Biochem. J. (2011) 439, 195–205 (Printed in Great Britain)
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doi:10.1042/BJ20110903
REVIEW ARTICLE
PDZ domains: the building blocks regulating tumorigenesis
Vanitha Krishna SUBBAIAH1 , Christian KRANJEC1 , Miranda THOMAS and Lawrence BANKS2
International Centre for Genetic Engineering and Biotechnology, Padriciano 99, I-34012 Trieste, Italy
Over 250 PDZ (PSD95/Dlg/ZO-1) domain-containing proteins
have been described in the human proteome. As many of these
possess multiple PDZ domains, the potential combinations of
associations with proteins that possess PBMs (PDZ-binding
motifs) are vast. However, PDZ domain recognition is a highly
specific process, and much less promiscuous than originally
thought. Furthermore, a large number of PDZ domain-containing
proteins have been linked directly to the control of processes
whose loss, or inappropriate activation, contribute to the
development of human malignancies. These regulate processes as
diverse as cytoskeletal organization, cell polarity, cell proliferation
and many signal transduction pathways. In the present review,
we discuss how PBM–PDZ recognition and imbalances therein
can perturb cellular homoeostasis and ultimately contribute to
malignant progression.
INTRODUCTION
STRUCTURAL BASIS OF PDZ–PBM RECOGNITION
The PDZ domain-containing family of proteins were first
recognized in the early 1990s and were classified as such,
by having stretches of amino acids in common with the first
such members to be identified, PSD95 (postsynaptic density
protein 95), Dlg (discs large) and ZO-1 (zonula occludens protein
1), hence the origin of the name [1]. They are found from
bacteria to vertebrates [2] and are involved in an extremely
large number of activities within the cell, including control of
cell migration and invasion, cell proliferation, cell polarity, cell
attachment and cell–cell contact, apoptosis and immune
cell recognition and signalling. PDZ domains themselves are sites
of protein–protein interaction, and, as many of these proteins have
multiple PDZ domains capable of multiple protein interactions,
they are generally considered, somewhat simplistically, to act
as scaffolding molecules, around which multi-protein signalling
complexes are assembled.
Before discussing how PDZ domain-containing proteins might
affect tumorigenesis, we need to consider the molecular basis for
PDZ domain recognition. It is often impossible to separate the
functions of PDZ domain proteins from those of their ligands
that possess PBMs (PDZ-binding motifs). Therefore one must
always remember that this is a two-way interaction where, for
example, the PDZ domain-containing protein may exert tumoursuppressor activity by regulating the activity of a PBM-containing
ligand, such as Scribble with β-Pix [3]. Conversely, a PBM ligand
may act directly on, and inactivate or sequester, a PDZ domaincontaining partner, for example, the interaction between the HPV
(human papillomavirus) E6 oncoprotein and Dlg [4].
PDZ domains are regions of usually 80–90 amino acid residues,
all having certain defining structural elements: six β-sheets (βA–
βF) and two α-helices, one short (αA) and one long (αB) [5–7].
These are shown as a cartoon in Figure 1(A), aligned with each
of the three PDZ domains of human Dlg1. Although there is
considerable variation in the length and structure of the linking
sequences, these conserved elements form a highly conserved
fold, which contains the carboxy-binding loop, between the
βA and βB sheets [5,6]. This is the so-called GLGF motif,
actually R/K-X-X-X-G--G- where X is any residue and is a hydrophobic residue; the side chains of these residues form
the hydrophobic pocket that provides the binding activity of PDZ
domains [5,8]. In fact, apart from the totally conserved second
glycine residue, the exact residues forming the GLGF motif can
vary quite significantly and thus contribute to binding specificity.
The canonical PDZ-binding domains fold to bring the N- and Ctermini of the domain close together at the ‘back’ of the structure,
while the binding groove is formed by the βB sheet and αB
helix, with the GLGF motif at the end, reminiscent of the contact
point in an electric socket. The shape of a correctly folded PDZ
domain is shown in Figure 1(B), based on the crystal structure
of the Dlg PDZ domain 2 [7]. It has been shown in the PDZ2
domain of PSD95, that the loop connecting the βA and βB sheets
(which contains the GLGF motif), and the loop connecting the
αB helix and βF sheet both retain flexibility in solution, whereas
the remainder of the structure is relatively rigid [9]. It is easy
to envisage that the flexibility of the loops could allow the rigid
elements to move relative to one another, facilitating the insertion
Key words: cancer, cell invasion, cell polarity, PDZ domain,
tumour virus.
Abbreviations used: AF-6, ALL1-fused gene from chromosome 6; APC, adenomatous polyposis coli; aPKC, atypical protein kinase C; Bcr, breakpoint
cluster region; CADM1, cell adhesion molecule 1; Cdc42, cell division cycle 42; Daam1, Dishevelled-associated activator of morphogenesis 1; Dlg,
discs large; Dvl, Dishevelled; EMT, epithelial–mesenchymal transition; ERK, extracellular-signal-regulated kinase; FAP-1, Fas-associated phosphatase 1;
GEF, guanine-nucleotide-exchange factor; GIPC1, GAIP (Gα -interacting protein)-interacting protein C-terminus 1; HPV, human papillomavirus; HTLV-1,
human T-cell leukaemia virus type 1; IGF-1, insulin-like growth factor 1; LARG, leukaemia-associated Rho-GEF; LNX1, Ligand of Numb protein X1; MAGI,
membrane-associated guanylate kinase with inverted domain structure; MyoGEF, myosin-interacting GEF; NHERF-1, Na + /H + -exchanger regulatory
factor 1; Par, partitioning defective; PBM, PDZ-binding motif; PDZ, PSD95/Dlg/ZO-1; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PSD95,
postsynaptic density protein 95; PTEN, phosphatase and tensin homologue deleted on chromosome 10; PTP, protein tyrosine phosphatase; RhPV, rhesus
papillomavirus; RIL, reversion-induced LIM protein; ROCK, Rho-associated kinase; S1P, sphingosine 1-phosphate; S1P1, S1P receptor 1; Smurf1, Smad
ubiquitylation-regulatory factor 1; Tiam1, T-cell lymphoma invasion and metastasis 1; TJ, tight junction; TRIP6, thyroid receptor-interacting protein 6; ZO,
zonula occludens protein.
1
These authors contributed equally to this review.
2
To whom correspondence should be addressed (email [email protected]).
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Figure 1
V. K. Subbaiah and others
PDZ domain structure
(A) Cartoon in linear format of the structural elements that compose a PDZ domain (based on data taken from [129]) aligned with the PDZ domains 1 (amino acids 218–308), 2 (amino acids
313–403) and 3 (amino acids 459–544) of human Dlg1 (hDlg) (GenBank® accession number NM_001098424.1). (B) Cartoon showing the folding of the structural elements in (A), based on the
crystal structure of Dlg PDZ2 [38] (PDB code 2I0L). The proximity of the N- and C-termini can be seen. (C) Cartoon showing the binding of a PBM, in this case the six C-terminal amino acids of
HPV-18 E6 (RRETQV), to the Dlg PDZ2 [38] (PDB code 2I0L). The baseline binding provided by valine and threonine residues is shown as yellow broken lines and the specific binding interactions
of the glutamine (Q2) and arginine (R5) residues are shown as red broken lines.
of the binding ligand, whereas the rigidity of the basic structure
would keep the domain in binding readiness, even in the absence
of a ligand.
The discussion above refers to simple PDZ structures, but as
PDZ domains are often found in multiples on the same protein, it is
clear that they may not necessarily work in isolation. Indeed, some
PDZ domains function in tandem, structurally stabilizing each
other, as in the case of the GRIP1 (glutamate-receptor-interacting
protein 1) tandem [10,11]. The PDZ1/PDZ2 domains of PSD95
and of Dlg may also function as tandems in order to bind certain
dimeric ligands [11,12], but they have also been shown to function
independently.
Another structural variation is dimerization, which can be either
interdomain or intradomain. In interdomain dimerization, the PDZ
domain of one protein molecule binds the PDZ domain of another;
usually ‘back-to-back’ and antiparallel, allowing two ligands to be
bound simultaneously and in close proximity. Such dimers have
been shown for MAGI (membrane-associated guanylate kinase
with inverted domain structure)-1 PDZ1 [7] and Shank1 PDZ
[13]. In intradomain dimers, two protein molecules intertwine
forming two PDZ domains, with each molecule providing part
of one domain and part of the other. However, these have only
been described in the ZO-1 and ZO-2 proteins [14,15], where
this type of PDZ domain structure appears to modulate the PBMcontaining ligand, such as the polymerization of claudins through
binding ZO-2 and the regulation of connexin43 through binding
ZO-1 [15,16].
c The Authors Journal compilation c 2011 Biochemical Society
A note of caution should be added at this stage. As will be
seen below, many PDZ domains and PBMs are reported to have
multiple protein partners and it is often difficult to determine
which are biologically relevant. This is often due to the context
in which the interactions have been analysed: at low stringency, a
class I PBM could bind any class I PDZ, and obviously this is not
the situation in vivo. This is perfectly illustrated with the example
of E6 and Dlg, where in vivo recognition is known to occur
through PDZ domain 2, yet under in vitro conditions, including
crystallization, E6 can also associate with PDZ domain 3 [7].
