Protein tyrosine phosphatases as adhesion receptors

Susann M Brady-Kalnay and Nicholas K Tonks

Cold Spring Harbor Laboratory, Cold Spring Harbor, USA

The intracellular segments of classic adhesion molecules such as N-CAM do

not show structural similarity to any known signaling molecules. This suggests
that their effects on signaling responses must be exerted indirectly through
associated proteins. In contrast, many receptor protein tyrosine phosphatases
(RPTPs) possess extracellular segments with homology to cell adhesion
molecules linked directly to intracellular segments comprising one or two
protein tyrosine phosphatase catalytic domains. Therefore, the RPTPs have
the potential for direct modulation of catalytic function through engagement of
the extracellular segment, suggesting they could be direct signal transducers of
cell contact phenomena. In the past few years, some RPTPs have been shown
to effect cell-cell adhesion directly via homophilic binding or indirectly by
association with known cell adhesion molecules. In addition, RPTPs have
been localized to points of cell-cell or cell-matrix contact, indicating their
potential to regulate these structures.

Current Opinion in Cell Biology 1995, 7:650-657

Introduction have the potential to regulate the intracellular catalytic

domains at two levels, either through direct effects
Tyrosine phosphorylation is known to regulate physio- on enzyme activity or indirectly through targeting to
logical events including cell-cell and cell-matrix contact. particular subcell&r locations. Although the precise
Cellular phosphotyrosine levels are controlled by the details remain to be defined, this concept of control
co-ordinated and competing actions of protein tyrosine of PTP activity through subcellular distribution is now
kinases (PTKs) and protein tyrosine phosphatases (PTPs). thought to apply to several members of the PTP family
The PTPs comprise a diverse family of transmembrane
and cytoplasmic enzymes. The diversity of these proteins
is achieved primarily through the variability in the Role of the RPTPs in cell-cell adhesion
non-catalytic sequences that are fused to the catalytic
domains [l]. The receptor PTPs (RPTPs) are composed A number of RPTPs contain multiple immunoglobulin
of either one or two tandem phosphatase domains (Ig) domains and/or fibronectin type III (FN III) repeats
in their intracellular segment, a single transmembrane in their extracellular segments, suggesting that they
domain, and variable extracellular segments frequently may function in cell-cell adhesion. Ig domains are
with features of cell adhesion molecules (reviewed disulfide-bonded structures that are found in a variety of
in [2]). Although originally grouped into five types proteins, including cell surface receptors. These domains
(reviewed in [3]), recent progress in identifying novel contain the homophilic binding site of cell-cell adhesion
PTPs suggests the existence of additional categories molecules such as N-CAM [4]. FN III motifs were
(Table 1). The striking variation in the extracellular originally observed in the extracellular matrix protein
segments of the RPTPs presumably reflects an equivalent tibronectin but have now been detected in more than 50
diversity of ligands to which these enzymes may respond. eukaryotic proteins. They comprise XI-100 amino acids
that are characterized by highly conserved hydrophobic
Many of the RPTPs contain structural features that are residues [5]. In most cases their function is unknown;
suggestive of a role in either cell-cell or cell-matrix however, the sequence RGD (single-letter code for
adhesion. We will discuss what is known about adhesion amino acids) in one FN III repeat in fibronectin has
mediated directly by some RPTPs and how the been shown to mediate cell attachment through binding
expression patterns and subcellular localization of other to integrins [6].
RPTPs implicates them in the control of adhesive
structures such as cell junctions. A number of the An additional motif, referred to as a MAM domain,
RPTPs and cell adhesion molecules that we will discuss has been noted in the extracellular segment of PTPp
are shown schematically in Figure 1. The adhesive and PTPK [7]. This domain has been identified
events mediated by the extracellular segment of RPTPs in five proteins to date: meprin A and B, the

Abbreviations
ECM-extracellular matrix; FAK-focal adhesion kinase; FN Ill-fibronectin type III repeat; ICAh4-intercellular cell adhesion molecule;
MAM-meprin/A5/PTPp; PTK-protein tyrosine kinase; PTP-protein tyrosine phosphatase; RPTP-receptor PTP.

650 0 Current Biology Ltd ISSN 0955-0674

 Protein tyrosine phosphatases as adhesion receptors Brady-Kalnay and Tonks 651

rable 1. Structuralorganizationof receptorprotein tyrosinephosphatases.

Structuralfeaturesof
rype Members extracellular segment

I CD45 Heavily glycosylated cysteine-rich

segment
Contains an FN Ill motif
Variable expression of three exons
at the amino terminus
produces isoform variability

2A LAR, DLAR, PTPB, Ig domains and FN Ill motifs

DPTP69D, CRYPa,
RPTPo*

26 PTPp and PTPK A MAM domain in addition to

Ig and FN Ill motifs

3 PTPB, DEP-l/PTPq, FN III motifs alone

OST-PTP, SAP-l,
CLEPPlIPTPU2,
DPTPl OD, DPTP4E
DPTP99A

4 PTPa and PTPE Short highly glycosylated

5 PTPy and PTPW
extracellular segments
PTPt,
Q 1995 Current ODinionanCell Biolw
Chondroitin sulfate proteoglycans
with an amino-terminal
carbonic anhydrase like motif

