L
I
-
Q
Q
-
Y
Y
-
C
R
-
P
-
S
V
-
V
Q
-
E
E
-
S
C
-
349
335
514
492
228
329
300
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
350
336
515
493
229
330
301
P
N
-
Y
Y
-
S
N
-
K
R
-
S
L
-
G
Q
-
P
H
-
A
A
-
L
V
-
P
P
-
L
L
P
A
G
D
D
D
E
D
S
N
S
S
R
G
D
R
L
Y
L
L
T
G
A
L
T
R
V
L
T
S
T
G
K
R
A
T
S
E
H
G
R
R
R
K
R
R
G
S
S
S
I
S
T
P
P
P
P
C
T
L
S
S
S
S
F
Q
V
I
I
T
-
D
D
D
D
-
S
S
S
S
-
A
I
I
Q
-
R
Q
Q
L
R
P
K
K
K
E
G
L
P
E
D
D
D
N
S
P
P
P
P
I
A
S
N
R
R
R
E
D
G
E
E
-
F
F
-
G
A
-
W
W
W
W
C
F
R
R
R
R
S
M
D
Q
D
D
D
G
E
D
P
P
P
P
L
M
I
E
E
E
E
T
T
D
L
L
L
L
I
L
L
P
P
P
P
P
E
P
E
E
E
E
K
R
S
V
V
V
V
A
A
A
I
L
I
I
V
V
V
A
A
Q
H
Q
S
K
M
M
M
M
Y
M
Y
L
L
L
L
L
L
L
G
R
Q
E
S
E
M
A
-
D
-
F
H
H
H
S
H
A
R
P
Q
Q
Q
M
S
L
V
F
F
D
P
D
D
D
P
P
E
P
P
A
P
S
S
K
S
N
V
V
V
V
Y
R
L
K
K
Q
Q
Q
I
Q
S
A
S
A
A
S
V
N
N
N
N
I
A
L
A
A
A
A
G
A
G
A
A
A
A
A
A
A
A
A
A
A
Y
T
A
388
380
572
550
267
375
341
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
389
381
573
551
268
376
342
Y
Y
Y
Y
Y
F
Y
L
L
L
L
I
I
I
Q
Q
Q
Q
Q
Q
Q
H
H
H
H
H
H
H
L
L
L
L
T
E
R
C
C
C
C
C
C
C
Y
F
F
F
F
F
Y
R
E
G
G
Q
Q
S
N
N
D
D
D
K
D
D
E
N
N
E
S
A
K
G
K
K
S
E
A
V
V
I
V
A
A
A
K
K
K
K
K
R
K
T
R
A
M
Q
K
K
D
R
E
E
Q
R
Q
V
V
I
V
V
V
A
R
R
R
C
Y
N
R
K
Q
R
R
Q
Q
S
L
L
Q
L
L
L
L
K
R
G
G
G
R
Q
G
G
G
G
G
G
A
I
L
I
I
I
I
V
P
P
Q
K
C
L
P
V
L
L
H
K
K
R
L
L
L
L
L
L
L
V
V
V
V
V
L
V
G
A
D
D
D
Q
K
L
L
L
L
L
L
L
L
L
L
L
L
L
F
D
D
D
D
R
K
N
H
H
H
H
S
V
H
P
P
R
R
P
Q
A
K
R
M
V
N
N
N
K
A
T
L
Q
E
Q
E
E
E
E
N
D
E
V
V
V
V
V
V
V
H
R
H
Q
Q
Q
Q
L
R
R
K
Q
R
R
G
R
S
N
A
A
H
A
A
A
A
A
V
A
C
C
C
C
A
C
T
G
G
G
G
G
G
G
A
A
A
A
A
A
A
L
L
L
L
L
L
M
K
R
R
R
R
R
R
N
N
N
N
N
N
N
I
L
L
L
L
L
L
S
S
V
V
V
V
I
F
Y
Y
F
F
F
Y
G
G
G
G
-
R
R
K
K
R
E
D
D
D
A
S
S
D
N
Q
T
N
T
T
N
V
D
D
D
D
T
D
D
D
E
-
N
N
N
N
N
N
N
K
K
K
K
K
K
K
I
A
I
I
L
L
L
A
A
A
A
E
E
A
I
I
L
M
T
V
L
447
439
632
610
325
433
399
Q
R
Q
Q
F
F
F
F
E
E
E
Q
K
R
R
R
L
L
L
L
T
T
T
T
R
R
R
R
A
A
E
E
L
L
L
L
E
E
E
E
E
Q
A
V
E
E
E
E
R
R
R
R
R
R
Q
Q
H
H
I
I
V
V
V
V
S
A
A
A
A
L
S
S
Q
Q
Q
Q
L
L
L
L
E
E
E
E
R
R
R
R
V
A
C
C
R
Q
K
R
V
Q
L
L
S
G
G
P
S
A
Q
E
E
D
-
A
-
N
T
S
P
P
G
P
L
G
S
S
M
M
M
I
A
V
S
A
N
S
S
S
G
G
M
T
T
S
S
L
S
S
T
A
T
R
E
E
R
E
K
H
Q
S
Q
F
F
N
Q
P
G
G
W
W
R
Q
R
S
S
Q
T
D
D
G
V
Q
P
K
N
D
T
G
V
I
S
E
K
D
P
Y G Y I R T V L G Q Q I L G Q L D S S S L A L P S E A - - - - - K L K L A G S S G R - - - G G Q - - - - - - - - - - - F L L S A L Q P E T G V C S L A L P S D L Q L D R R G - - - - - - - A E G - - - P E - - - A D R - - - - - - - - - - - -
68
53
115
103
0
49
40
Arm domain
Fig. 4. For legend see p. 1324.
p120 catenin roles in adhesion and signaling 1323
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
448
440
633
611
326
434
400
K
R
K
K
R
A
V
N
D
N
N
R
E
E
C
C
C
V
Q
L
E
D
G
G
G
N
N
N
G
G
G
G
G
G
G
V
V
I
I
I
V
I
P
P
P
P
R
P
F
A
A
A
A
E
R
E
L
L
L
L
A
L
L
V
V
V
L
V
L
L
R
R
R
R
S
Q
R
L
L
L
L
L
V
T
L
L
L
L
L
L
L
R
R
R
R
R
K
R
K
A
K
K
R
Q
E
A
A
T
S
T
T
Q
R
R
T
I
G
R
-
D
D
D
D
N
D
D
M
N
L
A
A
L
D
D
E
E
E
E
E
E
L
V
I
V
I
T
L
T
R
R
R
Q
K
R
E
E
E
E
K
K
K
V
L
L
L
Q
Q
N
I
V
V
V
L
I
V
T
T
T
T
T
T
T
G
G
G
G
G
G
G
T
T
V
V
L
L
I
L
L
L
L
L
L
L
W
W
W
W
W
W
W
N
N
N
N
N
N
N
L
L
L
L
L
L
L
S
S
S
S
S
S
S
S
S
S
S
S
S
S
H
Y
C
C
T
N
S
D
E
D
D
D
D
D
S
P
A
A
E
K
H
I
L
L
V
L
L
L
K
K
K
K
K
K
K
M
M
M
M
E
N
D
E
V
P
T
E
L
R
I
I
I
I
L
M
L
V
I
I
I
I
I
A
D
D
Q
R
A
T
R
H
H
D
D
D
E
D
A
G
A
A
A
A
T
L
L
L
L
L
L
L
H
Q
A
S
P
L
E
A
T
V
T
V
T
Q
L
L
L
L
L
L
L
T
T
T
T
A
T
T
D
H
N
N
D
E
D
E
E
A
T
R
N
L
V
V
V
V
V
I
V
I
I
I
I
I
I
L
I
V
I
V
I
I
S
P
P
P
P
P
P
P
H
H
H
H
F
F
L
S
S
S
S
S
S
S
G
G
G
G
G
G
G
507
499
692
670
385
493
458
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
508
500
693
671
386
494
459
W
W
W
W
W
W
P
E
E
E
N
C
P
G
R
R
N
N
D
E
G
E
E
S
S
-
P
P
P
S
G
-
N
N
L
F
N
G
-
E
E
Q
D
S
D
P
D
D
D
D
N
Y
P
C
S
D
D
P
L
K
K
R
H
M
K
I
P
P
K
K
S
A
Q
R
R
I
I
R
N
Q
H
D
Q
K
E
G
N
I
A
L
F
V
L
A
E
E
H
Q
V
L
S
W
W
S
T
D
D
E
E
T
S
S
P
F
A
S
T
Q
L
E
D
E
V
V
V
V
V
I
I
L
F
L
L
F
F
F
T
K
R
R
F
Y
Y
N
N
N
N
N
N
N
T
T
A
T
A
V
A
A
S
T
T
T
T
T
G
G
G
G
G
G
G
C
C
C
C
C
C
F
L
L
L
L
L
L
L
R
R
R
R
R
R
R
N
N
N
N
N
N
N
V
V
V
L
L
M
L
S
S
S
T
S
S
S
S
S
S
S
S
S
S
E
D
A
A
A
A
A
R
G
G
G
G
S
S
A
E
E
D
A
Q
E
E
E
E
A
D
A
A
A
A
A
G
G
T
R
R
R
R
R
R
R
R
R
R
K
Q
K
Q
K
R
R
Q
T
A
K
L
L
M
M
M
M
M
R
R
R
R
R
R
R
E
E
E
S
N
R
E
C
C
C
C
Y
C
C
D
E
D
E
S
D
H
G
G
G
G
G
G
G
L
L
L
L
L
L
L
V
V
T
V
I
I
V
D
D
D
D
D
D
D
A
A
A
S
S
S
A
L
L
L
L
L
L
L
I
L
L
L
M
V
V
F
H
Y
Y
A
H
T
I
A
V
V
Y
Y
Y
V
L
I
I
V
V
I
Q
Q
Q
H
Q
R
N
A
S
S
T
N
G
H
E
A
A
C
C
T
A
I
V
L
V
V
I
L
G
G
G
N
A
A
D
567
559
752
730
442
551
515
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
568
560
753
731
443
552
516
Q
R
S
T
A
D
V
K
K
S
S
S
Y
G
D
D
E
D
R
Q
K
S
T
I
Y
C
P
C
D
D
D
D
D
D
E
S
N
S
S
D
D
D
K
K
K
K
K
K
K
L
S
T
T
S
A
S
V
V
V
V
V
T
V
E
E
E
E
E
E
E
N
N
N
N
N
N
N
C
C
C
C
C
C
A
V
V
V
V
M
V
V
C
C
C
C
C
C
C
L
I
I
T
V
I
V
L
M
L
L
L
L
L
R
R
R
R
H
H
R
N
N
N
N
N
N
N
L
L
L
L
L
L
L
S
S
S
S
S
S
S
Y
Y
Y
Y
Y
Y
Y
Q
H
R
R
R
Q
R
V
V
L
L
L
L
L
H
H
A
E
D
E
Y
R
K
A
L
A
A
D
E
E
E
E
E
E
E
I
V
T
V
V
L
M
P
P
S
P
P
P
P
Q
G
Q
Q
T
E
P
A
A
G
A
S
E
D
Q
R
-
R
R
H
L
R
K
A
Y
Y
M
L
Y
Y
L
Q
Q
G
G
R
S
Q
E
E
T
L
Q
Q
R
A
A
D
N
L
N
L
A
E
E
E
E
I
E
P
P
L
L
Y
Y
G
N
G
D
D
N
I
R
P
G
D
Q
G
V
L
L
L
A
N
R
A
G
L
L
R
R
R
N
S
C
G
N
N
D
N
A
G
K
A
I
M
T
V
E
E
Y
Q
A
G
G
A
S
T
T
G
P
S
N
P
E
D
A
Q
P
R
G
S
-
R
K
K
-
R
D
D
N
P
R
A
S
K
N
G
H
D
E
E
S
K
E
A
D
S
P
S
S
M
A
A
S
S
T
I
V
S
S
G
G
G
G
C
C
C
C
C
C
C
F
F
W
W
F
F
F
G
G
G
G
S
G
T
A
G
K
K
N
S
P
621
619
811
788
495
606
572
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
622
620
812
789
496
607
573
K
K
K
K
K
R
Q
K
K
K
K
S
S
S
G
A
K
K
D
R
R
K
K
K
K
K
K
R
D
E
K
K
M
V
L
E
E
R
W
W
-
F
F
K
K
-
S
H
R
-
R
Q
-
G
G
-
K
K
-
K
K
T
-
P
D
P
-
G
-
I
E
S
Q
M
K
E
E
M
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N
E
L
D
D
D
D
N
Q
P
P
R
Q
Q
L
A
N
W
W
T
N
F
D
D
N
Y
A
D
D
G
G
Y
Q
D
T
T
V
V
D
D
A
V
L
G
G
C
V
L
D
D
P
P
P
P
T
F
L
L
I
L
M
F
P
P
P
P