PDZ-binding motifs
As the PDZ domains have a variety of structural characteristics to
give specificity to their interactions, so too do the PBMs of their
ligands.
PDZ domains have traditionally been classified by the sequence
of the PBM that binds them, the exact number of classes depending
on the criteria used. PBMs are short amino acid motifs, usually
found at the extreme C-termini of PDZ-binding proteins [17],
although internal PBMs exist [18,19]. In general, the ligand inserts
the C-terminal PBM into the binding fold of the PDZ domain
to contact the GLGF motif. In Class I PDZ domains, the PBM
binds the fold as a β-strand antiparallel to the βB strand and
parallel to the αB helix of the PDZ domain; baseline binding
being provided by the ligand’s C-terminal -COOH contact with
PDZ domains
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PKA phosphorylation of Class III ligands can enhance binding
[25]. Phosphorylation of the PDZ domain can also regulate
PBM recognition, with phosphorylation either inhibiting or
increasing the interaction, depending on the particular PDZ–PBM
combination [26,27]. In short, it is clear that modifications to
the PDZ-binding activity can have major downstream effects,
emphasizing the importance of control of PDZ interactions
in cellular homoeostasis, many of which may well be disrupted in
malignancy.
ONCOGENIC VIRUSES AND PDZ DOMAIN-CONTAINING PROTEINS
Figure 2
the PBM
PDZ domain classes are defined by the consensus sequence of
Based on data taken from [21].
the GLGF loop; and by the serine/threonine residue contacting a
conserved histidine residue in the αB helix [7]; this is shown in
cartoon form in Figure 1(C).
Traditionally, PDZ domains were classified into classes I–V,
depending on the consensus sequences of the PBMs. However,
studies showing that five, six [7] or even seven [20] amino acid
residues of the PBM can be involved in binding prompted an
analysis of 72 PDZ domains that gave a classification having 16
subclasses [21]. This classification is shown in an abbreviated
form in Figure 2, where it can be seen that even this system leaves
considerable flexibility. Thus the robustness of basic binding
combined with the variations in specificities induced by variation
of either the PDZ domain or the ligand combine to provide a
strong evolutionary pressure towards refining binding specificity.
Control of PDZ binding
Since many PDZ–PBM interactions involve signalling molecules,
it must be assumed that, in addition to having exquisite binding
specificity, there must also be a means of control. Many PBMs
have PKA (protein kinase A)-recognition sequences embedded
within the motif and subsequent PKA phosphorylation can
block the PBM–PDZ recognition, as in the case of Kir2.3
with PSD95 [22], and HPV E6 with Dlg [23]. Interestingly,
phosphorylation of the PTEN (phosphatase and tensin homologue
deleted on chromosome 10) PBM also blocks Dlg and MAGI
binding, but may stimulate binding to other targets [24], whereas
The demonstration that certain human tumour virus oncoproteins
could target PDZ domain-containing substrates provided an
exciting early indication of their relevance in the development
of human tumours.
One of the first suggestions that PBMs might confer oncogenic
potential and, by implication, that their PDZ domain-containing
substrates might have tumour-suppressor potential, came from
studies in a mouse model of mammary tumorigenesis. In
this system, adenovirus 9 E4ORF1 protein exhibited potent
transforming potential, which was dependent on an intact
PBM [28]. The precise contributions of specific PDZ domaincontaining substrates have remained elusive, although Dlg and
MAGI-1 appear to be good candidates as tumour suppressors in
this system [29]. However, studies suggest that, rather than simply
inhibiting Dlg function, the adenovirus 9 E4ORF1 interaction may
actually alter Dlg function such that it becomes pro-oncogenic
[30].
A particularly exciting development was the realization that
oncogenic HPVs, the causative agents of cervical cancer, also
encode an oncoprotein possessing a PBM [28,31]. Intriguingly,
only those HPV types that cause cervical cancer, so called ‘highrisk’ types, such as HPV-16 or HPV-18, possess an E6 oncoprotein
with PDZ-binding potential. Low-risk viruses, which cause
benign lesions, such as HPV-6 and HPV-11, do not have PBMs
on their E6 proteins. In addition, an intact PBM on E6 is essential
for many of E6’s associated activities, including the normal viral
life cycle, induction of EMT (epithelial–mesenchymal transition)
and induction of malignancy in transgenic mouse models [32].
Since continued E6 expression is required for maintenance of
the malignant phenotype in cervical tumours [33], this suggests
that E6 PBM–PDZ interactions play critical roles during the
viral life cycle and at different stages of malignant progression.
Another human tumour virus HTLV-1 (human T-cell leukaemia
virus type 1) also encodes an oncogene, Tax, which has a PBM,
through which it interacts with Dlg [28]. Unlike E6, Tax does not
seem to be involved in the later stages of disease, but an intact
PBM does seem essential for the capacity of Tax to transform cells
[34], suggesting that PBM–PDZ interactions might contribute to
tumour initiation by HTLV-1.
A great deal of attention has been paid to identifying
relevant PDZ domain-containing proteins for HPV-induced
carcinogenesis. Currently over ten such substrates of HPV-16 and
HPV-18 E6 have been described [32]. Which of these are critical
players in HPV-induced transformation remains to be elucidated.
This is complicated by the fact that different HPV E6 oncoproteins
target different PDZ domain-containing substrates with different
efficiencies. Because of single amino acid differences in the
PBMs, HPV-16 E6 interacts with Scribble, whereas HPV-18 E6
prefers Dlg [35]. Both are essential regulators of the cell polarity
control module, with perturbation of either being expected to
disturb the function of the whole complex [36]. However, the
precise outcome for viral-induced tumorigenesis is likely to be
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V. K. Subbaiah and others
different, depending on the choice of PDZ domain-containing
substrate by the different HPV E6 oncoproteins.
In human cells, the function of Dlg is still open to question,
although it has been linked with two known tumour suppressors,
APC (adenomatous polyposis coli) and PTEN (see below) and
two proto-oncogenes, PI3K (phosphoinositide 3-kinase) and Net1
(see below). Significantly more is known about Scribble. It has
been shown to be a potent regulator of the Ras/MAPK (mitogenactivated protein kinase) signalling pathway, with mutations in
or loss of human Scribble co-operating with activated Rasinduced carcinogenesis; similar results have also been found with
the c-Myc oncogene [37,38]. In both cases, Scribble appears
to function partly by down-regulating the ERK (extracellularsignal-regulated kinase) signalling pathway, possibly via direct
interaction with ERK [39]. Scribble also directly regulates the
JNK (c-Jun N-terminal kinase) signalling pathway and this
contributes to oncogene-induced transformation, and affects the
susceptibility of cells to enter apoptosis [40]. Thus Scribble can
be considered to be a true tumour suppressor in these models of
tumorigenesis. What about in human tumours? Certainly in many
cancers of cervix, breast and colon [41,42], Scribble protein levels
decrease dramatically as the tumours progress, and, by late-stage
metastatic cancer, the levels are invariably very low. However,
in pre-malignant cervical cancer, and in some other tumours
[43], Scribble is often overexpressed and mislocalized, suggesting
that aberrant patterns of expression might also contribute to
tumorigenesis, depending on the particular context.
Another intriguing PDZ target of HPV E6 was found to
be MAGI-1 [44]. As noted below, this is implicated in many
pathways, including the potential regulation of the PTEN tumour
suppressor. However, in the context of HPV-induced malignancy,
no alterations in PTEN signalling have been reported. However,
like most multi-PDZ domain-containing proteins, MAGI-1 is
multifunctional, and also has a role in the regulation of TJs
(tight junctions): the capacity of E6 to bind and degrade MAGI-1
correlates perfectly with the capacity of the virus to perturb TJ
assembly [45].
RhPV (rhesus papillomavirus) induces cervical cancer in the
rhesus macaque, and interestingly was found to have a PBM on
the E7 oncoprotein instead of E6. A proteomic screen of
interacting partners identified Par3 (partitioning defective 3) (see
below) as the PDZ domain-containing partner [46]. This was an
exciting observation since Par3 functions in the same pathway
of polarity control as Scribble and Dlg. While not wishing to
overinterpret a single study, it is nonetheless intriguing that
multiple studies in human cancers have suggested a role for the
Par complex in tumour development [47], and the demonstration
that cancer-causing RhPV E7 targets this complex supports this.
Thus, although the list of PDZ domain-containing targets
of HPV E6 is probably not complete, this viral protein has
nonetheless directed us towards a small number of cellular PDZ
domain-containing proteins that might be expected to play roles
in the development of human cancers. As we will see from the
following discussion, this seems to be the case for many of these
substrates.
PDZ DOMAINS AND WNT SIGNALLING
Many PDZ-containing proteins are involved in signalling, and
this is particularly striking in the case of Wnt signalling. This
facilitates communication between neighbouring cells through the
secretion of Wnt proteins, which interact with Frizzled receptors,
thereby triggering a signalling cascade in the stimulated cells.