6 Chicken PTPL Ser/Thr/Pro-rich segment m Catalytic protein tyrosine m Segment of homology to the
ohosohatase domain cadherin intracellular domain
One FN III motif
Spectrin-like repeat
Fig. 1. The lg superfamily members shown here include the neu-
ral cell adhesion molecules N-CAM and Ng-CAM and the receptor
7 PTPBR7 No structural similarity to known
protein tyrosine phosphatases (RPTPs) PTPp and, LAR. Also shown
molecules are a representative of the cadherin family of calcium-dependent
cell-cell adhesion molecules and the RPTP DEP-1, which contains
a IA2/ICA512 Cysteine-rich amino terminus only fibronectin type Ill repeats in its extracellular segment.
Activity not yet demonstrated
speculated that the MAM domain is involved in adhesion
*RPTPo also known as PTPNE3, LARPTPZ, PTPP-l/P-S, PTPNU-3,
[7]. When A5-expressing neurons were cultured on
CPTP-l/3. FN Ill, fibronectin type Ill motif; PTP, protein tyrosine
monolayers of L-cell transfectants also expressing A5,
phosphatase.
neurite outgrowth was promoted, consistent with a role
for this molecule in neuronal interactions. However, the
L-cell transfectants expressing A5 did not aggregate in
A5 glycoprotein, PTPp and PTPK [7]. Meprins are adhesion assays, suggesting that the presence of the
cell surface homodimers or heterodimers that have MAM domain is not sufftcient for mediating adhesion
metalloendopeptidase activity [8]. The A5 antigen is via homophilic binding [lo]. The role of this domain in
a transmembrane protein which, upon optic nerve PTP/.t and PTPK is discussed below.
innervation, is expressed in pre- and post-synaptic
neurons of the visual centers of the brain of Xenopus
luevis, an area where cell-cell contact is important [9]. PTPp and PTPK mediate cell-cell aggregation
The MAM domain (for meprin/A5/PTPk domain) It has now been demonstrated using overexpression
that is common to these proteins comprises 170 systems that PTPp and PTPK have the ability to induce
amino acids containing four conserved cysteine residues cell-cell aggregation [ll-131. Through a variety of
and two conserved sequence motifs tChtFahhxxtt and assays, including reconstitution of binding in vitro, it has
ttGhhxhD-hxh (where h=hydrophobic, acaromatic, been shown that these enzymes bind homophilically:
and t =turn or polar residues, and x =any amino acid) PTPp or PTPK on the surface of one cell binds
[7]. At present its function is unclear but some have to an identical molecule on an apposing cell. We
652 Cell-to-cell contact and extracellular matrix

have shown for PTPp that the extracellular segment and homophilic cell-cell adhesion molecules (chaoptin
alone is sufficient for homophilic binding [ll] and and connectin). The data suggest that DPTPlOD may
have identified the binding site within the extracellular regulate an adhesive function of gp150. This concept
segment. Only fragments of PTPp containing the Ig that RPTPs may interact with and regulate the function
domain underwent aggregation or displayed homophilic of established adhesion molecules is further illustrated by
binding in various in vitro and in viva assays [14-l. several examples described below.
Although these results suggest that neither the MAM
domain nor the FN III repeats are directly responsible for
homophilic binding, we cannot rule out their possible PhosphacanlRPTPWp binds to Ng-CAM, N-CAM and
involvement in heterophilic binding or in performing tenascin
other roles that assist homophilic binding mediated by RPTP</b contains a carbonic anhydrase like domain in
the entire extracellular segment in viva, such as lateral its extracehular segment. This domain, which lacks key
association in the plane of the membrane. In this regard, histidine residues required for hydration of CO2, has
Zondag et al. [15*] have shown recently that the MAM been proposed to function as a hydrophobic binding
domain plays a role in aggregation mediated by PTPp. pocket for a heterophilic ligand; such a ligand was
They made deletion mutants that lacked the MAM identified recently [20*]. Interestingly, these RPTPs
domain and observed that these proteins were unable to containing carbonic anhydrase domains have been
induce aggregation when expressed in insect St9 cells. shown recently to be chondroitin sulfate proteoglycans
However, when they constructed a chimeric molecule [21*,22,23]. Phosphacan, an RPTP</fi splice variant
in which the MAM domain in PTPI.~ was substituted comprising the extracellular segment, has been shown
with that of PTPK, expression of this chimera induced to interact heterophilically with N-CAM, Ng-CAM
aggregation of St9 cells. Mixing of cells expressing either and tenascin [24,25,26*], suggesting that this PTP may
PTPp, PTPK or the chimera revealed that whereas the regulate neuronal adhesion. RPTP</b is expressed on
chimera could self-associate, it did not bind to native radial glial cells in the developing central nervous
PTPp or PTPK. If, as the authors postulated [15*], system [27] which are thought to form barriers to
the MAM domain contained the homophilic binding neuronal migration. It now appears that RPTP</fi
site, one would anticipate that the chimera would have or phosphacan may play a role in this inhibition of
bound to PTPK; however, it did not. We suggest that neuronal migration. In addition, the interaction of
the homophilic binding site for PTPp resides in the phosphacan with the extracellular matrix (ECM) protein
Ig domain, whereas the MAM domain functions in tenascin is particularly interesting when considered in
‘sorting’ of PTPp from closely related molecules such the context of the effect of ECM proteins on intracellular
as PTPK during cell aggregation. tyrosine phosphorylation. The adhesive interactions
that occur at focal adhesions between integrins and
In addition to the homophilic binding that has been ECM proteins such as fibronectin have been shown
demonstrated for these molecules there is the possibility to initiate tyrosine phosphorylation-dependent signaling
of heterophilic binding. It is interesting to note that events through the activation of PTKs such as focal
axl/ark, a receptor PTK that displays features of the Ig adhesion kinase (FAK) (see Yamada and Miyamoto, this
superfamily of cell adhesion molecules in its extracellular issue, pp 681-689). When one considers that tenascin
segment, binds the soluble ligand gas6 at low cell can mediate anti-adhesive effects [28], its potential
density [16*], whereas at high cell density it binds interaction with RPTPc/P, which may promote ‘net
homophilically [17-l. In light of this precedent, it is dephosphorylation of tyrosyl residues in proteins, would
possible that at high cell densities homophilic binding provide an intriguing counterpoint to the integrin-in-
between RPTPs may predominate, whereas at lower duced activation of FAK. However, it remains to be
densities binding of distinct ligands may occur, thereby determined whether the full-length form of RPTPc/p
expanding the repertoire of physiological processes that displays similar binding properties to phosphacan and
may be controlled by RPTPs. what the effects of such an interaction would be on
phosphatase activity.