P
P
A
K
K
D
G
E
E
E
R
R
C
L
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T
T
A
S
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K
S
S
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K
T
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K
P
A
P
S
N
N
D
A
A
P
P
P
P
P
R
K
K
K
K
K
K
G
G
G
G
G
G
G
Y
F
I
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S
V
L
E
E
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E
G
E
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L
L
M
M
W
W
W
L
L
L
L
L
L
L
F
Y
W
W
Y
W
W
Q
Q
H
H
H
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P
P
P
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V
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R
R
K
K
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R
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P
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L
L
L
L
L
N
S
S
T
T
N
S
R
L
L
L
L
L
L
L
L
L
L
L
M
I
L
K
T
S
A
G
A
Q
E
E
E
E
K
K
R
S
S
C
S
S
S
C
K
R
S
S
K
V
E
T
N
N
N
K
R
L
P
F
P
P
D
N
N
R
A
N
D
A
A
Y
H
679
678
861
841
542
653
623
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
680
679
862
842
543
654
624
I
T
T
T
T
T
T
L
L
L
L
L
Q
T
E
E
E
E
E
E
E
A
A
G
G
A
A
A
S
A
A
S
C
S
A
A
A
A
A
A
L
A
G
G
G
G
G
G
G
A
A
A
S
A
A
A
I
L
L
L
L
L
L
Q
Q
Q
Q
Q
Q
Q
N
N
N
N
N
N
N
L
L
L
L
L
L
I
C
S
A
S
T
T
T
A
A
A
A
A
A
A
G
G
G
S
S
G
G
R
N
S
N
K
S
D
W
W
W
W
G
G
R
T
M
K
K
L
P
R
Y
W
W
F
M
M
W
G
A
S
A
S
P
A
R
T
V
A
S
T
G
Y
Y
Y
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V
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I
I
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M
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L
R
R
R
R
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A
S
S
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G
Q
Q
R
A
T
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L
T
L
L
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V
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G
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L
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R
R
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L
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K
K
K
K
K
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E
E
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R
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K
R
K
K
K
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R
A
G
G
G
G
G
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L
L
L
L
L
L
L
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P
P
P
P
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N
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P
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L
L
L
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L
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V
V
V
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R
L
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L
L
L
L
L
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L
L
L
L
L
L
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T
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R
R
Q
H
R
N
S
I
M
S
V
T
E
E
D
D
G
G
A
H
T
N
N
N
D
D
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D
D
D
S
P
H
R
K
R
R
D
S
N
V
V
V
V
V
V
Q
V
V
V
V
V
K
L
K
R
C
S
R
K
R
A
A
A
S
S
T
S
A
V
V
G
G
A
L
S
A
A
A
A
I
T
G
I
T
T
S
S
G
A
A
A
A
L
L
L
L
L
L
L
L
L
I
R
R
R
R
S
R
R
N
N
N
N
N
N
N
L
L
M
M
M
L
L
A
S
A
A
S
S
S
738
737
920
900
602
713
683
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
739
738
921
901
603
714
684
V
L
L
L
R
R
R
D
D
D
D
H
N
N
A
R
V
V
P
L
A
R
R
R
R
L
S
R
N
N
N
N
L
L
N
K
K
K
K
H
Q
K
E
D
E
E
R
N
D
L
L
L
L
V
E
E
I
I
I
I
M
I
M
G
G
G
G
G
A
S
K
S
K
K
N
K
T
H
Y
Y
Y
Q
E
K
A
A
A
A
V
T
V
I
M
M
M
F
L
V
P
A
R
R
P
P
S
N
E
D
D
E
D
H
L
L
L
L
V
L
L
V
V
V
V
T
V
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K
R
H
N
R
S
E
N
N
R
R
L
I
K
L
V
L
L
L
I
L
P
R
P
P
T
P
P
G
N
G
G
S
D
G
G
A
G
G
H
T
S
Q
Q
N
N
T
V
V
Q
A
N
G
G
P
G
P
S
P
-
P
N
S
-
N
-
N
R
T
-
S
P
A
-
S
G
S
N
S
E
W
A
K
T
T
K
N
C
A
V
S
D
C
F
L
M
L
N
L
P
S
E
S
S
S
L
P
E
E
D
D
E
I
A
D
D
D
E
D
E
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T
T
T
T
I
T
V
V
V
V
M
L
T
L
I
V
T
A
S
A
V
S
A
A
A
S
S
N
I
V
V
I
A
A
I
L
L
C
C
C
C
I
N
N
C
C
Y
Y
A
T
T
T
A
T
T
V
I
I
L
L
V
L
L
N
H
H
H
R
N
N
E
E
E
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N
N
N
V
I
V
V
L
I
L
I
V
I
T
M
I
V
A
S
T
S
A
Q
V
E
D
K
K
S
N
A
N
S
N
N
Q
S
S
L
L
M
M
P
Y
P
E
D
E
E
Q
Q
I
A
N
N
N
L
N
A
A
A
A
A
A
A
A
K
R
K
K
K
R
R
K
S
A
A
Q
D
D
795
796
980
955
657
768
738
p120-h1ABC
ARVCF
NPRAP-D-cat
HSP0071
plakophilin 1
plakophilin 2a
plakophilin 3
796
797
981
956
658
769
739
L
L
L
L
Y
L
L
R
L
R
A
F
L
L
E
Q
D
D
S
N
Y
T
A
A
S
S
T
F
Q
R
G
G
S
G
D
G
G
G
G
M
G
G
I
V
I
I
L
I
L
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P
E
E
N
Q
R
K
A
K
K
N
K
K
L
L
L
L
I
I
L
V
V
V
V
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M
V
L
A
G
N
N
A
F
I
L
I
I
L
I
I
N
V
S
T
C
S
K
K
A
K
K
R
A
K
S
S
S
G
S
G
K
G
K
R
D
R
G
G
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D
D
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N
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R
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R
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H
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K
K
K
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V
A
A
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V
A
V
V
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S
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K
K
K
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S
S
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R
S
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L
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Q