Normally active during embryonic development, the unscheduled
c The Authors Journal compilation c 2011 Biochemical Society
reactivation of Wnt signalling in adult tissues is a hallmark of
tumorigenesis [48].
Central to the Wnt signalling cascade is Dvl (Dishevelled), a
single PDZ domain-containing protein that transduces the signal
from activated Frizzled receptors to the downstream effectors of
the pathway (Figure 3). Dvls bind directly to Frizzled receptors,
the majority of which also have PBMs, in a PDZ-dependent
manner, through an internal PBM located in the intracellular
segment of Frizzled [49].
Depending on the particular combination of Wnt protein and
Frizzled receptor, Dvl can activate the canonical or the noncanonical Wnt signalling pathways [50]. The former involves the
disassembly of the β-catenin destruction complex, resulting in βcatenin stimulation of cell proliferation through the transcriptional
activation of TCF (T-cell factor)/LEF (lymphoid enhancer factor)
target genes [51]. The non-canonical or PCP (planar cell
polarity) pathway, promotes cytoskeleton remodelling and
cell migration [52,53]. This involves Dvl activation of Daam1
(Dvl-associated activator of morphogenesis 1), in a DEP (Dvl,
Egl-10 and pleckstrin)- and PDZ domain-dependent manner.
Active Daam1 and Dvl form a ternary complex with WGEF
[weak-similarity GEF (guanine-nucleotide-exchange factor)],
which in turn leads to the activation of the Rho/ROCK (Rhoassociated kinase) signalling and cytoskeleton remodelling
[53,54]. Both the canonical and non-canonical Wnt pathways
are implicated in tumorigenesis, with the former enhancing
proliferation and in loco tumour formation and the latter
contributing to invasion and cancer progression [55,56].
In human cancers Dvl is frequently overexpressed [57,58],
and a role for Dvl–PDZ interactions in tumorigenesis have
been confirmed using inhibitory compounds, peptides and
mutagenesis. In all cases, loss of PDZ binding potential reduces
tumorigenesis [57,59,60].
PDZ regulation of the tumour suppressor APC
APC plays a fundamental role in the Wnt pathway by promoting
the degradation of β-catenin. Germline mutations in the APC
gene are associated with familial adenomatous polyposis [61],
characterized by hyperplasia of colon epithelial cells, leading to
the formation of polyps, which invariably progress to carcinoma.
APC has multiple protein interaction sites, one of which
includes a C-terminal class 1 PBM [6,62]. The PBM-dependent
interaction with Dlg appears to regulate the correct localization of
APC, with important consequences for the regulation of cell-cycle
progression and cell adhesion [63,64]. The APC PBM also binds
to the PDZ domain of the FAP-1 (Fas-associated phosphatase 1)
tyrosine phosphatase (see below), through which components of
the APC–β-catenin destruction complex can be regulated [65],
and overexpression of FAP-1 inhibits the proliferation of Wnt3astimulated cells in a phosphatase-dependent manner [66].
The APC PBM appears to be critical for some of its tumoursuppressor functions. Although many cancer-causing mutations
occur in the N-terminal half of APC, truncating mutations that
abolish only the PBM have been found in cancers [67,68].
Furthermore, there is compelling experimental evidence linking
the PDZ-binding potential of APC with its ability to influence cell
spreading and regulate cell substratum adhesion, both of which
appear to require association with Dlg [64].
PDZ DOMAINS AND THE REGULATION OF EMT
Although Wnt signalling is a critical regulator of EMT, a number
of other cell signalling pathways are also involved. As can be
PDZ domains
Figure 3
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PDZ domain interactions and the regulation of EMT and Wnt signalling
Schematic diagram of some of the critical regulators involved in the regulation of the canonical and non-canonical Wnt signalling pathways. Interlinked with this are PDZ interactions important in the
regulation of EMT. Proteins possessing PDZ domains are shown in red and those possessing PBMs are shown in blue. β-CAT, β-catenin; CK2, casein kinase 2; GSK-3β, glycogen synthase kinase
3β; PCP, planar cell polarity; TCF, T-cell factor; WGEF, weak-similarity GEF.
seen from Figure 3, many of the critical regulatory steps in these
pathways are subject to regulation by PDZ–PBM combinations.
For example, β-catenin has a PBM through which it can interact
with the PDZ domain-containing proteins MAGI-1 and NHERF1 (Na + /H + -exchanger regulatory factor 1). Likewise, the PTEN
phosphatase, a known tumour suppressor [69], has a PBM which
confers interaction with the PDZ domains of Par3, MAGI-1 and
NHERF-1, which incidentally are also targets of the HPV E6
oncoproteins. Of these, Par3 and NHERF-1 have been closely
linked to cancer development, and MAGI-1 somewhat less so.
Par3 belongs to the Par complex of proteins [Par3, Par6,
Cdc42 (cell division cycle 42) and aPKC (atypical protein kinase
C)] which it recruits to TJs in polarized epithelium in part via
a homotypic PDZ domain interaction with Par6. This in turn
recruits Cdc42 and aPKC [70]. Spatial restriction of this complex
is essential for correct apico-basal polarity, and mislocalization
or overexpression of Par6 and aPKC are common to many
cancers [47]. Par3 also interacts with the Tiam1 (T-cell lymphoma
invasion and metastasis 1) (see below) Rac-GEF [71]; this is
essential for TJ assembly and contributes to the control of
polarized cell migration and of EMT by restricting Rac activity. In
contrast, a pro-oncogenic activity has been indicated for Par6, with
overexpression being linked to increased proliferation and also the
induction of TJ breakdown. Furthermore, TGFβ (transforming
growth factor β)-induced phosphorylation of Par6 increases its
interaction with the ubiquitin ligase Smurf1 (Smad ubiquitylationregulatory factor 1), thereby resulting in RhoA degradation and the
induction of a more mesenchymal phenotype [72]. Thus the PDZ
domain-containing components of the Par complex can function
as promoters and inhibitors of EMT, depending on the balance of
Par3/Par6 activities [47].
The function of the MAGI family of proteins is still poorly
understood, but tumour-suppressor potential was indicated by
their targeting by viral oncoproteins [44], and MAGI-1 expression
is down-regulated in acute lymphoblastic leukaemia [73]. The
MAGI PDZ2 domain binds PTEN, protecting it from proteasomemediated degradation [74], while MAGI PDZ domain 5 can
associate with β-catenin [75], potentially creating a trimeric
β-catenin–MAGI–PTEN complex [76]. This membrane-bound
PTEN down-regulates the PI3K signalling pathway [77], thus
inhibiting several processes related to tumour formation and
cancer progression, including cell growth, survival and migration
[69,77].
Although PTEN is a tumour suppressor [69], the contribution
of its PBM and PDZ domain-containing substrates to this activity
are still unclear, and only one study has described a PTEN
mutant with a defective PBM in human cancers [78]. In addition,
although MAGI-1 is a target of the HPV E6 oncoproteins,
there is scant indication that HPV E6 directly perturbs PTEN
function.
A further intriguing link between the regulation of Wnt
signalling and PTEN and PDZ domain interactions is provided by
NHERF-1. This protein has two PDZ domains, has been reported
to be down-regulated during the development of colon cancer [79]
and mutations have been reported in its PDZ domain in a number
of breast cancers [80]. A recent report also suggests a direct
interaction of NHERF-1 with Frizzled receptors in a PBM–PDZdependent manner, resulting in down-regulation of β-catenin [19].
It had also been shown that NHERF-1 could potentially associate
with PTEN and thereby regulate receptor signalling and PI3K/Akt
activity [81]. Furthermore, NHERF-1 has recently been found to
be a target of HPV-16 E6 [81a], an activity also linked to increased
PI3K signalling and Akt activity. Thus, although the roles of
the PDZ interactions of NHERF-1, particularly with PTEN, are
the subject of some debate, it seems highly likely that some of
these activities directly link growth factor receptor signalling to
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V. K. Subbaiah and others
control of the Wnt pathway and again suggests a potential tumoursuppressor role in the context of some cancers.
PDZ DOMAIN-CONTAINING PTPs (PROTEIN TYROSINE
PHOSPHATASES)
Three PDZ domain-containing PTPs, FAP-1, PTPH1 and PTPMEG1 [82], have been described, with PTPH1 and FAP-1 closely
linked to tumorigenesis, although their roles are still controversial.
Early studies suggested a possible tumour-suppressor potential
for PTPH1 (PTPN3), since mutations were reported in some
colorectal cancers [83]: however, more recent studies are
indicative of pro-oncogenic activity. K-Ras was shown to increase
the expression levels of PTPH1 and p38γ [84], with PTPH1
and p38γ interacting in a PDZ–PBM-dependent manner. This
resulted in dephosphorylation of phospho-p38γ and inhibition of
the phospho-p38γ -mediated down-regulation of Ras signalling
[84,85], generating a positive-feedback loop. PTPH1 was also
found to be overexpressed in a number of breast cancers,
resulting in a perturbation of vitamin D receptor localization and
stimulation of cell proliferation [86]. Thus, although PTPH1 has
also been reported to be a PDZ target of the HPV E6 oncoprotein,
suggesting tumour-suppressive potential in some contexts [87], in
others a pro-oncogenic activity seems most likely.