RPTPs in Drosophila may regulate neuronal adhesion

Two Drosophila RPTPs, DPTP99A and DPTPlOD, are A potential role of CD45 in lymphocyte adhesion
expressed in developing central nervous system and their CD45 is established as an essential component of
expression pattern is suggestive of a role in axonal antigen-induced signaling events in lymphocytes. It
migration and pathfinding (reviewed in [18]). Both of is a positive regulator of signal transduction through
these RPTPs have FN III repeats in their extracellular T- and B-cell receptors (reviewed in [29]). There is
segments. Although the identity of the ligand for these now mounting evidence to implicate CD45 in the
RPTPs is not known, a recently identified substrate control of cell adhesion at two levels: involvement
of DPTPlOD, gp150, suggests that it has a role in in signaling pathways that regulate integrin-dependent
cell adhesion [19]. gp150 is a transmembrane protein adhesion and in binding to proteins that may modulate
that contains leucine-rich repeats; such repeats are adhesion. CD45 regulates adhesion mediated by the
found in a family of proteins that include proteoglycans integrin LFA-1 binding to intercellular cell adhesion
involved in cell-matrix adhesion (biglycan and decorin) molecule (ICAM)-l or ICAM3, which are members of
 Protein tyrosine phosphatases as adhesion receptors Brady-Kalnay and Tonks 653

the Ig super&nily. The effects of engagement of CD45 activity, by addition of 0-phospho-L-tyrosine, resulted
appear to vary according to cell type. In activated human in growth inhjbition of renal and breast carcinoma
T cells [30’] and thymocytes [31*], CD45 induces cell lines [40]. The PTPs that mediate this growth
homotypic interactions. However, in T- and B-cell regulation have yet to be identified; however, RPTPs are
lines, incubation with antibodies to the extracellular attractive candidates because their extracellular segments
segment of CD45 prevented LFA-l/ICAM-1 or LFA- may ‘sense’ directly cell-cell contact and transmit a signal
l/ICAM-3-dependent adhesion [32*,33]. Addition of in response to that stimulus. One such candidate was
the antibodies to these cells also caused a change in described recently. This enzyme, DEP-1, is an RPTP
the tyrosine-phosphorylation status of various cellular containing eight FN III repeats in its extracellular
proteins [32*,33]. Thus it is possible that, rather than segment that is dramatically increased in expression in
modifying adhesion through steric effects involving the dense relative to sparse cultures [41*]. The physiological
extracellular segment, CD45 may act by modulating the substrates for DEP-1 remain to be defined.
state of tyrosine phosphorylation of key components
of the signaling pathways that regulate celI adhesion.
Perhaps the antibodies used to engage the extracellular Shedding of the extracellular segment of RPTPs at high
segment of CD45 in these experiments are mimicking cell density
the natural ligand of this RPTI? In addition to changes in the level of expression,
alternative mechanisms for modifjring the activity or
The identity of the ligand for CD45 remains unclear; function of PTPs at high cell density have been
however, there are two examples of proteins that bind described. Interestingly, as originally described for LAR
CD45 that are suggestive of a role in cell adhesion. [42], the extracellular segment of some RPTPs is
Engagement of the extracellular segment of CD45 by released as a proteolytic fragment Tom the cell surface at
the B cell surface protein CD22 has been shown to high density. LAR is processed by post-translational pro-
mediate early signaling events triggered by the T-cell teolysis of the full length protein into two non-covalently
receptor [34]. CD22, a member of the Ig superfamily, is associated tiagments, the E-subunit (containing most of
a sialic acid binding lectin and therefore interacts with the extracellular segment) and a P-subunit (consisting
the sialic acid moieties on CD45 [34]. Interestingly, predominantly of the transmembrane and intracellular
sialic acid binding proteins have been implicated in segments). This is a common modification that has
various adhesive phenomena [35] raising the possibility been observed in both cell-cell adhesion molecules,
that the CD22-CD45 interaction has the potential to such as neurofascin, Ng-CAM/L1 and Bravo/Nr-CAM,
play a role in lymphocyte adhesion. The effect of this and now in other RPTPs, including PTPK and PTPp.
association is not entirely understood but a recent study Cleavage occurs at basic sequences close to the external
has shown that binding of CD22 to CD45 amplifies face of the plasma membrane (reviewed in [39]). In
(i.e. positively regulates) early signals through the T-cell some celI types, the extracellular segment (E-subunit) of
receptor [36*]. One could speculate that binding of PTPl.r is also shed fi-om cells at high density (C Bianchi,
CD22 may upregulate the activity of CD45, con- B Neel, S Brady-Kalnay, NK Tonks, unpublished data).
comitantly decreasing adhesion and stimulating T-cell As the E-subunit contains the homophilic binding site,
activation/proliferation. There also appear to be other the potential shedding of this segment could generate
ligands for CD45. Using a co-culture model system a fragment of PTPp that would retain the capacity for
for the interaction of hematopoietic precursors with homophilic binding and antagonize interactions between
the bone marrow stroma, it has been shown that heparin molecules of PTPp on the surfaces of adjacent cells.
sulfate on stromal cells serves as a ligand for CD45 [37*]. There are indications that the extracellular segment of
Further characterization of ligands for CD45 and its RPTPs may exert a regulatory constraint on phosphatase
effects on adhesion-induced signaling will be required activity either directly or indirectly through control of
to define precisely its role in modulating cell contact localization. Therefore, it is also possible that proteolytic
phenomena. cleavage and/or shedding of the E-subunit may relieve
such regulatory constraints.