L
V
S
V
V
V
V
L
L
L
L
L
L
L
L
L
L
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Q
N
N
S
Y
A
T
T
S
T
D
S
N
I
V
M
L
M
L
L
W
W
W
W
W
W
W
G
S
Q
Q
S
A
Q
Y
Y
Y
Y
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H
Y
K
K
R
R
K
T
S
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E
D
D
E
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K
L
L
L
L
L
L
L
R
R
R
R
Q
H
H
K
G
S
S
G
H
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P
T
L
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V
A
D
L
L
Y
Y
L
Y
F
E
Q
K
K
R
K
R
K
K
K
K
Q
K
A
E
D
D
D
Q
A
K
G
G
G
G
G
Q
G
W
W
W
W
F
F
Y
K
T
S
N
D
K
R
K
K
Q
Q
R
K
K
S
A
Y
N
N
T
E
D
R
H
H
M
D
D
F
F
F
F
L
F
F
Q
Q
V
I
G
V
L
V
S
A
T
T
N
G
N
A
S
P
L
S
P
L
A
S
V
A
R
853
853
1040
1015
714
827
797
854 N N A S
p120-h1ABC
854 A T A K
ARVCF
1041
S T I E
NPRAP-D-cat
1016 S T L E
HSP0071
715 G A N S
plakophilin 1
plakophilin 2a 828 T A K A
798
plakophilin 3
G
R
R
Y
P
D
D
L
H
R
K
R
R
R
S
G
Q
N
-
R
-
P
-
Y
F
F
L
S
K
T
K
S
S
S
D
S
H
R
R
P
F
T
S
P
L
S
S
I
T
S
T
P
N
V
Q
R
Q
V
M
S
S
P
P
N
I
N
I
R
Q
S
S
A
V
S
G
A
S
P
T
A
S
S
S
P
S
R
P
E
A
M
L
I
L
S
G
S
A
L
I
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L
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S
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P
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G
K
R
S
G
T
S
D
E
Y
F
Y
Y
D
D
E
D
D
D
C
R
S
S
T
T
T
T
G
Q
L
L
S
P
P
P
N
P
L
L
A
M
I
V
T
Q
D
D
Y
Y
R
K
H
Y
875
878
1100
1072
726
837
797
876 N
p120-h1ABC
879 S
ARVCF
NPRAP-D-cat 1101 G
1073 N
HSP0071
727
plakophilin 1
plakophilin 2a 838
798
plakophilin 3
Q
L
A
S
K
E
K
Q
S
G
G
G
D
E
E
D
K
K
H
A
K
T
T
T
P
G
S
H
D
S
R
K
R
R
K
G
E
D
D
-
E
V
A
-
I
I
M
L
Q
P
T
Y
M
M
A
P
S
D
Q
G
N
A
N
S
M
L
T
S
G
G
G
K
S
P
I
P
N
S
S
T
T
P
K
-
S
L
I
L
Y
Y
D
D
R
I
N
G
N
S
N
S
S
Y
Y
Y
Y
S
S
G
S
T
T
A
S
P
V
P
P
N
D
A
A
R
E
R
E
E
R
R
D
Q
G
E
I
N
D
R
K
R
H
R
H
R
N
P
N
L
R
R
Q
Q
T
G
V
H
L
A
S
Q
D
S
A
Q
R
S
Q
L
P
Y
V
Y
S
A
P
S
G
G
Q
Q
D
E
E
D
L
A
P
D
G
S
S
S
N
R
R
K
K
D
E
D
N
M
K
Y
F
E
E
E
D
P
P
T
A
L
L
Y
Y
929
926
1157
1129
726
837
797
930 K
p120-h1ABC
927 K
ARVCF
NPRAP-D-cat 1158 Q
1130 R
HSP0071
727
plakophilin 1
plakophilin 2a 838
798
plakophilin 3
G
L
P
L
T
D
F
Y
T
Q
L
P
P
N
Q
L
S
S
S
M
R
T
P
Q
K
R
H
D
N
S
E
Y
Y
G
A
D
E
Q
P
E
D
E
P
S
P
S
P
F
Y
L
G
F
F
E
P
E
D
E
S
D
D
E
R
Q
R
L
P
V
V
D
A
H
H
V
V
H
F
R
-
P
P
P
A
A
S
S
T
E
D
Y
Y
T
S
M
T
H
Q
L
Y
G
G
L
L
K
K
S
S
T
T
G
T
L
R
N
N
V
L
Y
Y
L
V
V
V
D
D
D
D
D
A
F
F
E
V
Y
Y
G
G
S
S
G
D
A
T
Q
A
A
K
V
K
R
R
S
P
P
P
Y
-
S
-
E
-
L
-
N
S
Y
Y
E
R
T
A
S
E
H
Q
Y
Q
Y
Y
962
956
1217
1184
726
837
797
963 P
p120-h1ABC
957 P
ARVCF
NPRAP-D-cat 1218 P
1185 P
HSP0071
727
plakophilin 1
plakophilin 2a 838
798
plakophilin 3
A
G
S
S
S
V
P
P
M
D
D
D
Q
S
S
S
K
W
W
W
I
V
V
V Y D Q D A Q Q R N S F F L T L F R L R
Arm domain
PDZ-binding motif
968
962
1225
1211
726
837
797
Fig. 4. For legend see p. 1324.
1324 P. Z. Anastasiadis and A. B. Reynolds
Fig. 4. CLUSTAL W alignment of human p120ctn1ABC, ARVCF, δcatenin/NPRAP, p0071 and plakophilins 1a, 2a and 3. Dark-boxed
areas designate amino acid identity between at least 4 out of the
seven sequences. Light gray regions show similarity rather than
identity. The conservation between family members in the central
Arm domain is clear, whereas divergence is evident in the N- and Cterminal ends. A conserved coiled-coil domain in the extreme Nterminal domain of p120, ARVCF, δ-catenin/NPRAP and p0071 is
depicted. A putative PDZ-binding domain at the extreme C-terminal
of ARVCF, δ-catenin/NPRAP and p0071 (but not p120) is also
shown. Closer inspection, coupled with functional data, justifies
further division into two subgroups consisting of the top four
sequences (the p120 family) and the bottom three sequences (the
plakophilin family). Database accession numbers: p120ctn1ABC:
AF062341; ARVCF: U51269; δ-catenin/NPRAP: U96136; p0071:
X81889, plakophilin 1a: Z34974; plakophilin 2a: X97675;
plakophilin 3: AF053719.
organization of the Arm-repeat domain (see Figs 2, 3), which
suggests an ancient evolutionary relationship. However, two
groups have emerged that differ both in the degree of similarity
that they share with p120, and in their subcellular localizations.
The first group includes ARVCF (Armadillo repeat gene
deleted in Velo-Cardio-Facial syndrome; Sirotkin et al., 1997),
δ-catenin/NPRAP/neurojungin (neural plakophilin-related
Armadillo protein; Paffenholz and Franke, 1997; Zhou et al.,
1997) and p0071 (Hatzfeld and Nachtsheim, 1996). These
proteins share >45% identity with p120 in their Arm domains
and, with the possible exception of p0071 (Hatzfeld and
Nachtsheim, 1996), bind to and colocalize with classical
cadherins at adherens junctions (Lu et al., 1999; Paffenholz et
al., 1999; Mariner et al., 2000). The intron-exon boundaries of
p120 and ARVCF are nearly identical (Keirsebilck et al.,
1998), further highlighting the similarity between these
proteins. The second group, the plakophilins, have ~30%
identity to p120 in their Arm domains, which are otherwise
organized similarly to that of p120. Unlike the first group,
which interact with cadherins through their Arm domains,
plakophilins localize to desmosomes through interactions
EC
mediated by their head (N-terminal) domain, and coordinate
intermediate filaments (Hatzfeld et al., 1994; Heid et al., 1994;
Mertens et al., 1996; Schmidt et al., 1999; Bonne et al., 1999;
Kowalczyk et al., 1999; Schmidt et al., 1997; Smith and Fuchs,
1998). They exhibit significantly higher similarity to one
another than to p120 (Bonne et al., 1999). Because of the
significant differences between these subgroups, we will
hereafter refer to them separately as the p120 subfamily (which
includes ARVCF, δ-catenin/NPRAP and p0071), and the
plakophilin subfamily (which includes plakophilins 1, 2 and 3).