FAP-1 (PTPN13) has also been reported to possess both oncogenic and tumour-suppressive activity, depending on the particular
cellular context. Originally identified as a Fas-associated protein,
FAP-1 was shown to suppress the Fas-induced apoptosis in a
PDZ domain-dependent manner [88,89]. FAP-1 was implicated
in the development of ESFT (Ewing’s sarcoma family of tumours),
being a direct transcriptional target for EWS-FLI1 (Ewing
sarcoma breakpoint region 1/Friend leukaemia virus integration 1)
[90], and being progressively up-regulated as tumours progressed
towards malignancy. However, in other settings, FAP-1 has all
the hallmarks of a tumour suppressor. As noted above, high
levels of FAP-1 can down-regulate Wnt signalling, and mutations
in FAP-1 have been reported in colorectal cancers [83]. It can
act to down-regulate Src kinase (Figure 3 and see below), an
activity that is dependent on the PDZ–PBM interaction between
the Src regulator RIL (reversion-induced LIM protein) and
FAP-1, thereby recruiting FAP-1 to the Src–RIL complex to
dephosphorylate Src [91,92]. RIL expression is also lost in a
number of cancer-derived cells, including those from colon,
liver and breast cancers [91], providing further evidence of
an important role for the FAP-1/RIL module in tumorigenesis.
Interestingly, FAP-1 appears to also act downstream of Src,
through its PDZ2 domain-dependent interaction with the Src
effector protein TRIP6 (thyroid receptor-interacting protein 6),
which it dephosphorylates and inhibits downstream targeting of
the focal adhesion-associated proteins Crk and p130cas [93,94].
Clinically, FAP-1 expression is a prognostic marker for survival
in breast cancer [95], and expression is lost in many tumour
types [96,97]. Furthermore, mutation within the PDZ2 domain
has been reported in a number of different cancers, resulting in a
loss of Fas- and TRIP6-binding activity [96]. Taken together with
previous studies showing that FAP-1 is a target of the HPV-16 E6
oncoprotein [98], this underlines further the role of FAP-1 as a
PDZ-dependent tumour suppressor.
PDZ interactions of Src
Discussion of PDZ-containing PTPs would be incomplete without
further mention of the PBM-containing Src tyrosine kinase [99],
mutations in which have been associated with a number of
cancers [100]. Src is activated by dephosphorylation of the
c The Authors Journal compilation c 2011 Biochemical Society
C-terminal Tyr530 , followed by autophosphorylation at Tyr419 .
Dephosphorylation of Tyr530 , which is close to the PBM, allows
Src to bind a number of PDZ proteins, including the E3
ubiquitin ligase LNX1 (Ligand of Numb protein X1), which
has been reported to be down-regulated in some cancers.
Src phosphorylates LNX1, which in turn ubiquitylates Src,
promoting its degradation [101], thus restricting the levels of
activated Src. Src dephosphorylated at Thr530 also binds the PDZ
domain-containing junctional adhesion protein AF-6 (ALL1fused gene from chromosome 6) (see below), which connects
the cytoskeleton to transmembrane proteins at cell junctions and
also binds and regulates Ras and Rap1 GTPases. Binding AF-6
prevents Src autophosphorylation, holding Src in a semi-activated
state at specific regions in the cell periphery, thus confining its
access to a subset of potential substrates [99].
Mutation of the Src PBM in breast epithelial cells promotes Src
activation and the development of invasive characteristics [102].
These findings, combined with the fact that PBMs are found
only in those Src proteins expressed in adherent cells, indicates
the importance of the PDZ-mediated control of Src activation in
epithelia. Although activating mutations in Src are rare, the Gln531∗
truncation, which lacks the PBM, is found in colon cancer (Sanger
Catalogue of Somatic mutations in Cancer, COSMIC http://www.
sanger.ac.uk/perl/genetics/CGP/cosmic?action=bygene&ln=SRC
&start=1&end=5378coords=AA:AA), suggesting that loss
of PDZ-mediated control of Src can contribute to cancer
development, implicating LNX1 and AF-6 as being critical PDZ
domain-containing regulators of Src.
PDZ DOMAINS AND CYTOSKELETAL REMODELLING
Cell motility is a fundamental feature of eukaryotic cells during
embryogenesis and in the development and progression of
cancer metastasis [103]. Migration is tightly controlled by the
organization of the actin cytoskeleton and arguably the most
important regulators of this are the family of Rho GTPases [104].
Rho proteins shuttle between an inactive GDP-bound and an
active GTP-bound conformational state. This switch is controlled
by different regulatory proteins: positive regulators of which are
GEFs that stimulate the exchange of GDP for GTP, resulting in
the active GTPase. More than 70 different Rho-GEFs have now
been described and 37 % of these possess PBMs at their C-termini
[105], others have PDZ domains, and some have both PBMs and
PDZ domains (Figure 4) implicating PDZ–PBM interactions as
critical regulators of Rho-GEF function.
One of the first examples of this in cancer development is
Bcr (breakpoint cluster region), which is rearranged in human
leukaemia and is fused with the tyrosine kinase Abl, forming the
Bcr–Abl fusion gene. The Bcr–Abl chimaera has constitutively
activated Abl kinase, which is thought to be responsible for most
of its oncogenic properties [106]. However, Bcr also has a Cterminal PBM [107] which allows complex formation with the
AF-6 PDZ domain protein in epithelial cells [27]. Normally,
the ternary complex of Bcr, AF-6 and Ras at cell junctions
down-regulates Ras-mediated signalling and cell proliferation;
however, in the Bcr–Abl fusion gene product, this PDZ-binding
capacity is lost, thereby contributing to increased Ras signalling
and malignant potential [27].
The PDZ-containing RhoA-specific GEF LARG (leukaemiaassociated Rho-GEF) is another example of mutational
inactivation of a GEF during tumorigenesis. LARG is fused
to the mixed-lineage leukaemia gene in primary acute myeloid
leukaemia [108], resulting in loss of the LARG N-terminus
and its PDZ domain, suggesting that, in this context, loss of
PDZ domains
Figure 4
201
Schematic representation of some of the PDZ–PBM-dependent interactions of GEFs and their downstream consequences
The upper panel shows the normal GEF domain organization, with the PDZ domain and PBM being optional. The lower panel shows interactions that are PDZ-dependent, PBM-dependent and
those that potentially involve both PDZ and PBM. CAMKII, Ca2 + /calmodulin-dependent protein kinase II; DH, Dbl homology; EGFR, epidermal growth factor receptor hScrib, human Scribble; PH,
pleckstrin homology; PLC, phospholipase C; SAP 102, synapse-associated protein 102; SH3, Src homology 3.
PDZ-binding capacity might contribute to tumorigenesis.
However, the LARG PDZ domain has been reported to
interact with multiple protein partners, including the IGF-1
(insulin-like growth factor 1) receptor, where it is required
for transmission of extracellular IGF-1 to the generation of
cytoskeletal rearrangements by activation of Rho/ROCK [109].
The PDZ domain also interacts with CD44, which it links to
EGFR (epidermal growth factor receptor) signalling and Rho/Ras
activation in the development of head and neck squamous
cell carcinomas [110]. Furthermore, LARG is overexpressed
in Shwachman–Diamond syndrome patients, who have a high
propensity to develop acute myeloid leukaemia [111]. However,
in breast and colorectal cancers, LARG has tumour-suppressor
characteristics, with frequent gene deletion and underexpression
of the protein in many of the tumours [112]. Thus it seems likely
that LARG may have both tumour-suppressor and oncogenic
potential, depending on the precise cellular context.
Another PDZ domain-containing GEF implicated in tumour
development is the Rac-GEF P-Rex1, a critical regulator of ErbB2
signalling in breast cancer [113,114] and possibly having a role
in prostate cancer metastasis [115]. In both cases, P-Rex1 is
overexpressed, resulting in increased activation of Rac signalling
and cell invasion. How the PDZ domain contributes to this activity
is not clear, as little is known about its PBM-containing interacting
partners. However, S1P (sphingosine 1-phosphate) receptors are
one such target. S1P is also involved in regulating cell migration
and it is possible that the interaction between P-Rex1 and S1P1
(S1P receptor 1) can regulate the correct localization of S1P1 at
the cell membrane, with an increase in P-Rex1 increasing S1P1
membrane localization, thereby contributing to increased cell
migratory potential [116]. Regardless of the precise mechanism of
action, overexpression of this particular PDZ domain-containing
GEF is strongly associated with cancer development in a variety
of different contexts.