Regulation of RPTP expression by cell contact

The role of PTPs in cell junctions
A role for RPTPs in contact inhibition of growth
As normal cells in culture reach confluence, growth Cell junctions are specialized areas that link cell-cell
is inhibited. In cancer such ‘contact inhibition of (adherens junctions) or cell-matrix (focal adhesions)
growth’ is abrogated. A role for PTPs in adhesion-based adhesion receptors to the cytoskeleton. It is now
signal transduction leading to growth inhibition is becoming apparent that junctions are not only structural
suggested by several observations. PTP activity has but also are areas in which signaling events are initiated
been shown to be enhanced in cells harvested at [43,44]. PTKs such as src localize to these areas and
high density [38]. In addition, when cells were treated phosphorylate junctional Proteins in both normal and
with broad specificity PTP inhibitors such as vanadate, transformed cells [44]. There is also evidence to suggest
they overcame density-dependent growth inhibition PTPs play an important role in regulating these junctions
(reviewed in [39]). Conversely, stimulation of PTP (reviewed in [39]).
654 Cell-to-cell contact and extracellular matrix

The LAR PTP localizes to focal adhesions A number of cytoplasmic and receptor PTKs including
Cells adhere to the ECM at focal adhesions. The src, epidermal growth factor receptor and met, the
ECM components are bound by cell surface receptors, receptor for,, scatter factor, phosphorylate components
integrins, which are linked via a series of proteins to of the cadherin-catenin complex ([51*]; reviewed in
the actin tytoskeleton [45]. Focal adhesions are sites [52]). A substantial body of evidence now suggests
of signal transduction: they transmit signals resulting that tyrosine phosphorylation of components of the
from binding to extracellular matrix. They are dynamic cadherin-catenin complex suppresses cadherin-mediated
structures, being assembled and disassembled during adhesion and destabilizes adherens Junctions (Fig. 2;
processes such as mitosis and migration [46]. The reviewed in [39]). For example, in human breast
assembly/disassembly process requires signals that are epithelial cells transformed by rus, the adherens junctions
thought to be mediated by tyrosine phosphorylation. are disrupted coincident with a change from an
Indeed, various tyrosine kinases such as src and FAK epithelial to a more fibroblast-like morphology and
localize to focal adhesions. Assembly of focal adhesions an increase in invasiveness. In these ras-transformed
(i.e. binding of ECM components to integrins) results in cells, fi-catenin is tyrosine phosphorylated and its
tyrosine phosphorylation of ppl25 FAK and paxillin [45]. interaction with E-cadherin is decreased. Inhibition
Presumably disassembly may require dephosphorylation of PTK activity abolishes tyrosine phosphorylation of
events mediated by a PTP. Consistent with this idea, p-catenin, restoring binding to E-cadherin and the
treatment of Madin-Darby canine kidney (MDCK) cells epithelial morphology [53*]. Similar effects are observed
with a PTP inhibitor, pervanadate, led to an increase in MDCK cells transformed by a temperature-sensitive
in the amount of focal adhesions present in high mutant of V-X [54]: at the permissive temperature,
density cultures [47]. Similarly, pervanadate treatment tyrosine phosphorylation of fi-catenin and E-cadherin
of neutrophils induced cell spreading on the substratum was observed to coincide with the epithelial to fibroblast
[481. change in morphology. After switching back to the
non-permissive temperature, the epithelial morphology
Interestingly, the LAR PTP has been shown recently was rapidly restored, implying rapid dephosphorylation
to localize to focal adhesions [49*]. More importantly, of the cadherin-catenin complex by a PTP [54]. In
LAR appears to bind to proximal ends of focal addition, treatment of rat fibroblasts with vanadate,