All of these proteins also localize to the nucleus (Bonne et al.,
1999; Schmidt et al., 1997; Mertens et al., 1996; Van Hengel
et al., 1999; Mariner et al., 2000); this interesting phenomenon
has obvious implications for signaling between cell junctions
and the nucleus.
p120 family structure
The p120 relatives share several structural features. Each has
ten Arm repeats, which are organized identically and contain
interruptions within repeats 4, 6 and 9 (see Figs 2 and 3). Fig.
3 shows the sequence and predicted boundaries of each p120
Arm repeat according to the recently elucidated β-catenin
crystal structure (Huber et al., 1997). An alignment of all
known p120 family members is shown in Fig. 4 and highlights
the sequence conservation shared by these proteins. The
interruptions noted above are thought to represent looped-out
structures positioned between helices H2 and H3 – as occurs
in β-catenin (Huber et al., 1997). In the loop within Arm repeat
6, all of the p120 relatives contain motifs postulated to act as
nuclear localization sequences. In ARVCF, there appears to be
a bipartite nuclear-localization signal (NLS; Imamura et al.,
1998), whereas p120, p0071 and δ-catenin/NPRAP have a
highly conserved basic motif (CW/FGxKKxKxKK).
Interestingly, the presence of p120 exon C alters this basic
motif (Keirsebilck et al., 1998). Although it is suggested that
these basic motifs play a role in nuclear localization (Lu et al.,
1999), indirect data suggest otherwise (Mariner et al., 2000).
The plakophilins also contain basic motifs within this loop, and
several lines of evidence suggest that they also are not required
JMD
CBD
E-cadherin
Fig. 5. p120 binds to the
conserved cadherin
juxtamembrane domain
(JMD), a region highly
Core Binding Region
775
734
conserved among type I
(p120 binding)
(classical) and type II
AAA
AAA AAA AAA AAA
AAA
AAA AAA
AAA
cadherins. β-catenin or
E-cad
R A V V K E P L L P P E - D D T R D N V Y Y Y D E E G G G E E D Q D - F D L S Q L H R G
plakoglobin binds to the soE R Q A K Q L L I D P E - D D V R D N I L K Y D E E G G G E E D Q D - Y D L S Q L Q Q P
N-cad
called catenin-binding domain
P-cad
K R K I K E P L L L P E - D D T R D N V F Y Y G E E G G G E E D Q D - Y D I T Q L H R G
R-cad4
E R H T K Q L L I D P E - D D V R E K I L K Y D E E G G G E E D Q D - Y D L S Q L Q Q P
(CBD). Triple-alanine (AAA)
R L R K Q A R A H G K S V P E I H E Q L V T Y D E E G G G E M D T T S Y D V S V L N S V
VE-cad5
substitution mutations
cad6
R Q R K K E P L I I S K - E D I R D N I V S Y N D E G G G E E D T Q A F D I G T L R N P
(indicated) spanning the Ecad8
R H Q K N E P L I I K D D E D V R E N I I R Y D D E G G G E E D T E A F D I A T L Q N P
cadherin JMD define a core
R Q R K K E P L I L S K - E D I R D N I V S Y N D E G G G E E D T Q A F D I G T L R N P
cad10
OB-cad11 R R Q K K E P L I V F E E E D V R E N I I T Y D D E G G G E E D T E A F D I A T L Q N P
region (the p120-binding core)
cad12
R R Q K K H T L M T S K - E D I R D N V I H Y D D E G G G E E D T Q A F D I G A L R N P
within the JMD that is
R R S K K E P L I I S E - E D V R E N V V T Y D D E G G G E E D T E A F D I T A L R N P
cad14
required for interaction with
cad15
Q S R G K G L L H G P Q - D D L R D N V L N Y D E Q G G G E E D Q D A Y D I S Q L R H P
p120 in yeast two-hybrid
cad18
R R S K K E P L I I S E - E D V R E N V V T Y D D E G G G E E D T E A F D I T A L R N P
assays (Thoreson et al., 2000;
+ denotes normal p120 binding; – denotes loss of p120 binding). The triple substitution mutant 764 (EED/AAA) has been tested in mammalian
cells and shown to uncouple p120 binding in vivo.
p120 catenin roles in adhesion and signaling 1325
for nuclear translocation (Klymkowsky, 1999; Schmidt et al.,
1997).
A highly conserved N-terminal motif in p120, ARVCF,
p0071 and δ-catenin/NPRAP encodes a putative coiled-coil
domain. Coiled-coil motifs are typically involved in proteinprotein interactions. This region is spliced out in p120 isoforms
2, 3 and 4, whose translation begins at downstream ATGs.
Given that p120 type 1 isoforms are prevalent in motile cell
types (e.g. fibroblasts), they might be important for promoting
more dynamic cadherin interactions. Roles in homo- or heterodimerization can also be envisioned, although such a
mechanism would pertain selectively to type 1 isoforms.
Alternatively, this domain could be responsible for the
recruitment of novel effectors to the cadherin complexes. A
different conserved region is present in the N terminus of all
plakophilins (Bonne et al., 1999) and might be involved in
desmosomal localization.
In the C-terminal end, ARVCF, δ-catenin/NPRAP and
p0071, but not p120, share a third region of similarity. The
conserved sequence DSWV is a PDZ-binding motif (type I;
Fanning and Anderson, 1999), which in the case of δcatenin/NPRAP binds to S-SCAM, a PDZ-domaincontaining scaffold protein (Ide et al., 1999). Interactions
between p120 family members and scaffold proteins could
play a role in the recruitment of signaling molecules to
cadherin junctions, and/or in promoting cadherin clustering –
an event important in cadherin-mediated adhesion, which we
discuss in detail later.
REGULATION OF THE p120-CADHERIN
INTERACTION
Stoichiometry of the cadherin-p120 interaction
The relatively weak interaction between cadherins and p120 in
detergent cell lysates led investigators to estimate that only 520% of total cellular p120 is in complex with cadherins (Ozawa
and Kemler, 1998; Shibamoto et al., 1995; Papkoff, 1997;
Staddon et al., 1995). In contrast, immunofluorescence analysis
generally indicates precise colocalization of p120 with
endogenous cadherins (Reynolds et al., 1994; Thoreson et al.,
2000), which suggests a significantly higher stoichiometry.
Recent evidence strongly favors the latter view. In cadherindeficient cell lines (e.g. A431D, MDA-231 and L-cells), p120
is stranded in the cytosol, which is consistent with the
hypothesis that cadherins are the only p120 receptor in the
membrane (Thoreson et al., 2000; Ohkubo and Ozawa, 1999).
Expression of intact E-cadherin, but not of an E-cadherin
mutant containing minimal substitutions that uncouple p120
association, results in efficient recruitment of p120 to cell-cell
junctions. Moreover, biochemical fractionation of these
transfected cell lines in the absence of detergents shows that
>90% of the p120 fractionates with membranes in the presence
of wild-type E-cadherin (Thoreson et al., 2000). In contrast,
p120 fractionates with the cytosol when the same experiment
is carried out with p120-uncoupling E-cadherin mutants.
Therefore, cadherins are both necessary and sufficient for
recruitment of p120 to membranes, and the in vivo
stoichiometry of p120 in cadherin complexes is likely to be
high and similar to that of β-catenin (Nathke et al., 1994;
Papkoff, 1997).
p120 binds to the cadherin juxtamembrane domain
Early work showed that immunoprecipitates of p120 contained
β-catenin and vice versa, suggesting that the two proteins bind
simultaneously to different regions of the cadherin cytoplasmic
tail (Reynolds et al., 1994; Daniel and Reynolds, 1995).
Subsequent studies demonstrate that p120 associates with the
cadherin juxtamembrane domain (JMD; Finnemann et al.,
1997; Lampugnani et al., 1997; Ozawa and Kemler, 1998; Yap
et al., 1998; Aono et al., 1999; Ohkubo and Ozawa, 1999;
Thoreson et al., 2000), whereas β-catenin and plakoglobin bind
to the so-called catenin-binding domain (CBD; Nagafuchi and
Takeichi, 1989; Ozawa et al., 1990; Stappert and Kemler, 1994;
see Fig. 5). Yeast two-hybrid data and mutational analyses
point to a stretch of ~10 residues that makes up the core of the
JMD and constitutes the critical p120-binding sequence
(Thoreson et al., 2000; Ohkubo and Ozawa, 1999). An
engineered triple-alanine substitution, termed 764 EED/AAA,
in this region of E-cadherin effectively uncouples the cadherinp120 interaction in mammalian cells (Thoreson et al., 2000).
The core p120-binding domain is the most highly conserved
region among classical cadherins, which is consistent with the
concept that p120 plays a fundamental role in regulation of
these proteins.