Tiam1 is a ubiquitously expressed Rac-specific GEF and
contains a single PDZ domain and potential class I PBM,
and thus can connect directly to other PDZ domain-containing
proteins. Although Tiam1 itself has not been reported to be lost/
c The Authors Journal compilation c 2011 Biochemical Society
202
V. K. Subbaiah and others
overexpressed during tumorigenesis, a reported PBM-containing
partner CADM1 (cell adhesion molecule 1)/TSLC1 (tumour
suppressor in lung cancer 1) has. This glycoprotein belongs to
the Ig-like family of cell adhesion molecules, loss of which is
common to many different tumour types [117,118]. Although the
role of PDZ binding has not been shown in tumour development,
the CADM1 PBM was found to be essential for correct cellular
localization and for suppression of EMT in vitro. Intriguingly, this
correlated with high levels of Rac activity [119], suggesting that
the interaction between Tiam1 and CADM1 may contribute to
the regulation of this pathway. However, whereas CADM1 may
be a tumour suppressor in most contexts, in ATL (adult T-cell
leukaemia/lymphoma), CADM1 binding to Tiam1 and induction
of Rac activation and actin reorganization is believed to contribute
to the cell’s invasive characteristics [120], once again underlining
the context dependence by which PDZ–PBM interactions need
to be evaluated. As noted above, Tiam1 interacts with Par3
[71], and this interaction also restricts Tiam1 Rac activity. Since
Tiam1 contains a class I PBM, one would have expected that the
association would have been via this motif; however, this does not
seem to be the case [71].
A key feature of many GEFs is their ability to control the
Rho-GTPase activity both spatially and temporally, and this often
occurs through its interaction via PBM–PDZ recognition. βPix is a PBM-containing GEF which plays a critical role in
the regulation of polarized cell migration through activation of
Rac and Cdc42. However, the correct localization of β-Pix is
determined by Scribble [3]. As noted above, Scribble is a target
of HPV E6 and, as with many multi-PDZ domain-containing
proteins, Scribble can be considered to be multifunctional. In
the case of β-Pix, the interaction with Scribble is PDZ domaindependent and is essential for the correct cellular localization of βPix and localized activation of Cdc42 and Rac at the leading edge
of migrating cells. In contrast, loss of Scribble does not destroy
a cell’s migratory capacity, but directionality is lost [121]. What
does this mean from a tumour perspective? Again, as noted above,
there are major changes in the levels and patterns of Scribble
expression during the development of many cancers, and these in
turn could be expected to perturb the normal positioning of the
PBM-containing partners such as β-Pix.
Similar functions have also been reported for Dlg, which
also interacts with several PBM-containing GEFs, such as Net1,
where Dlg has been reported to regulate Net1 localization and
activity. Conversely, oncogenic mutants of Net1 are believed to
function through inhibition of Dlg function [122]. Alterations in
Dlg expression during cancer development are common, with
high levels of expression, and loss of junctional localization
in early-stage cancer, and complete loss of expression in latestage metastases [41]. Taken together, these results suggest that
mislocalization of the PDZ domain-containing protein is a key
factor in oncogenic progression. It also raises the possibility
that, at certain stages of cancer development, the overexpression
of such proteins might be oncogenic, something that has been
implied for Dlg [30]. Thus, again, in context-dependent settings,
these PDZ domain-containing proteins, by interacting with a
variety of GEFs, may possess oncogenic or tumour-suppressive
activity.
In pancreatic cancers, the single PDZ domain-containing
protein GIPC1 [GAIP (Gα -interacting protein)-interacting
protein C-terminus 1]/synectin is often overexpressed [123].
Furthermore, GIPC1 has also been reported to be a PDZ domaincontaining target of the HPV E6 oncoprotein, suggesting further
a role in tumour development [124]. In a mouse model of
pancreatic tumour invasion, it was also shown that blocking
synectin’s PDZ-binding potential inhibits tumour growth [125],
c The Authors Journal compilation c 2011 Biochemical Society
providing compelling evidence that the PDZ–PBM interactions of
synectin are important in the development of certain malignancies.
Although many PBM-containing targets of synectin have been
identified, including the IGF-1 receptor [126], which is a strong
candidate as a clinically relevant PBM-containing target of
synectin [123], a particularly intriguing PBM-containing partner
is MyoGEF (myosin-interacting GEF). This GEF has been shown
in vitro to be capable of regulating breast cancer cell polarization
and invasion through its ability to activate RhoA and RhoC
signalling [127]. Therefore the temporal and spatial control
provided by synectin in regulating RhoA and RhoC signalling
through controlling the localization of MyoGEF is an additional
possible route by which overexpressed synectin might contribute
to tumorigenesis.
CONCLUSIONS
PDZ domain-containing proteins play essential roles in most
aspects of cellular homoeostasis and, not surprisingly, are
implicated in diverse aspects of tumour growth, development
and metastasis. These can have both tumour-suppressive and
oncogenic potentials, and the underlying characteristics of many
of these proteins are their particular tissue-specific activities. The
relevant PDZ–PBM interactions often differ from one tissue to
another, and, in many cases, contradictory effects of either loss or
overexpression of a given PDZ domain-containing protein or its
PBM-containing partner have been reported; invariably this is due
to differences in the particular experimental model or tissues that
are being analysed. Thus the specificity of PDZ–PBM interactions
is highly dependent on cellular context [128]. This underlines their
essential roles as nodes in multiple signal transduction pathways,
critical aspects of which are reflected in very minor changes in
the levels of protein expression or in its precise cellular location.
Although acquiring a global understanding of their role in cancer
development is still a long way off, the amount of information
now available about the details and regulation of PBM–PDZ
interactions offers unique potentials for the development of novel
cancer therapeutics, tailored to specifically target a given PBM–
PDZ interaction. The coming years will undoubtedly see great
strides in the targeting of these PBM–PDZ nodes in the treatment
of cancer.
FUNDING
L.B. gratefully acknowledges research support provided by the Associazione Italiana per
la Ricerca sul Cancro, the Association for International Cancer Research, Telethon and the
Wellcome Trust.
REFERENCES
1 Ponting, C. P., Phillips, C., Davies, K. E. and Blake, D. J. (1997) PDZ domains: targeting
signalling molecules to sub-membranous sites. BioEssays 19, 469–479
2 Ponting, C. P. (1997) Evidence for PDZ domains in bacteria, yeast, and plants. Protein
Sci. 6, 464–468
3 Audebert, S., Navarro, C., Nourry, C., Chasserot-Golaz, S., Lecine, P., Bellaiche, Y.,
Dupont, J. L., Premont, R. T., Sempere, C., Strub, J. M. et al. (2004) Mammalian
Scribble forms a tight complex with the βPIX exchange factor. Curr. Biol. 14, 987–995
4 Thomas, M., Dasgupta, J., Zhang, Y., Chen, X. and Banks, L. (2008) Analysis of
specificity determinants in the interactions of different HPV E6 proteins with their PDZ
domain-containing substrates. Virology 376, 371–378
5 Doyle, D. A., Lee, A., Lewis, J., Kim, E., Sheng, M. and MacKinnon, R. (1996) Crystal
structures of a complexed and peptide-free membrane protein-binding domain:
molecular basis of peptide recognition by PDZ. Cell 85, 1067–1076
6 Morais Cabral, J. H., Petosa, C., Sutcliffe, M. J., Raza, S., Byron, O., Poy, F., Marfatia,
S. M., Chishti, A. H. and Liddington, R. C. (1996) Crystal structure of a PDZ domain.
Nature 382, 649–652
PDZ domains
7 Zhang, Y., Dasgupta, J., Ma, R. Z., Banks, L., Thomas, M. and Chen, X. S. (2007)
Structures of a human papillomavirus (HPV) E6 polypeptide bound to MAGUK proteins:
mechanisms of targeting tumor suppressors by a high-risk HPV oncoprotein. J. Virol.
81, 3618–3626
8 Songyang, Z., Fanning, A. S., Fu, C., Xu, J., Marfatia, S. M., Chishti, A. H., Crompton,
A., Chan, A. C., Anderson, J. M. and Cantley, L. C. (1997) Recognition of unique
carboxyl-terminal motifs by distinct PDZ domains. Science 275, 73–77
9 Tochio, H., Hung, F., Li, M., Bredt, D. S. and Zhang, M. (2000) Solution structure and
backbone dynamics of the second PDZ domain of postsynaptic density-95. J. Mol. Biol.