adhesions that are presumably undergoing disassembly. a general PTP inhibitor, inhibited cadherin-mediated
This localization is mediated by the interaction of adhesion, highlighting the importance of PTPs in main-
LAR with a novel cytoplasmic protein of 160 kDa, taining the cadherin-catenin complex in a functional,
termed LAR-interacting protein 1 (LIP.l), which binds dephosphorylated state [55]. Until recently, the PTPs
to the second, membrane-distal PTP domain of LAR involved in regulating cadherin-mediated adhesion were
which is thought to be catalytically inactive [49-l. LIP.1 unknown, however it now appears that PTPp may serve
contains coiled-coil a-helical domains that are found in a such a function.
number of cytoskeletal proteins and allow self-association
into homodimers or higher-order structures [40*]. This
potential for self-association of LIP.1 could promote PTPp associates with cadherins and catenins
dimerization of the LAR protein which may affect One novel structural feature of PTPp is its juxtamem-
enzymatic activity. LIP 1 is not a tyrosine-phosphorylated brane segment which is -70 residues longer than the
protein and is therefore unlikely to be a substrate for equivalent segment in other RPTPs and is homologous
LAR. It has been proposed that LIP.1 serves to anchor to the intracellular segment of members of the cadherin
LAR to focal adhesions, thus directing the PTP to its family [56]. This is the segment of the cadherins that is
substrates and facilitating control of the assembly and essential for their adhesive function and which indirectly,
disassembly of adhesion plaques. through the binding of catenins, targets their interaction
with the actin cytoskeleton. This led us to speculate that
this region of PTPp may associate with the cytoskeleton
Adherens junctions through an interaction with a cadherin- or catenin-like
Adherens junctions are composed of various proteins molecule.
linking the membrane to the actin cytoskeleton. The
integral membrane components include the cadherin Recently, we demonstrated that PTPp associates with a
family of cell-cell adhesion molecules. The extracellular complex containing cadherins, a-catenin and p-catenin
calcium-binding segment of the cadherin mediates in mink lung (MvLu) cells and in rat heart, lung
cell-cell aggregation by a homophilic mechanism. The and brain tissues [57’]. Greater than 80% of the
cytoplasmic domain interacts with three molecules total cellular cadherin is associated with PTPp in
termed catenins (a-, p- and y-catenin) which associate MvLu cells. 1~ vitro binding studies demonstrated that
with cortical actin (reviewed in [50*]). a-catenin the intracellular segment of PTPp binds directly to
is homologous to the cytoskeleton-associated protein the intracellular domain of E-cadherin, but not to
vinculin. p-catenin is homologous to plakoglobin and to a-catenin or fl-catenin. Consistent with their ability
armadillo, the product of a Drosopt~ila segment polarity to interact irl vim, PTPp, cadherins and catenins all
gene. The association with catenins appears to be crucial localized to points of cell-cell contact in MvLu cells,
to the adhesive function of cadherins. as assessed by immunocytochemical staining. Following
 Protein tyrosine phosphatases as adhesion receptors Brady-Kalnay and Tonks 655

Promotes adhesion
to permit rapid reversible tyrosine phosphorylation and
)estabilizes adhesion
modulation of the strength of cadherin-driven adhesive
reactions during processes such as migration and cell
division. In addition, our data and that of others suggest
that, for adhesion in normal cells, the cadherins are
normally maintained in a dephosphorylated state, at
least in part by PTPp. The potential importance of
cadherin-associated PTPs, such as PTPp, is clear when
one considers that tyrosine phosphorylation of the
cadherin-catenin complex can lead to loss of cell-cell
adhesion, transformation and metastasis.