Potential roles of the cadherin juxtamembrane
domain
Increasing evidence indicates that the JMD and the CBD of
cadherins contribute different functions. Early deletion studies
indicate that the CBD and its association with β-catenin, αcatenin and the actin cytoskeleton, are required for cadherinmediated adhesion (Nagafuchi and Takeichi, 1989; Ozawa et
al., 1990; Fujimori and Takeichi, 1993; Barth et al., 1997;
Kawanishi et al., 1995; Watabe et al., 1994). Subsequently,
Kintner (1992) demonstrated that overexpression of a
membrane-tethered N-cadherin JMD construct inhibits
ectodermal cell-cell adhesion in Xenopus embryos. Dominant
negative constructs lacking either the JMD or the CBD
independently blocked adhesion, which suggests that these
domains have separate but indispensable roles. Interestingly, in
the JMD construct used by Kintner in these studies, a
‘proximal’ JMD sequence was deleted; the recently identified
‘core’ p120-binding region was left intact (Thoreson et al.,
2000). Thus, the observed effects may not be due to the failure
of the JMD deletion to selectively eliminate binding to p120.
Interestingly, a peptide mimicking the ‘proximal’ JMD region
(and lacking the core JMD p120-binding site) reportedly binds
to endogenous N-cadherin and apparently displaces the
tyrosine kinase Fer from the N-cadherin complex (Balsamo et
al., 1999; Lilien et al., 1999). These data suggest that the JMD
contains two binding motifs, a ‘distal’ one that binds p120 and
a ‘proximal’ one that may be involved in cadherin dimerization
and/or binding to Fer. Although the full spectrum of molecular
interactions supported by these domains and their function in
adhesion remain to be elucidated, the reported interaction
between Fer and p120 (Kim and Wong, 1995; Rosato et al.,
1998) suggests that these proteins may act in concert to
modulate adhesion. For clarity subsequent references to the
JMD in this review will refer to the p120-binding region.
In other work, the JMD has been implicated in the ability of
ectopically expressed cadherin to suppress invasion and
motility. Chen et al. (1997) have shown that introduction of a
1326 P. Z. Anastasiadis and A. B. Reynolds
JMD-deleted E-cadherin in WC5 cells (which lack cadherin
expression) induces aggregation, but is unable to suppress
motility. The authors suggest that the adhesion and motility
functions of the cadherin cytoplasmic domain can be
functionally uncoupled. As these studies were conducted in
cells expressing a temperature-sensitive Src mutant, it is not
yet clear whether the data are broadly relevant.
The JMD also appears to be required for neuronal outgrowth
mediated by N-cadherin attachment, since overexpression of
dominant negative constructs containing the JMD, but not the
CMD, were inhibitory (Riehl et al., 1996). N-cadherin
homophilic binding induces neurite extension in a manner
dependent on intracellular signaling by the FGF receptor
(Saffell et al., 1997), which is thought to bind to the N-cadherin
extracellular domain. One possible interpretation is that Ncadherin binding between adjacent cells promotes the
activation of FGF receptor tyrosine kinase signaling by
inducing clustering of the receptors at areas of cell-cell contact.
Further work in these systems to clarify the role of p120 is
warranted.
Two recent reports appear to contradict the idea that the JMD
is involved in cell-cell adhesion: using dominant negative JMD
constructs, Zhu and Watt (1996), and Nieman et al. (1999) did
not detect an inhibition of adhesion measured by aggregation
assays. A potentially unifying hypothesis is that the JMD
modulates the transition from weak to strong adhesion – these
two processes relate to the ability of cadherin-dependent cellcell aggregates to withstand distracting forces (e.g. shear
forces, such as pipetting through a narrow aperture). Indeed, if
overexpression of membrane-tethered JMD constructs block
strong, but not weak adhesion, the aggregation assays used in
the later studies would not be predicted to show an inhibitory
effect, because they do not discriminate between these adhesive
states.
Early studies suggested that dominant negative cadherins
that contain both the JMD and the CBD but lack the
extracellular domain block adhesion by sequestering catenins.
However, several reports indicate that the dominant negative
effect of the CBD is not due to sequestration of classical
catenins (i.e. α-catenin, β-catenin and plakoglobin; Fujimori
and Takeichi, 1993; Zhu and Watt, 1996; Nieman et al., 1999;
Troxell et al., 1999) but rather to downregulation of
endogenous cadherin expression (Zhu and Watt, 1996; Nieman
et al., 1999; Troxell et al., 1999). Nonetheless, dominant
negative effects of cadherin cytoplasmic domains containing
both the JMD and the CBD cannot always be ascribed to
downregulation of endogenous cadherin expression (Kintner,
1992; Fujimori and Takeichi, 1993; Troxell et al., 1999). In
some cases, the dominant negative effect of these constructs
might be mediated by the JMD and its ability to competitively
uncouple p120 from endogenous cadherins. β-Catenin and αcatenin are stabilized by cadherin binding; thus, their levels in
most normal cells are strongly dependent on binding to
cadherins. Dominant negative cytoplasmic cadherin constructs
may simply stabilize increased levels of these proteins. By
contrast, the amount of p120 is not significantly changed by
the presence or absence of ectopic E-cadherin (Thoreson et al.,
2000; Papkoff, 1997). Therefore, dominant negative constructs
may inhibit adhesion largely through sequestration of the
limited amount of available p120.
Interestingly, membrane-tethered cadherin cytoplasmic
domains expressed at levels that do not affect endogenous
cadherin expression localize at cell-cell junctions and inhibit
adhesion in a manner consistent with inhibition of endogenous
cadherin clustering (Fujimori and Takeichi, 1993; Troxell et al.,
1999). It is not yet clear whether the adhesive defect is due to
direct inhibition of cadherin dimerization or clustering or,
alternatively, to the inhibition of cadherin function through
dominant negative interactions with p120. Nonetheless, the
data suggest that the cadherin cytosolic domain (Fujimori and
Takeichi, 1993; Amagai et al., 1995; Katz et al., 1998), and
specifically the JMD (Navarro et al., 1998; see below), is
responsible for the selective recruitment of membraneassociated cadherins into areas of cell-cell contact.
CONTROVERSIES REGARDING THE ROLE OF p120
IN ADHESION
Experiments focused specifically on the role of p120 in
mediating JMD function have led to two results that appear
initially to be diametrically opposed. The first strongly
implicates the JMD and p120 in cadherin clustering and the
induction of strong adhesion independently of the CBD,
whereas the second implicates p120 in negative regulation of
cell-cell adhesion.
‘Activation’ of p120 and positive effects on cell-cell
adhesion
Stable expression in cadherin-deficient CHO cells of a Ccadherin construct lacking the CBD induced strong adhesion,
despite the lack of any detectable association of the protein
with the actin cytoskeleton (Yap et al., 1998). This strong
adhesion was dependent on the clustering of cadherins
mediated by contact with immobilized extracellular cadherin
fragments. A construct lacking the JMD did not induce
clustering, despite evidence that the mutated cadherin could
associate with the cytoskeleton. Interestingly, the clustering
potential of the JMD appeared to be activated by the
homophilic interaction between cadherin extracellular domains
(formation of adhesive or trans dimers) and was not observed
in the absence of cadherin trans association (Yap et al., 1998).
Thus, cadherin clustering in vivo might be secondary to the
formation of adhesive cadherin dimers, and requires the JMD
but not the CBD (or the interaction with the actin cytoskeleton
that the CBD mediates). Coupled with the demonstration that
p120 associates with the JMD construct that was used in these
experiments, these data strongly implicate p120 in liganddependent activation of cadherin clustering. An active p120mediated clustering process is also consistent with lasertrapping experiments measuring the kinetics of cadherin lateral
diffusion. The kinetic data argue that cadherin clustering is an
active process occurring too rapidly to be dependent on passive
diffusion alone (Kusumi et al., 1999).
Overexpression in CHO cells of a VE-cadherin construct
lacking the CBD also induces aggregation independently of
cytoskeletal association (Navarro et al., 1995). This CBDnegative protein localizes appropriately to cell-cell junctions
and recruits p120 (Navarro et al., 1995; Lampugnani et al.,
1997). In related experiments, Navarro et al. (1998) show that
VE-cadherin selectively excludes N-cadherin from cell-cell
junctions when co-expressed in cadherin-deficient CHO cells,
p120 catenin roles in adhesion and signaling 1327
and provide evidence that VE-cadherin binds to p120 with
greater affinity than does N-cadherin. Interestingly, VEcadherin constructs lacking the JMD (and therefore unable to
bind to p120) cannot exclude N-cadherin (Navarro et al., 1998),
which suggests that p120 plays a role in this phenomenon. An
implication is that high-affinity binding of p120 to VEcadherin, and/or low-affinity binding of p120 to N-cadherin,
results in differential recruitment of these cadherins to the
adherens junction. High-affinity interactions with p120 may
favor selective clustering of VE-cadherin at cell-cell contacts,
and affinity modulation might be further regulated by posttranslational modification. The data generated in this model
system reflect the natural scenario in endothelial cells, in which
both cadherins are present, and VE- but not N-cadherin is
found at the adherens junction.