295, 225–237
10 Feng, W., Shi, Y., Li, M. and Zhang, M. (2003) Tandem PDZ repeats in glutamate
receptor-interacting proteins have a novel mode of PDZ domain-mediated target
binding. Nat. Struct. Biol. 10, 972–978
11 Long, J. F., Tochio, H., Wang, P., Fan, J. S., Sala, C., Niethammer, M., Sheng, M. and
Zhang, M. (2003) Supramodular structure and synergistic target binding of the
N-terminal tandem PDZ domains of PSD-95. J. Mol. Biol. 327, 203–214
12 Lue, R. A., Brandin, E., Chan, E. P. and Branton, D. (1996) Two independent domains of
hDlg are sufficient for subcellular targeting: the PDZ1-2 conformational unit and an
alternatively spliced domain. J. Cell Biol. 135, 1125–1137
13 Im, Y. J., Lee, J. H., Park, S. H., Park, S. J., Rho, S. H., Kang, G. B., Kim, E. and Eom,
S. H. (2003) Crystal structure of the Shank PDZ–ligand complex reveals a class I PDZ
interaction and a novel PDZ–PDZ dimerization. J. Biol. Chem. 278, 48099–48104
14 Utepbergenov, D. I., Fanning, A. S. and Anderson, J. M. (2006) Dimerization of the
scaffolding protein ZO-1 through the second PDZ domain. J. Biol. Chem. 281,
24671–24677
15 Wu, J., Yang, Y., Zhang, J., Ji, P., Du, W., Jiang, P., Xie, D., Huang, H., Wu, M., Zhang, G.
et al. (2007) Domain-swapped dimerization of the second PDZ domain of ZO2 may
provide a structural basis for the polymerization of claudins. J. Biol. Chem. 282,
35988–35999
16 Chen, J., Pan, L., Wei, Z., Zhao, Y. and Zhang, M. (2008) Domain-swapped dimerization
of ZO-1 PDZ2 generates specific and regulatory connexin43-binding sites. EMBO J. 27,
2113–2123
17 Saras, J. and Heldin, C. H. (1996) PDZ domains bind carboxy-terminal sequences of
target proteins. Trends Biochem. Sci. 21, 455–458
18 Cowburn, D. (1997) Peptide recognition by PTB and PDZ domains. Curr. Opin. Struct.
Biol. 7, 835–838
19 Wheeler, D. S., Barrick, S. R., Grubisha, M. J., Brufsky, A. M., Friedman, P. A. and
Romero, G. (2011) Direct interaction between NHERF1 and Frizzled regulates β-catenin
signaling. Oncogene 30, 32–42
20 Zhang, Y., Yeh, S., Appleton, B. A., Held, H. A., Kausalya, P. J., Phua, D. C., Wong, W. L.,
Lasky, L. A., Wiesmann, C., Hunziker, W. and Sidhu, S. S. (2006) Convergent and
divergent ligand specificity among PDZ domains of the LAP and zonula occludens (ZO)
families. J. Biol. Chem. 281, 22299–22311
21 Tonikian, R., Zhang, Y., Sazinsky, S. L., Currell, B., Yeh, J. H., Reva, B., Held, H. A.,
Appleton, B. A., Evangelista, M., Wu, Y. et al. (2008) A specificity map for the PDZ
domain family. PLoS Biol. 6, e239
22 Cohen, N. A., Brenman, J. E., Snyder, S. H. and Bredt, D. S. (1996) Binding of the inward
rectifier K + channel Kir 2.3 to PSD-95 is regulated by protein kinase A phosphorylation.
Neuron 17, 759–767
23 Kühne, C., Gardiol, D., Guarnaccia, C., Amenitsch, H. and Banks, L. (2000) Differential
regulation of human papillomavirus E6 by protein kinase A: conditional degradation of
human discs large protein by oncogenic E6. Oncogene 19, 5884–5891
24 Adey, N. B., Huang, L., Ormonde, P. A., Baumgard, M. L., Pero, R., Byreddy, D. V.,
Tavtigian, S. V. and Bartel, P. L. (2000) Threonine phosphorylation of the MMAC1/PTEN
PDZ binding domain both inhibits and stimulates PDZ binding. Cancer Res. 60, 35–37
25 von Nandelstadh, P., Ismail, M., Gardin, C., Suila, H., Zara, I., Belgrano, A., Valle, G.,
Carpen, O. and Faulkner, G. (2009) A class III PDZ binding motif in the myotilin and
FATZ families binds enigma family proteins: a common link for Z-disc myopathies. Mol.
Cell. Biol. 29, 822–834
26 Gardoni, F., Mauceri, D., Fiorentini, C., Bellone, C., Missale, C., Cattabeni, F. and Di
Luca, M. (2003) CaMKII-dependent phosphorylation regulates SAP97/NR2A interaction.
J. Biol. Chem. 278, 44745–44752
27 Radziwill, G., Erdmann, R. A., Margelisch, U. and Moelling, K. (2003) The Bcr kinase
downregulates Ras signaling by phosphorylating AF-6 and binding to its PDZ domain.
Mol. Cell. Biol. 23, 4663–4672
28 Lee, S. S., Weiss, R. S. and Javier, R. T. (1997) Binding of human virus oncoproteins to
hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor
protein. Proc. Natl. Acad. Sci. U.S.A. 94, 6670–6675
29 Javier, R. T. (2008) Cell polarity proteins: common targets for tumorigenic human
viruses. Oncogene 27, 7031–7046
203
30 Frese, K. K., Latorre, I. J., Chung, S. H., Caruana, G., Bernstein, A., Jones, S. N.,
Donehower, L. A., Justice, M. J., Garner, C. C. and Javier, R. T. (2006) Oncogenic
function for the Dlg1 mammalian homolog of the Drosophila discs-large tumor
suppressor. EMBO J. 25, 1406–1417
31 Kiyono, T., Hiraiwa, A., Fujita, M., Hayashi, Y., Akiyama, T. and Ishibashi, M. (1997)
Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of
the Drosophila discs large tumor suppressor protein. Proc. Natl. Acad. Sci. U.S.A. 94,
11612–11616
32 Thomas, M., Narayan, N., Pim, D., Tomaic, V., Massimi, P., Nagasaka, K., Kranjec, C.,
Gammoh, N. and Banks, L. (2008) Human papillomaviruses, cervical cancer and cell
polarity. Oncogene 27, 7018–7030
33 Butz, K., Ristriani, T., Hengstermann, A., Denk, C., Scheffner, M. and Hoppe-Seyler, F.
(2003) siRNA targeting of the viral E6 oncogene efficiently kills human
papillomavirus-positive cancer cells. Oncogene 22, 5938–5945
34 Higuchi, M., Tsubata, C., Kondo, R., Yoshida, S., Takahashi, M., Oie, M., Tanaka, Y.,
Mahieux, R., Matsuoka, M. and Fujii, M. (2007) Cooperation of NF-κB2/p100 activation
and the PDZ domain binding motif signal in human T-cell leukemia virus type 1
(HTLV-1) Tax1 but not HTLV-2 Tax2 is crucial for interleukin-2-independent growth
transformation of a T-cell line. J. Virol. 81, 11900–11907
35 Thomas, M., Massimi, P., Navarro, C., Borg, J. P. and Banks, L. (2005) The hScrib/Dlg
apico-basal control complex is differentially targeted by HPV-16 and HPV-18 E6
proteins. Oncogene 24, 6222–6230
36 Humbert, P. O., Grzeschik, N. A., Brumby, A. M., Galea, R., Elsum, I. and Richardson,
H. E. (2008) Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module.
Oncogene 27, 6888–6907
37 Dow, L. E., Elsum, I. A., King, C. L., Kinross, K. M., Richardson, H. E. and Humbert, P. O.
(2008) Loss of human Scribble cooperates with H-Ras to promote cell invasion through
deregulation of MAPK signalling. Oncogene 27, 5988–6001
38 Zhan, L., Rosenberg, A., Bergami, K. C., Yu, M., Xuan, Z., Jaffe, A. B., Allred, C. and
Muthuswamy, S. K. (2008) Deregulation of scribble promotes mammary tumorigenesis
and reveals a role for cell polarity in carcinoma. Cell 135, 865–878
39 Nagasaka, K., Pim, D., Massimi, P., Thomas, M., Tomaic, V., Subbaiah, V. K., Kranjec,
C., Nakagawa, S., Yano, T., Taketani, Y. et al. (2010) The cell polarity regulator hScrib
controls ERK activation through a KIM site-dependent interaction. Oncogene 29,
5311–5321
40 Wu, M., Pastor-Pareja, J. C. and Xu, T. (2010) Interaction between RasV12 and scribble
clones induces tumour growth and invasion. Nature 463, 545–548
41 Gardiol, D., Zacchi, A., Petrera, F., Stanta, G. and Banks, L. (2006) Human discs large
and scrib are localized at the same regions in colon mucosa and changes in their
expression patterns are correlated with loss of tissue architecture during malignant
progression. Int. J. Cancer 119, 1285–1290
42 Navarro, C., Nola, S., Audebert, S., Santoni, M. J., Arsanto, J. P., Ginestier, C., Marchetto,
S., Jacquemier, J., Isnardon, D., Le Bivic, A. et al. (2005) Junctional recruitment of
mammalian Scribble relies on E-cadherin engagement. Oncogene 24, 4330–4339
43 Vaira, V., Faversani, A., Dohi, T., Maggioni, M., Nosotti, M., Tosi, D., Altieri, D. C. and
Bosari, S. (2011) Aberrant overexpression of the cell polarity module Scribble in human
cancer. Am. J. Pathol. 178, 2478–2483
44 Glaunsinger, B. A., Lee, S. S., Thomas, M., Banks, L. and Javier, R. (2000) Interactions
of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6
oncoproteins. Oncogene 19, 5270–5280
45 Kranjec, C. and Banks, L. (2011) A systematic analysis of human papillomavirus (HPV)
E6 PDZ substrates identifies MAGI-1 as a major target of HPV type 16 (HPV-16) and
HPV-18 whose loss accompanies disruption of tight junctions. J. Virol. 85, 1757–1764
46 Tomaić, V., Gardiol, D., Massimi, P., Ozbun, M., Myers, M. and Banks, L. (2009) Human
and primate tumour viruses use PDZ binding as an evolutionarily conserved mechanism