Conclusions
Phosphorylated PTPp -Pi Dephosphorylated
cadherin-catenin cadherin-catenin A considerable body of evidence now demonstrates that
complex complex RPTPs mediate and/or modulate cell adhesion. Future
0 1995 Current Opinion in Cell Biolog
studies should focus on defining the effect of RPTPs
on intracellular signaling. This should lead to a greater
understanding of the role of cell contact in regulating
Fig. 2. This is a schematic representation of the effects of tyrosine
phosphorylation on the cadherins and the role of PTPp in the regu-
cell growth and development and how such signaling
lation of their adhesion. Tyrosine phosphorylation of cadherins and events are disrupted to produce the aberrant adhesion
catenins (mediated by protein tyrosine kinases, PTKs) reduces ad- and growth of tumor cells.
hesion. This event is opposed by the activity of protein tyrosine
phosphatases (PTPs), such as PTPp, which promote adhesiveness
by maintaining cadherins in the functional, dephosphorylated state.
Acknowledgements
See Figure 1 for explaination of symbols. a, fi, y represent a-, B- and
y-catenin, respectively.
Work in the authors’ laboratory is supported by grants from
pervanadate treatment of MvLu cells, which inhibits the National Institutes of Health (CA53840 and CA53840).
cellular tyrosine phosphatase activity including that of The Council for Tobacco Research and the Mellam and
Goldring Family Foundations. NK Tonks is a Pew Scholar
PTP& the cadherins associated with PTPp are now
in the Biomedical Sciences and S Brady-Kalnay is supported
found in a tyrosine-phosphorylated form, indicating by an NIH Training Grant fellowship (5T32CA09311).
that the cadherins may be an endogenous substrate
for this enzyme. These data suggest that PTPp may
be one of the enzymes that regulates the dynamic References and recommended reading
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cadherin-catenin complex in vivo. Therefore, rather Further comment on selected papers (a), published within the annual
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Due to the restricted tissue distribution of PTPp, phosphatases: functional and evolutionary implications. Semin
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similarity at the amino acid level to PTPp, including the 4. Rao Y, Wu X, Cariepy J, RutishauserU, Siu C: Identification
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656 Cell-to-cell contact and extracellular matrix
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/ Biol Chem 1994, 269:28472-28477.
In this study, various fragments of the extracellular segment of PTPp were
used in binding assays in vitro. In addition, the interaction between these
fragments and PTPp as it is normally expressed on the surface of mink
lung cells was investigated. These experiments demonstrate that the site
of homophilic binding resides in the Ig domain of PTPp.
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. WH, Cebbink M: Homophilic interactions mediated by
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This study demonstrates that, despite their close structural similarity,
PTPp and PTPK do not bind heterophilically; that is, homophilic binding
interactions involving these molecules are highly specific. The authors
imply that the MAM domain of PTPp contains the homophilic binding
site; however, their data are more consistent with a role for this domain
in ‘sorting’ PTPp from closely related molecules.
16. Stitt TN, Conn G, Gore M, Lai C, Bruno J, Radziejewski
. C, Mat&son K, Fisher J, Gies DR, Jones PF et al.: The
anticoagulation factor protein S and its relative, gas6, are
ligands for the tyro 3/axl family of receptor tyrosine kinases.
Cell 1995, 80:661-670.
See annotation [17*1.
17. Bellosta P, Costa M, Lin DA, Basilic0 C: The receptor tyrosine
. See annotation 132.1.
kinase Ark mediates cell aggregation by homophilic binding.
MO/ Cell Biol 1995, 15:614-625.
This paper and [16*1 illustrate that the specificity of ligand binding to
the axl/ark protein tyrosine kinase may vary with cell density. At low cell
density there is a heterophilic interaction with a soluble ligand, whereas
at high cell density homophilic binding interactions prevail.
1 a. Zinn K: Drosophila protein tyrosine phosphatases. Semin Cell
Eiol 1993, 4397-401.
19. Tian S, Zinn K: An adhesion molecule-like protein that interacts
with and is a substrate for a Drosophila receptor-linked protein
tyrosine phosphatase. ) Biol Chem 1994, 269:28478-28486.
20. Peles E, Nativ M, Campbell PL, Sakurai T, Martinez R, Lev
. S, Clary DO, Schilling J, Barnea G, Plowman CD et al.: The
carbonic anhydrase domain of receptor tyrosine phosphatase
p is a functional lignad for the axonal recognition molecule