In two separate cadherin-deficient cell model systems, p120uncoupled E-cadherin mutants failed to induce the strong
adhesion observed in cells transfected with wild-type Ecadherin (Thoreson et al., 2000), which is consistent with the
observations reviewed above. Minimal triple-alanine mutants
(e.g. E-cad 764 EED/AAA, see Fig. 5) within the p120-binding
region were used to reduce the chance that the observed effects
are due to conformational artifacts or disruption of other
cadherin-protein interactions, such as the above-noted potential
association between N-cadherin and Fer. In aggregation assays,
the p120-uncoupled cadherins failed to induce compaction
even after overnight incubation, and aggregates of cells
expressing p120-uncoupled cadherins readily dissociated to
single cells upon pipetting, unlike their wild-type-cadherinexpressing counterparts. Correlating with the loss of
compaction, colonies of cells expressing the mutant cadherins
exhibited a disruption of the cortical actin cytoskeleton. This
suggests that p120-induced events (presumably clustering) are
prerequisite for the organization of the actin cytoskeleton in
epithelial cells.
The above evidence suggests that the clustering of
cadherins at cell-cell junctions requires the JMD and, by
implication, p120. On the basis of these studies, we have
defined the apparent activity of p120 that is associated with
clustering (and the strengthening of adhesion) as ‘activation’
of p120.
Inactivation of p120 and negative effects on cell-cell
adhesion
A second group of studies appears to contradict the above
results and suggests that p120 plays a crucial role in the
disassembly of adherens junctions. In Colo205 cells, the
known components of the E-cadherin complex are essentially
intact, but the cells remain rounded and largely non-adherent
in cell cultures (Aono et al., 1999). Interestingly, p120 is
constitutively hyperphosphorylated in these cells. Brief
trypsinization under conditions that protect cadherins, or
treatment with the serine/threonine kinase inhibitor
staurosporine, correlates with decreased p120 phosphorylation
and restored adhesiveness (Aono et al., 1999). Moreover,
expression of an N-terminally deleted p120 construct that lacks
most of the phosphorylation sites also restores adhesion. One
interpretation is that an aberrant constitutive signaling event in
Colo205 cells leads to inactivation of p120’s ability to promote
clustering and adhesion. Although Colo205 cells are clearly
exceptional, experiments in K-562 leukemia cells and murine
L-fibroblasts also suggest that p120 can block adhesion
(Ozawa and Kemler, 1998; Ohkubo and Ozawa, 1999). In K562 cells, expression of membrane-tethered E-cadherin
extracellular domains promotes aggregation, whereas similar
constructs containing the JMD, but lacking the CBD, block
aggregation. Moreover, minimal mutation of the JMD in the
latter construct restores adhesiveness (Ozawa and Kemler,
1998). Inhibition of adhesion again correlated with
hyperphosphorylation of p120, and N-terminally deleted p120
restored adhesiveness (Ohkubo and Ozawa, 1999). These
results implicate p120 in inhibition of cell-cell adhesion.
Mechanisms and models
The above data indicate that the JMD and p120 can mediate
both positive and negative regulation of adhesion. One obvious
problem is how to integrate the seemingly inconsistent results
in one all-encompassing model. The most likely explanation is
that trans binding between cadherins is somehow linked to the
positive effect of the JMD (p120 activation; Yap et al., 1998;
Navarro et al., 1998; Thoreson et al., 2000), whereas
intracellular signaling can induce its negative function (Aono
et al., 1999; Ohkubo and Ozawa, 1999). Rapid activation of
adhesion in Colo205 cells by brief trypsinization might, for
example, result from clipping of a receptor and subsequent loss
of an aberrant constitutive signaling event acting ultimately on
p120. Thus, p120 could act as a switch that induces cadherin
clustering and strong adhesion when activated, and also
mediate junction disassembly following signaling events
leading to its inactivation. Although there is evidence that
serine or tyrosine phosphorylation constitutes the switch
between these forms (Aono et al., 1999; Ohkubo and Ozawa,
1999), this has not yet been proven, and the terms activation
and inactivation cannot be assumed to reflect changes in
phosphorylation status.
Fig. 6 illustrates a p120-centric view of cadherin-mediated
adhesion that summarizes our interpretation of these data and
possible mechanisms of p120 action. Cadherins are thought to
exist both as monomers and as lateral (or cis) dimers in the
plasma membrane. On the basis of the N-cadherin-repeat
crystal structure and other data (Shapiro et al., 1995; Nagar et
al., 1996; Pertz et al., 1999; Tamura et al., 1998), it has been
proposed that the Ca2+-dependent homophillic association of
adhesive trans dimers (connecting adjacent cells) occurs after
the association of lateral dimers. Strengthening of adhesion is
correlated with both cadherin clustering and association with
the actin cytoskeleton – experimentally separable events
related to JMD and CBD functions, respectively. As mentioned
earlier, the formation of adhesive dimers might activate the
clustering potential of p120 and the JMD. The mechanism of
this activation is not known, but it could involve simple
conformational changes affecting p120 binding or an adhesionsensitive signaling cascade (phosphorylation?) ultimately
impacting on p120 function. Under normal conditions, p120
activation induces clustering and results in significant
enhancement of adhesive strength. When p120 is constitutively
inactivated, adhesive dimers cannot cluster and revert back to
form lateral dimers, which are not adhesive. In this view, the
CBD mediates subsequent or possibly concomitant
immobilization of cadherin complexes by actin crosslinking.
The latter might not be necessary for strong adhesion, per se,
but is probably a key factor in compaction – a term used to
1328 P. Z. Anastasiadis and A. B. Reynolds
Fig. 6. A p120-centric model for
cadherin-mediated adhesion. Both
Stage I
Stage II
monomers and lateral (cis) dimers are
thought to exist at the plasma
Lateral
Adhesive
Cadherin
membrane. Formation of lateral dimers
Monomer
dimerization
dimerization
(stage I) is believed to temporally
precede the formation of adhesive
(trans) dimers (stage II) between
Ca2+
cadherins on adjacent cells. Adhesive
dimers cluster (stage III) at areas of cellPM
cell contact, which results in the
establishment of strong adhesion.
Although diffusion alone might bring
p120
trans-dimers on adjacent cells into
"Activation"
contact, several lines of evidence
suggest that the cytoplasmic domain is
required for proper targeting of these
Stage III
complexes to cell-cell junctions.
Cadherin clustering
Evidence suggests that cadherin
clustering requires ligand binding (transadhesive dimerization), an intact JMD
(presumably to coordinate p120
binding) and RhoA, but not the CBD
and/or α-catenin-mediated interaction
with the actin cytoskeleton (see text). In
all of the models, formation of an
adhesive dimer leads somehow to
‘activation’ of p120, which facilitates
subsequent cadherin clustering. The
[A]
[B]
[C]
switch that regulates the activated (blue)
Direct p120
Indirect p120
Cadherin-mediated
and inactivated (orange) states is not yet
dimerization
dimerization
dimerization
clear. Possible mechanisms include
changes in p120 phosphorylation,
conformation or binding-partner
Stage IV
interactions. The interaction between
cadherins and other catenins through the
Actin crosslinking
CBD (depicted in dark green) is omitted
here for simplicity. Three possible
models are proposed for p120-induced
clustering. In the first (A; direct p120
dimerization), direct homodimerization
of 120 is responsible for the clustering
of adhesive dimers. Heterodimerization
of p120 with other p120 family
members is a related possibility. In the
second model (B; indirect p120
dimerization), clustering is also
mediated by a dimerization mechanism,
but unknown crosslinking proteins are
postulated. Finally, the third model
(C; cadherin-mediated dimerization)
predicts that binding of activated p120 to cadherin adhesive dimers induces conformational changes in the cadherin itself, which subsequently
promotes clustering. This model is supported by evidence that the extracellular and/or transmembrane domains can in fact dimerize on their own but
are regulated somehow by intracellular interactions. Finally, the last stage of cadherin-mediated adhesion, actin crosslinking (stage IV), is probably
coordinated with clustering but further requires the CBD, Rac1 and Cdc42, and direct association with the actin cytoskeleton. The distinction
between clustering (stage III) and actin crosslinking (stage IV), both of which result in so-called strong adhesion in aggregation assays, may be
relevant for distinguishing the specific role of p120 in the complex.
reflect an even-tighter consolidation of cellular aggregates
(Adams et al., 1996, 1998).
Fig. 6 also shows three potential mechanisms by which p120
could affect adhesion. In the simplest scenario, activated p120
mediates the physical interaction between cadherins by direct
homodimerization, or heterodimerization involving other p120
family members (Fig. 6A). Although this scenario is intuitively
attractive, p120 does not interact with itself in yeast two-hybrid
assays (Daniel and Reynolds, 1995) or in direct GST-pulldown
assays (Yap et al., 1998). In the second scenario, p120 mediates
cadherin clustering by interacting with unidentified
crosslinking proteins (Fig. 6B). For example, in neuronal
synapses the p120 relative δ-catenin/NPRAP interacts directly
with S-SCAM (Ide et al., 1999), a scaffold protein implicated
p120 catenin roles in adhesion and signaling 1329
in the clustering of membrane receptors. Crosslinking to
scaffold proteins might therefore facilitate the clustering
process. This scenario is necessarily vague because it invokes
additional p120-binding partners that have not yet been
identified. In the third scenario, association of adhesive dimers
with activated p120 leads to conformational changes in the
cadherins themselves, which in turn facilitate cadherinclustering mechanisms involving the extracellular,
transmembrane, or proximal juxtamembrane domains (Fig.