of targeting cell polarity regulators. Oncogene 28, 1–8
47 Aranda, V., Nolan, M. E. and Muthuswamy, S. K. (2008) Par complex in cancer: a
regulator of normal cell polarity joins the dark side. Oncogene 27, 6878–6887
48 Thiery, J. P. (2002) Epithelial–mesenchymal transitions in tumour progression. Nat. Rev.
Cancer 2, 442–454
49 Wong, H. C., Bourdelas, A., Krauss, A., Lee, H. J., Shao, Y., Wu, D., Mlodzik, M., Shi,
D. L. and Zheng, J. (2003) Direct binding of the PDZ domain of Dishevelled to a
conserved internal sequence in the C-terminal region of Frizzled. Mol. Cell 12,
1251–1260
50 Gao, C. and Chen, Y. G. (2010) Dishevelled: the hub of Wnt signaling. Cell. Signalling
22, 717–727
51 Clevers, H. (2006) Wnt/β-catenin signaling in development and disease. Cell 127,
469–480
52 Veeman, M. T., Axelrod, J. D. and Moon, R. T. (2003) A second canon: functions and
mechanisms of β-catenin-independent Wnt signaling. Dev. Cell 5, 367–377
53 Habas, R., Kato, Y. and He, X. (2001) Wnt/Frizzled activation of Rho regulates vertebrate
gastrulation and requires a novel Formin homology protein Daam1. Cell 107, 843–854
c The Authors Journal compilation c 2011 Biochemical Society
204
V. K. Subbaiah and others
54 Liu, W., Sato, A., Khadka, D., Bharti, R., Diaz, H., Runnels, L. W. and Habas, R. (2008)
Mechanism of activation of the Formin protein Daam1. Proc. Natl. Acad. Sci. U.S.A.
105, 210–215
55 Weeraratna, A. T., Jiang, Y., Hostetter, G., Rosenblatt, K., Duray, P., Bittner, M. and Trent,
J. M. (2002) Wnt5a signaling directly affects cell motility and invasion of metastatic
melanoma. Cancer Cell 1, 279–288
56 Yuzugullu, H., Benhaj, K., Ozturk, N., Senturk, S., Celik, E., Toylu, A., Tasdemir, N.,
Yilmaz, M., Erdal, E., Akcali, K. C. et al. (2009) Canonical Wnt signaling is antagonized
by noncanonical Wnt5a in hepatocellular carcinoma cells. Mol. Cancer 8, 90
57 Uematsu, K., Kanazawa, S., You, L., He, B., Xu, Z., Li, K., Peterlin, B. M., McCormick, F.
and Jablons, D. M. (2003) Wnt pathway activation in mesothelioma: evidence of
Dishevelled overexpression and transcriptional activity of β-catenin. Cancer Res. 63,
4547–4551
58 Nagahata, T., Shimada, T., Harada, A., Nagai, H., Onda, M., Yokoyama, S., Shiba, T., Jin,
E., Kawanami, O. and Emi, M. (2003) Amplification, up-regulation and over-expression
of DVL-1, the human counterpart of the Drosophila disheveled gene, in primary breast
cancers. Cancer Sci. 94, 515–518
59 Shan, J., Shi, D. L., Wang, J. and Zheng, J. (2005) Identification of a specific inhibitor of
the dishevelled PDZ domain. Biochemistry 44, 15495–15503
60 Grandy, D., Shan, J., Zhang, X., Rao, S., Akunuru, S., Li, H., Zhang, Y., Alpatov, I.,
Zhang, X. A., Lang, R. A. et al. (2009) Discovery and characterization of a small molecule
inhibitor of the PDZ domain of dishevelled. J. Biol. Chem. 284, 16256–16263
61 Kinzler, K. W. and Vogelstein, B. (1996) Lessons from hereditary colorectal cancer. Cell
87, 159–170
62 Giles, R. H., van Es, J. H. and Clevers, H. (2003) Caught up in a Wnt storm: Wnt
signaling in cancer. Biochim. Biophys. Acta 1653, 1–24
63 Matsumine, A., Ogai, A., Senda, T., Okumura, N., Satoh, K., Baeg, G. H., Kawahara, T.,
Kobayashi, S., Okada, M., Toyoshima, K. and Akiyama, T. (1996) Binding of APC to the
human homolog of the Drosophila discs large tumor suppressor protein. Science 272,
1020–1023
64 Etienne-Manneville, S., Manneville, J. B., Nicholls, S., Ferenczi, M. A. and Hall, A.
(2005) Cdc42 and Par6-PKCζ regulate the spatially localized association of Dlg1 and
APC to control cell polarization. J. Cell Biol. 170, 895–901
65 Erdmann, K. S., Kuhlmann, J., Lessmann, V., Herrmann, L., Eulenburg, V., Muller, O. and
Heumann, R. (2000) The adenomatous polyposis coli protein (APC) interacts with the
protein tyrosine phosphatase PTP-BL via an alternatively spliced PDZ domain.
Oncogene 19, 3894–3901
66 Welters, H. J., Oknianska, A., Erdmann, K. S., Ryffel, G. U. and Morgan, N. G. (2008) The
protein tyrosine phosphatase-BL, modulates pancreatic β-cell proliferation by
interaction with the Wnt signalling pathway. J. Endocrinol. 197, 543–552
67 Pedemonte, S., Sciallero, S., Gismondi, V., Stagnaro, P., Biticchi, R., Haeouaine, A.,
Bonelli, L., Nicolo, G., Groden, J., Bruzzi, P. et al. (1998) Novel germline APC variants in
patients with multiple adenomas. Genes Chromosomes Cancer 22, 257–267
68 Miyoshi, Y., Ando, H., Nagase, H., Nishisho, I., Horii, A., Miki, Y., Mori, T., Utsunomiya,
J., Baba, S., Petersen, G. et al. (1992) Germ-line mutations of the APC gene in 53
familial adenomatous polyposis patients. Proc. Natl. Acad. Sci. U.S.A. 89, 4452–4456
69 Salmena, L., Carracedo, A. and Pandolfi, P. P. (2008) Tenets of PTEN tumor suppression.
Cell 133, 403–414
70 Joberty, G., Petersen, C., Gao, L. and Macara, I. G. (2000) The cell-polarity protein Par6
links Par3 and atypical protein kinase C to Cdc42. Nat. Cell Biol. 2, 531–539
71 Chen, X. and Macara, I. G. (2005) Par-3 controls tight junction assembly through the
Rac exchange factor Tiam1. Nat. Cell Biol. 7, 262–269
72 Ozdamar, B., Bose, R., Barrios-Rodiles, M., Wang, H. R., Zhang, Y. and Wrana, J. L.
(2005) Regulation of the polarity protein Par6 by TGFβ receptors controls epithelial cell
plasticity. Science 307, 1603–1609
73 Kuang, S. Q., Tong, W. G., Yang, H., Lin, W., Lee, M. K., Fang, Z. H., Wei, Y., Jelinek, J.,
Issa, J. P. and Garcia-Manero, G. (2008) Genome-wide identification of aberrantly
methylated promoter associated CpG islands in acute lymphocytic leukemia. Leukemia
22, 1529–1538
74 Valiente, M., Andres-Pons, A., Gomar, B., Torres, J., Gil, A., Tapparel, C., Antonarakis,
S. E. and Pulido, R. (2005) Binding of PTEN to specific PDZ domains contributes to
PTEN protein stability and phosphorylation by microtubule-associated serine/threonine
kinases. J. Biol. Chem. 280, 28936–28943
75 Dobrosotskaya, I. Y. and James, G. L. (2000) MAGI-1 interacts with β-catenin and is
associated with cell–cell adhesion structures. Biochem. Biophys. Res. Commun. 270,
903–909
76 Kotelevets, L., van Hengel, J., Bruyneel, E., Mareel, M., van Roy, F. and Chastre, E.
(2005) Implication of the MAGI-1b/PTEN signalosome in stabilization of adherens
junctions and suppression of invasiveness. FASEB J. 19, 115–117
77 Leslie, N. R. and Downes, C. P. (2002) PTEN: the down side of PI 3-kinase signalling.
Cell. Signalling 14, 285–295
c The Authors Journal compilation c 2011 Biochemical Society
78 Deichmann, M., Thome, M., Benner, A., Egner, U., Hartschuh, W. and Naher, H. (2002)
PTEN/MMAC1 expression in melanoma resection specimens. Br. J. Cancer 87,
1431–1436
79 Hayashi, Y., Molina, J. R., Hamilton, S. R. and Georgescu, M. M. (2010) NHERF1/EBP50
is a new marker in colorectal cancer. Neoplasia 12, 1013–1022
80 Dai, J. L., Wang, L., Sahin, A. A., Broemeling, L. D., Schutte, M. and Pan, Y. (2004)
NHERF (Na + /H + exchanger regulatory factor) gene mutations in human breast cancer.