contactin. Cell 1995, B2:251-260.
The authors make the exciting observation that the carbonic anhydrase
domain in the extracellular segment of PTPfl binds specifically
to contactin, a glycosylphosphatidylinositol-anchored neuronal cell
recognition molecule. This domain of PTPrjB can act as a substrate
for neuronal adhesion and the induction of neurite outgrowth and
differentiation in a manner that is dependent on the presence of
contactin on the surface of the neurons. These observations suggest that
interactions between PTP&@ and contactin may underlie a mechanism
of unidirectional or bidirectional signaling between cells during neuronal
development.
21. Barnea G, Grumet M, Milev P, Silvennoinen 0, Levy 1, Sap J,
. Schlessinger J: Receptor tyrosine phosphatase fI is expressed in
the form of proteoglycan and binds to the extracellular matrix
protein tenascin. ] Bio/ Chem 1994, 26914349-14352.
See annotation [26*J.
22. Maeda N, Hamanaka H, Shintani T, Nishiwaki T, Noda M:
Multiple receptor-like protein tyrosine phosphat&es in the
form of chondroitin sulfate proteoglycan. FEBS Left 1994,
354167-70.
23. Shitara K, Yamada H. Watanabe K. Shimonaka M. Yamaeuchi
Y: Brain-specific receptor-type protein-tyrosine phosph%se
RPTPg is a chondroitin sulfate proteoglycan in vivo. / Viol
Chem 1994, 269:20189-20193.
24. Grumet M, Milev P, Sakurai T, Karthikeyan. L, Bourdon
M, Margolis RK, Margolis RU: Interactions with tenascin
and differential effects on cell adhesion of neurocan and
phosphacan, two major chondroitin sulfate proteoglycans of
nervous tissue. I Biol Chem 1994, 269:12142-l 2146.
25. Maurel P, Rauch U, Flad M, Margolis RK, Margolis RU:
Phosphacan, a chondroitin sulfate proteoglycan of brain that
interacts with neurons and neural cell-adhesion molecules, is
an extracellular variant of a receptor-type protein tyrosine
phosphatase. Proc Nat/ Acad Sci USA 1994, 91:2512-2516.
26. Milev P, Friedlander D, Sakurai T, Karthikeyan L, Flad M,
. Margolis RK, Grumet M, Margolis RU: Interactions of the
chondroitin sulfate proteoglycan phosphacan, the extracellular
domain of a receDtor-tvw Drotein tvrosine ohosohatase. with
neurons, glia and’ neuri c&l adhesion mol&d&. / Cei/ Biol
1994, 127:1703-1715.
This paper and 121.1 describe a heterophilic interaction between the
extracellular segment of an RPTP and cell adhesion molecules.
27. Cannoll P, Barnea G, Levy 1, Sap U, Ehrlich M, Silvennoinen 0,
Schlessinger J, Musacchio 1: The expression of a novel receptor-
type tyrosine phosphatase suggests a role in morphogenesis
and plasticity of the nervous system. Dev Brain Res 1993,
75:293-298.
28. Spring J, Beck K, Chiquet-Ehrismann R: Two contrary functions
of tenascin: dissection of the active sites by recombinant
tenascin fragments. Cell 1989, 59:325-334.
29. Trowbridge IS, Thomas ML: CD45: an emerging role as
a protein tyrosine phosphatase required for lymphocyte
activation and development. Annu Rev lmmunol 1994,
12:85-l 16.
30. Spertini F, Wang AVr, Chatila T, Geha RS: Engagement of the
. common leukocyte antigen CD45 induces homotypic adhesion
of activated human T cells. ) lmmunol 1994, 153:1593-1602.
31. Bernard G, Zoccola D, Ticchioni M, Breittmayer JP,
. Aussel C. Bernard A: Engagement of the CD45 molecule
induces homotypic adhesiin- of human thymocytes through
a LFA-l/ICAhG3-dependent pathway. / lmmunol 1994,
151:5162-5170. -
See annotation [32*].
32. Arroyo AC, Campanero MR, Sanchez-Mateos P, Zapata
. JM, Angeles Ursa MA, Del Pozo MA, Sanchez-Madrid F:
Induct&n of tyrosine phosphorylation .during ICAM- and
LFA-l-mediated intercellular adhesion, and its regulation
by the CD45 tyrosine phosphatase. / Cell Sior 1994,
126:1277-l 286.
This paper and [30*,31 ‘I describe the demonstration that engagement of
the extracellular segment of CD45 with specific monoclonal antibodies
modulates homotypic adhesion in human lymphocytes. It is suggested
that rather than steric interference with adhesion, binding of antibody
to the extracellular segment of CD45 modifies its protein tyrosine
phosphatase activity which modulates a tyrosine phosphorylation
dependent, adhesion-induced signal.
33. Wagner N, Engel P, Tedder TF: Regulation of the tyrosine
kinase-dependent adhesion pathway in human lymphocytes
through CD45. / lmmunol 1993, 150:4887-4899.
34. Sgroi D, Varki A, Braesch-Andersen S, Stamenkovic I: CD22, a
B cell-specific immunoglobulin superfamily member, is a sialic
acid-binding lectin. J Biol Chem 1993, 266:701 l-701 8.
35. Shimizu Y, Shaw S: Mucins in the mainstream. Nature 1993,
366:63&631.
36. Sgroi D, Koretzky GA, Stamenkovic I: Regulation of CD45
. engagement by the B-cell receptor CD22. Proc Nat/ Acad Sci
USA 1995, 92:402&4030.
 Protein tyrosine phosphatases as adhesion receptors Brady-Kalnay and Tonks 657