6C). Inside-out signaling analogous to that which occurs with
integrins (for review see Kolanus and Zeitlmann, 1998; Faull
and Ginsberg, 1996; Tozer et al., 1996) may be involved. The
ability of the extracellular domains to support clustering has
been proposed on the basis of structural data (Shapiro et al.,
1995; Nagar et al., 1996) but is not supported by other evidence
(Fujimori and Takeichi, 1993; Katz et al., 1998; Troyanovsky,
1999). However, Huber et al. (1999) recently showed that the
cadherin transmembrane domain can homodimerize, and
Balsamo et al. (1999) reported that peptides mimicking the
proximal JMD bind cadherins. All of these models predict
increased adhesion due to p120 activation and are not
necessarily mutually exclusive.
Rho family GTPases and cadherin-mediated
adhesion
An important consideration in all of these models is the
incompletely understood role of the Rho family of GTPases in
cadherin function (Braga et al., 1997; Takaishi et al., 1997;
Braga et al., 1999; Jou and Nelson, 1998). RhoA transiently
localizes to cell-cell junctions upon induction of calciumdependent adhesion (Takaishi et al., 1995; Kotani et al., 1997),
which raises the possibility that it is recruited to junctions
and activated following the formation of adhesive dimers. In
addition, several studies indicate that Rac1 and Cdc42
activities mediate the crosslinking of cadherins with the
actin cytoskeleton (Braga et al., 1997; Jou and Nelson, 1998;
Takaishi et al., 1997; Kodama et al., 1999). RhoA is thought
to act at an earlier step, because inhibition of RhoA by C3
exotransferase expression blocks both cadherin localization at
areas of cell-cell contact (Braga et al., 1997; Zhong et al., 1997;
Takaishi et al., 1997) and Rac1-mediated actin recruitment
(Braga et al., 1997). Furthermore, forced clustering of
cadherins on antibody-coated beads abolishes the ability of C3
to inhibit Rac1-mediated actin recruitment (Braga et al., 1997),
which suggests that RhoA is required for cadherin clustering.
Together, these data suggest potential links between RhoA,
p120 and the JMD in cadherin clustering.
p120 PHOSPHORYLATION
p120 is a superb Src substrate both in vivo and in vitro
(reviewed by Daniel and Reynolds, 1997). Although
constitutive tyrosine phosphorylation of p120 in cells
expressing activated Src correlates with cell transformation
(Reynolds et al., 1989), we cannot yet distinguish the direct
effects of p120 phosphorylation from the many other events
associated with Src activation. Multiple lines of evidence
suggest that tyrosine phosphorylated p120 binds with increased
affinity to various cadherins (Kinch et al., 1995; Skoudy et al.,
1996b; Papkoff, 1997; Calautti et al., 1998). There is also
evidence that transient tyrosine phosphorylation of p120 occurs
in nascent cell-cell junctions (Calautti et al., 1998; Lampugnani
et al., 1997; Kinch et al., 1997), although, under steady-state
conditions, tyrosine phosphorylation of p120 is generally not
detected. p120 is also tyrosine phosphorylated in response to
EGF, PDGF, CSF-1, VEGF and NGF (Downing and Reynolds,
1991; Shibamoto et al., 1995; Daniel and Reynolds, 1997;
Esser et al., 1998), but it is not clear whether the implicated
receptors phosphorylate p120 directly or through the
recruitment of associated tyrosine kinases, such as Src.
Nonetheless, the numerous reports linking cadherin complexes
with Src, receptor tyrosine kinases, and a variety of tyrosine
phosphatases (reviewed by Daniel and Reynolds, 1997), argue
strongly for an important role for tyrosine phosphorylation in
the regulation of cadherin function. Discriminating the direct
effects of tyrosine phosphorylation of p120 and β-catenin on
cadherin function will probably require the mapping and
subsequent mutation of the relevant sites.
In most cells, p120 is extensively phosphorylated on serine
residues (and to a lesser extent on threonine residues; Downing
and Reynolds, 1991; Ratcliffe et al., 1997, 1999; Aono et al.,
1999; Ohkubo and Ozawa, 1999). In fact, even the receptor
tyrosine kinase ligand EGF induces extensive serine
phosphorylation of p120 (Downing and Reynolds, 1991). p120
isoforms generally migrate diffusely on polyacrylamide gels,
mostly because of serine phosphorylation, and phosphatase
treatment collapses the bands into sharply migrating species
(Staddon et al., 1995; Aono et al., 1999; Ohkubo and Ozawa,
1999; Thoreson et al., 2000). Early work demonstrated that
only membrane-associated Src can phosphorylate p120
(Reynolds et al., 1989). The observation that tyrosine
phosphorylation and serine/threonine phosphorylation of p120
require recruitment of p120 to cell membranes through
association with cadherins is consistent with this (Reynolds et
al., 1994; Ohkubo and Ozawa, 1999; Thoreson et al., 2000).
Conversely, when p120 is stranded in the cytoplasm (e.g. in
metastatic cell lines that have lost cadherin expression), it is
virtually unphosphorylated (Ohkubo and Ozawa, 1999;
Thoreson et al., 2000) and probably unavailable to receive
membrane-associated signals. The level of serine
phosphorylation of p120 can be reduced by the kinase inhibitor
staurosporine (Ratcliffe et al., 1997, 1999; Aono et al., 1999),
and by either inhibition or activation of protein kinase C, which
implicates a PKC-modulated protein kinase (Ratcliffe et al.,
1997, 1999). As mentioned earlier, two important studies now
implicate serine dephosphorylation as a mechanism for the
activation of p120’s adhesive function (Aono et al., 1999;
Ohkubo and Ozawa, 1999). However, given that concrete
evidence of the relevant phosphorylation events is lacking,
other events mediated by the N-terminal domain of p120 might
also account for these effects. The mapping of specific serine
phosphorylation sites and identification of respective kinases
will be crucial for an understanding of how these events
modulate p120 function.
NUCLEAR SIGNALING
p120 was recently added to the list of Arm-repeat proteins that
have dual localization at cell-cell junctions and in the nucleus
(Van Hengel et al., 1999; Mariner et al., 2000). Perhaps the
1330 P. Z. Anastasiadis and A. B. Reynolds
best-known example is β-catenin, which plays a key role in
both adhesion and signaling (reviewed by Ben-Ze’ev and
Geiger, 1998, and references therein). A novel transcription
factor, Kaiso, binds directly to the p120 Arm domain,
providing the first candidate for a nuclear target of a p120
family member (Daniel and Reynolds, 1999). Kaiso belongs to
a growing POZ/ZF (Pox virus and zinc finger) superfamily of
transcription factors (reviewed by Bardwell and Treisman,
1994; Albagli et al., 1995), members of which are
characterized by a conserved N-terminal hydrophobic domain
of ~120 residues (the POZ domain) and C-terminal C2H2-type
zinc-finger motifs (the ZF domain). Many POZ/ZF proteins are
sequence-specific transcriptional repressors that apparently
recruit histone-deacetylase complexes via their POZ domains
(Grignani et al., 1998; Lin et al., 1998; David et al., 1998).
Although the functional significance of the Kaiso-p120
interaction is currently speculative, the known activities of the
other POZ/ZF proteins in development and cancer make Kaiso
an attractive signaling candidate for a conveyor of information
related to cell-cell adhesion. Van Hengel et al. (1999) have
demonstrated that p120 enters the nucleus. Moreover, a
nuclear-exclusion signal that appears to mediate p120 export
is present in alternatively spliced forms of p120 containing
exon B. The simplest hypothesis, therefore, is that p120
interacts with Kaiso in the nucleus, thereby modifying its
predicted transcriptional activity. Further analysis of this
interaction awaits the characterization of Kaiso transcriptional
targets, which will also allow elucidation of the roles of p120
and cadherin in Kaiso-mediated effects. It is likely that other
members of the p120 subfamily also have nuclear partners. An
interesting observation is that the nuclear localization of p120
is enhanced in cadherin-deficient cells (Van Hengel et al.,
1999). Thus, aberrant regulation of Kaiso by p120 might
contribute in previously unsuspected ways to the pleiotropic
effects of cadherin loss in metastatic cells.
ECTOPIC p120 OVEREXPRESSION
Overexpression studies offer an obvious avenue for testing the
biological functions of novel proteins. p120-overexpression
studies have been hindered because of unexplained problems
in generating stable cell lines. Interestingly, transient
overexpression of p120 in fibroblasts induces severe branching
of cellular processes, resulting in a so-called dendritic
phenotype (Reynolds et al., 1996). Morphological changes,
albeit less dramatic, are also induced in other cell types.
Overexpression of other Arm-domain proteins, including the
closest relative of p120, ARVCF (Mariner et al., 2000), has
little effect in fibroblasts. Moreover, deletions in the Armrepeat domain completely block the effect (Reynolds et al.,
1996). A similar phenotype is observed under a variety of
conditions that disrupt RhoA-mediated contractility (Jalink et
al., 1994; Kranenburg et al., 1999), further suggesting a
functional link between p120 and Rho signaling.
Ventral overexpression of p120-1A or 1N in Xenopus
embryos does not induce Wnt signaling or the duplicate axis
formation associated with ventral overexpression of β-catenin.
In contrast, overexpression of p120 in dorsal blastomeres
perturbs gastrulation (Geis et al., 1998; Paulson et al., 1999),
apparently because of reduced cell motility, reduced adhesion
between blastomeres, and ectodermal defects. These data
suggest that p120 affects morphogenetic events, which is
consistent with a role for p120 in cell-cell adhesion.
p120 EXPRESSION IN TUMORS
Although knockout data are not yet available, analysis of p120
expression in human tumors suggests that p120 plays an
important role in malignancy. Loss of p120 expression has been
demonstrated in a variety of human tumors and in some cases
is statistically linked to an aggressive tumor phenotype (Dillon
et al., 1998; Gold et al., 1998; Shimazui et al., 1996; Skoudy et
al., 1996a; Syrigos et al., 1998; Valizadeh et al., 1997). By
contrast, Jewhari et al. (1999) report striking upregulation of
p120 expression in ~66% of gastric carcinomas. In addition,
expression of p120 isoforms is remarkably heterogeneous in
human tumor cell lines (Wu et al., 1998; Skoudy et al., 1996a;
Keirsebilck et al., 1998), but the significance of this observation
is unknown. One possibility is that misexpressed p120 isoforms
promote tumor progression by dysregulating cadherin-mediated
adhesion, or promoting cell motility and invasion. Finally, the
correlation of constitutive p120 phosphorylation with defects in
Colo205 cell adhesion (Aono et al., 1999) suggests that
signaling pathways contribute to malignancy through direct
modification of p120 function.
FUNCTIONAL ROLES OF p120 FAMILY MEMBERS
Competition among p120 relatives for cadherin
binding
A largely unexplored issue involves the potential functional
crosstalk between p120 and other closely related family
members. The existence of p120 relatives suggests that they
have functional similarities and differences that play out in
different cell types. For example, p120 family members may
compete for cadherin binding. δ-catenin/NPRAP, like p120,
interacts directly with the JMD (Lu et al., 1999), and the
binding of ARVCF and p120 to E-cadherin is apparently
mutually exclusive (Mariner et al., 2000). One clue comes from
the selective expression of δ-Catenin/NPRAP/neurojungin in
neuronal tissues, which suggests that it has cell-type specific
functions. In addition, although ubiquitously expressed,
ARVCF appears to be present in most adult tissues at extremely
low levels (Mariner et al., 2000). Thus, it is unlikely to act as
a direct p120 competitor in vivo. Thus far, p120 appears to be
the most abundant member of the family in most cell types,
which suggests that it is the dominant player in cadherin
function. However, p0071 is also believed to be abundant and
is a potential, although largely unstudied, rival for this role
(Hatzfeld and Nachtsheim, 1996). An important area of future
research is to determine whether these family members bind to
the same or different cadherins and whether (and if so how)
competition for the JMD imparts functional diversity on
cadherin-mediated adhesion.
Specific functional roles of individual p120 relatives
Table 1 summarizes the expression patterns, cellular
localizations, binding partners and chromosomal locations of
all known p120 family members. Specific functions have been
p120 catenin roles in adhesion and signaling 1331
Table 1. p120 family expression and localization
Expression
p120 ctn
ARVCF
Ubiquitous, high level expression.
Not in B/T cells
Ubiquitous, low level expression
δ-Catenin/NPRAP
Neuroepithelium, neuroendocrine
P0071
Ubiquitous expression
PKP 1
Epithelial tissues, especially
stratified epithelia
PKP 2
PKP 3
Ubiquitous expression
Stratified and single layered epithelia.
Not hepatocytes, foreskin fibroblasts,
sarcoma-derived cells
Subcellular
localization
Chromosomal
localization
Binding partners
Adherens junctions, nucleus
Adherens junctions, nucleus
Classical cadherins, Kaiso,
BP180*, FER kinase‡
Classical cadherins
Adherens junctions, nucleus
tissues
Desmosomes and adherens
junctions§
Desmosomes, nucleus
Classical cadherins, presinilin 1,
S-SCAM
Presinilin 1¶
Nucleus, desmosomes
Desmosomes, nucleus
Desmoplakin, cytokeratins
Not identified
Desmoplakin, cytokeratins,
Dsg 1
11q11||
22q11 (region deleted in
Velo-cardio-facial syndrome)
5p15 (region involved in
Cri-du-chat Syndrome
2q23-q31
1q32 (linked to ectodermal
dysplasia/skin fragility
syndrome)
12p11, 12p13 (pseudogene)
11p15
*p120ctn reportedly interacts with the hemidesmosomal protein BP180 (Aho et al., 1999) but the significance of this interaction is unknown.
‡p120ctn interacts with FER kinase either directly or indirectly (Kim and Wong, 1995).
§It is not known whether p0071 is also found in the nucleus.
¶Direct association of p0071 with components of the desmosomes or adherens junctions has not been reported to date.
||For chromosomal localization of p120 family members see Bonne et al. (1998) and references therein.
suggested for particular p120 relatives and plakophilins. For
example, it is possible that p0071 has dual roles in both
adherens junctions and desmosomes (Hatzfeld and
Nachtsheim, 1996). Furthermore, p0071 (Stahl et al., 1999;
Tanahashi and Tabira, 1999) and δ-catenin/NPRAP (Levesque
et al., 1999; Zhou et al., 1997; Tanahashi and Tabira, 1999)
interact with presenilin 1, a protein that when mutated leads to
familial Alzheimer’s disease (Nishimura et al., 1999); this
raises the possibility that p120 family members are involved in
neurodegeneration. In addition, Sirotkin et al. (1997) have
linked the gene that encodes ARVCF to Velo-Cardio-Facial
syndrome, whereas δ-catenin/NPRAP maps to a region
involved in Cri-du-chat syndrome (cat cry; Bonne et al., 1998).
Although the involvement of ARVCF or δ-catenin/NPRAP in
these syndromes has not been confirmed, it is interesting that
both syndromes exhibit developmental facial and heart defects.
As mentioned earlier, p120 induces a striking branching
phenotype when overexpressed in fibroblasts. δ-Catenin/
NPRAP induces morphological changes in MDCK cells
(increased spreading, and formation of lamelipodia and
filopodia), negatively regulates cadherin adhesiveness and
increases motility in response to HGF (Lu et al., 1999).
Although these phenotypic changes are similar to those induced
by p120 in MDCK cells (unpublished observation), δ-catenin/
NPRAP does not induce branching in fibroblasts (Q. Lu and K.
Kosik, personal communication). Interestingly, overexpression
of the plakophilin 1 Arm domain but not overexpression of
full-length plakophilin 1 induces a similar phenotype in
epithelial cells (M. Hatzfeld, personal communication),
whereas overexpression of ARVCF in fibroblasts or epithelial
cells does not alter cell morphology (Mariner et al., 2000). The
significance of the observation that p120 is particularly difficult
to express stably in cells is unclear: stable expression of both
ARVCF (Mariner et al., 2000) and δ-catenin/NPRAP (Lu et al.,
1999) has been accomplished in a variety of cell lines. Clearly,
there are important differences between these proteins, and each
is likely to contribute unique functions at cell junctions and in
the nucleus.
CONCLUSIONS
It is now clear that p120 is a major cadherin-binding partner
and the likely mediator of JMD function. Further elucidation
of the mechanism of p120 action in cadherin-mediated
adhesion will undoubtedly clarify our understanding of
processes
involved
in
cadherin-dependent
tissue
morphogenesis and related issues in metastatic cells. It is likely
that p120 has both positive and negative roles in cadherin
adhesion, functions that are probably regulated by posttranslational modifications. Genetic studies in mice and
other organisms are likely to provide further insight on the
specific functions of p120 and family members in cell-cell
adhesion and morphogenesis. Detailed mapping of p120
phosphorylation sites and identification of new p120-binding
partners and effectors are also important goals for future
progress. Another interesting and largely unexplored issue is
the significance of the apparently universal dual localization of
p120 family members in junctions and nuclei. The relative
stability of p120 and its cytoplasmic/nuclear localization in
cadherin-deficient cells raises the possibility that aberrant
p120/Kaiso signaling contributes to the pleiotropic effects of
cadherin loss in metastatic cells. An important possibility is
that the interplay between oncogenes, catenins and nuclear
signaling is responsible for tumor-cell defects associated with
the contact inhibition of cell growth, a hallmark of malignancy
that remains unexplained at the molecular level.
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