This oaoer and [37*] report the identification of potential physiological This is an intriguing example of the potential regulation of the
liganbs’for CD45. Binding of CD22 to CD45 amplifies early signals physiological function of a PTP by restriction of its subcellular
through theT-cell receptor, raising the possibility that this interaction may distribution.
modulate the protein tyrosine phosphatase activity of CD45.
50. Cowin P: Unraveling the cytoplasmic interactions of the
. cadherin suoetfamilv. Proc Nal/ Acad Sci USA 1994,
37. Coombe DR, Watt SM, Parish CR: Mac-l (CDllb/CD18) and
. CD45 mediate the adhesion of hematopoietic progenitor cells
91:10759-10761. ’
This is an excellent review of the proteins that interact with the
to stromal cell elements v-a recognition of stromal heparan
cadherin family of cell adhesion molecules and the significance of these
sulfate. Blood 1994, 3:739-752.
associations.
See annotation [36*].
51. Shibamoto S, Hayakawa M, Takeuchi K, Hori T, Oku N,
38. Pallen CJ, Tong PH: Elevation of membrane tyrosine . Miyazawa K, Kitamura N, Takeichi M, Ito F: Tyrosine
phosphatase activity in density-dependent growth-arrested phosphorylation of kcatenjn and plakoglobin enhanced by
fib&lasts. Proc Nat/ Acad Sci USA 1991, 88:6996-7000. hepatocyte growth factor and epidermal growth factor
in human carcinoma cells. Cell Adhesion Commun 1994,
39. Brady-Kalnay SM, Tonks NK: Receptor protein tyrosine
1:295-305.
phosphatases, cell adhesion and signal transduction. Adv Prot
See annotation L53.1.
Phosphatases 1994, 8:241-274.
52. Kemler R: From cadherim to catenins: cytoplasmic protein
40. Mishra S, Hamburger A: 0.phospho-1.tyrosine inhibits cellular interactions and regulation of cell adhesion. Trends Genet
growth by activating protein tyrosine phosphatases. Cancer Res 1993, 9:317-321.
1993, 53:557-563.
53. Kinch MS, Clark Cl, Der Cl, Burridm K: Tvrosine phospho-
41. &man A, Yam? 0, Tonks NK: Expression of DEP.1, a receptor- . rylation regulates the adhesions of ras-t&sformeb breast
. like prote&&si~e-phosphatase; is enhanced with in&sing epithelia. 1 Cell Biol 1995, 1301461-471.
cell density. Proc /Vat/ Acad Sci USA 1994, 91:9680-9684. This pa& and [51*,54,551 illustrate the potential importance of
This paper reports’the isolation and characterization of a specific RPTP, reversible tyrosine phosphorylation in controlling the adhesive function
the expression of which varies with cell density and which may play a of cadherins.
role in contact inhibition of cell growth.
54. Behrens J, Vakaet L, Friis R, Winterhager E, Van Roy F, Mareel
MM, Birchmeier W: loss of epithelial differentiation and
42. Streuli M, Krueger N, Ariniello P, Tang M, Munro J,
Blattler W, Adler D, Disteche C, Saito H: Expression of eain of invasiveness correlates with tvrosine ohosohorvlatiop
the LAR: proteolytic cleavage and shedding of the CAM-like Gf the E-cadherin/p catenin comple; in ceils &a&ormed
extracellular region. EMBO / 1992, 11:897-907. with a temperature-sensitive v-SRC gene. / Cell Biol 1993,
1201757-766.
43. Kirkpatrick C, Peifer M: Not just glue: cell-cell junctions as Matsuyoshi N, Hamaguchi M, Taniguchi S, Nagafuchi A,
55.
cellular signaling centers. Curr Opin Genet Dev 1995, 5:56-65. Tsukita S, Takeichi M: Cadherin-mediated cell-cell adhesion
is perturbed by v-src tyrosine phosphorylation in metastatic
44. Tsukita S, Tsukita S, Nagafuchi A, Yonemura S: Molecular
fibroblasts. / Cell Biol 1992, 118:703-714.
linkage between cadherim and actin filaments in cell-cell
adherens junctions. Curr Opin Cell Biol 1992, 4834-839. 56. Tonks NK, Yang Q, Flint A, Cebbink M, Franza 8, Hill D,
Sun H, Brady-Kalnay SM: Protein tyrosine phosphatases: the
45. Schaller MD, Parsons JT: Focal adhesion kinase: an integrin- problems of a growing family. Co/d Spring Harbor Symp @ant
linked protein tyrosine kinase. Trends Cell Biol 1993, Bio/ 1992, 57:87-94.
31258-262.
57. Brady-Kdnay SM, Rimm DL, Tonks NK: The receptor protein
46. Dunlevy JR, Couchman JR: Controlled induction of focal . tyrosine phosphatase PTPp associates with cadherins and
adhesion disassembly and migration in primary fibroblasts. catenins in vivo. 1 Cell Biol 1995, 130:977-986.
1 Cell Sci 1993, io5:489-500. This report identifies a specific RPTP, PTPp, as a potential regulator of
the adhesive function of cadherins.
47. Volberg T, Zick Y, Dror R, Sabanay I, Cilon C, Levitz A, Geiger
B: The effed of tyrosine-specific protein phosphorylation 58. Jiang VP, Wang H, D’Eustachio PD, Musacchio JM, Schlessinger
on the assembly of adherens-type junctions. FMBO j 1992, J, Sap J: Cloning and characterization of R-PTP-K, a new
11:1733-l 742. member of the receptor protein tyrosine phosphatase family
with a proteolytically cleaved cellular adhesion molecule-like
48. Bennett P, Dixon R, Kellie S: The phosphotyrosine phosphatase extracellular region. MO/ Cell Bio/ 1993, 13:2942-2951.
inhibitor vanadyl hydroperoxide induces morphological alter-
ations, cytoskeletal rearrangements and increased adhesiveness
in rat neutrophil leucocytes. 1 Cell Sci 1993, 106:891-901. S Brady-Kalnay, Department of Molecular Biology, Case Western
Keserve University, Cleveland, Ohio 44106, USA.
49. Serra-Pages C, Kedersha NL, Fazikas L, Medley Q, Debant A,
NK Tonks, Cold Spring Harbor Laboratory, Demerec Building,
. Streuli M: The LAR transmembrane protein tyrosine phos-
phatase and a coiled-coil LAR-interacting protein colocalize 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
at focal adhesions. EMBO / 1995, 14:2827-2838. Author for correspondence: NK Tonks.