Oncogene 23, 8681–8687
81 Takahashi, Y., Morales, F. C., Kreimann, E. L. and Georgescu, M. M. (2006) PTEN tumor
suppressor associates with NHERF proteins to attenuate PDGF receptor signaling.
EMBO J. 25, 910–920
81a Accardi, R., Rubino, R., Scalise, M., Gheit, T., Shahzad, N., Thomas, M., Banks, L.,
Indervi, C., Sylla, B. S., Cardone, R. A. et al. (2011) E6 and e7 from human
papillomavirus type 16 cooperate to target the PDZ protein Na/H exchange regulatory
factor 1. J. Virol. 85, 8208–8216
82 Alonso, A., Sasin, J., Bottini, N., Friedberg, I., Friedberg, I., Osterman, A., Godzik, A.,
Hunter, T., Dixon, J. and Mustelin, T. (2004) Protein tyrosine phosphatases in the human
genome. Cell 117, 699–711
83 Wang, Z., Shen, D., Parsons, D. W., Bardelli, A., Sager, J., Szabo, S., Ptak, J., Silliman,
N., Peters, B. A., van der Heijden, M. S. et al. (2004) Mutational analysis of the tyrosine
phosphatome in colorectal cancers. Science 304, 1164–1166
84 Hou, S. W., Zhi, H. Y., Pohl, N., Loesch, M., Qi, X. M., Li, R. S., Basir, Z. and Chen, G.
(2010) PTPH1 dephosphorylates and cooperates with p38γ MAPK to increase ras
oncogenesis through PDZ-mediated interaction. Cancer Res. 70, 2901–2910
85 Han, J. and Sun, P. (2007) The pathways to tumor suppression via route p38. Trends
Biochem. Sci. 32, 364–371
86 Zhi, H. Y., Hou, S. W., Li, R. S., Basir, Z., Xiang, Q., Szabo, A. and Chen, G. (2011)
PTPH1 cooperates with vitamin D receptor to stimulate breast cancer growth through
their mutual stabilization. Oncogene 30, 1706–1715
87 Jing, M., Bohl, J., Brimer, N., Kinter, M. and Vande Pol, S. B. (2007) Degradation of
tyrosine phosphatase PTPN3 (PTPH1) by association with oncogenic human
papillomavirus E6 proteins. J. Virol. 81, 2231–2239
88 Saras, J., Engstrom, U., Gonez, L. J. and Heldin, C. H. (1997) Characterization of the
interactions between PDZ domains of the protein-tyrosine phosphatase PTPL1 and the
carboxyl-terminal tail of Fas. J. Biol. Chem. 272, 20979–20981
89 Ungefroren, H., Kruse, M. L., Trauzold, A., Roeschmann, S., Roeder, C., Arlt, A.,
Henne-Bruns, D. and Kalthoff, H. (2001) FAP-1 in pancreatic cancer cells: functional and
mechanistic studies on its inhibitory role in CD95-mediated apoptosis. J. Cell Sci. 114,
2735–2746
90 Abaan, O. D., Levenson, A., Khan, O., Furth, P. A., Uren, A. and Toretsky, J. A. (2005)
PTPL1 is a direct transcriptional target of EWS-FLI1 and modulates Ewing’s sarcoma
tumorigenesis. Oncogene 24, 2715–2722
91 Zhang, Y., Tu, Y., Zhao, J., Chen, K. and Wu, C. (2009) Reversion-induced LIM
interaction with Src reveals a novel Src inactivation cycle. J. Cell Biol. 184,
785–792
92 Glondu-Lassis, M., Dromard, M., Lacroix-Triki, M., Nirde, P., Puech, C., Knani, D.,
Chalbos, D. and Freiss, G. (2010) PTPL1/PTPN13 regulates breast cancer cell
aggressiveness through direct inactivation of Src kinase. Cancer Res. 70,
5116–5126
93 Cuppen, E., van Ham, M., Wansink, D. G., de Leeuw, A., Wieringa, B. and Hendriks, W.
(2000) The zyxin-related protein TRIP6 interacts with PDZ motifs in the adaptor protein
RIL and the protein tyrosine phosphatase PTP-BL. Eur. J. Cell Biol. 79, 283–293
94 Lai, Y. J., Lin, W. C. and Lin, F. T. (2007) PTPL1/FAP-1 negatively regulates TRIP6
function in lysophosphatidic acid-induced cell migration. J. Biol. Chem. 282,
24381–24387
95 Révillion, F., Puech, C., Rabenoelina, F., Chalbos, D., Peyrat, J. P. and Freiss, G. (2009)
Expression of the putative tumor suppressor gene PTPN13/PTPL1 is an independent
prognostic marker for overall survival in breast cancer. Int. J. Cancer 124, 638–643
96 Yeh, S. H., Wu, D. C., Tsai, C. Y., Kuo, T. J., Yu, W. C., Chang, Y. S., Chen, C. L., Chang,
C. F., Chen, D. S. and Chen, P. J. (2006) Genetic characterization of fas-associated
phosphatase-1 as a putative tumor suppressor gene on chromosome 4q21.3 in
hepatocellular carcinoma. Clin. Cancer Res. 12, 1097–1108
97 Ying, J., Li, H., Cui, Y., Wong, A. H., Langford, C. and Tao, Q. (2006) Epigenetic
disruption of two proapoptotic genes MAPK10/JNK3 and PTPN13/FAP-1 in multiple
lymphomas and carcinomas through hypermethylation of a common bidirectional
promoter. Leukemia 20, 1173–1175
98 Spanos, W. C., Hoover, A., Harris, G. F., Wu, S., Strand, G. L., Anderson, M. E.,
Klingelhutz, A. J., Hendriks, W., Bossler, A. D. and Lee, J. H. (2008) The PDZ binding
motif of human papillomavirus type 16 E6 induces PTPN13 loss, which allows
anchorage-independent growth and synergizes with ras for invasive growth. J. Virol. 82,
2493–2500
PDZ domains
99 Radziwill, G., Weiss, A., Heinrich, J., Baumgartner, M., Boisguerin, P., Owada, K. and
Moelling, K. (2007) Regulation of c-Src by binding to the PDZ domain of AF-6. EMBO J.
26, 2633–2644
100 Ishizawar, R. and Parsons, S. J. (2004) c-Src and cooperating partners in human cancer.
Cancer Cell 6, 209–214
101 Weiss, A., Baumgartner, M., Radziwill, G., Dennler, J. and Moelling, K. (2007) c-Src is a
PDZ interaction partner and substrate of the E3 ubiquitin ligase Ligand-of-Numb protein
X1. FEBS Lett. 581, 5131–5136
102 Baumgartner, M., Radziwill, G., Lorger, M., Weiss, A. and Moelling, K. (2008)
c-Src-mediated epithelial cell migration and invasion regulated by PDZ binding site.
Mol. Cell. Biol. 28, 642–655
103 DeMali, K. A. and Burridge, K. (2003) Coupling membrane protrusion and cell adhesion.
J. Cell Sci. 116, 2389–2397
104 Nobes, C. D. and Hall, A. (1999) Rho GTPases control polarity, protrusion, and adhesion
during cell movement. J. Cell Biol. 144, 1235–1244
105 Garcı́a-Mata, R. and Burridge, K. (2007) Catching a GEF by its tail. Trends Cell Biol. 17,
36–43
106 Advani, A. S. and Pendergast, A. M. (2002) Bcr-Abl variants: biological and clinical
aspects. Leuk. Res. 26, 713–720
107 Boguski, M. S. and McCormick, F. (1993) Proteins regulating Ras and its relatives.
Nature 366, 643–654
108 Kourlas, P. J., Strout, M. P., Becknell, B., Veronese, M. L., Croce, C. M., Theil, K. S.,
Krahe, R., Ruutu, T., Knuutila, S., Bloomfield, C. D. and Caligiuri, M. A. (2000)
Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor:
evidence for its fusion with MLL in acute myeloid leukemia. Proc. Natl. Acad. Sci. U.S.A.
97, 2145–2150
109 Taya, S., Inagaki, N., Sengiku, H., Makino, H., Iwamatsu, A., Urakawa, I., Nagao, K.,
Kataoka, S. and Kaibuchi, K. (2001) Direct interaction of insulin-like growth factor-1
receptor with leukemia-associated RhoGEF. J. Cell Biol. 155, 809–820
110 Bourguignon, L. Y., Gilad, E., Brightman, A., Diedrich, F. and Singleton, P. (2006)
Hyaluronan–CD44 interaction with leukemia-associated RhoGEF and epidermal growth
factor receptor promotes Rho/Ras co-activation, phospholipase Cε–Ca2 + signaling,
and cytoskeleton modification in head and neck squamous cell carcinoma cells. J. Biol.
Chem. 281, 14026–14040
111 Rujkijyanont, P., Beyene, J., Wei, K., Khan, F. and Dror, Y. (2007) Leukaemia-related gene
expression in bone marrow cells from patients with the preleukaemic disorder
Shwachman–Diamond syndrome. Br. J. Haematol. 137, 537–544
112 Ong, D. C., Ho, Y. M., Rudduck, C., Chin, K., Kuo, W. L., Lie, D. K., Chua, C. L., Tan, P.
H., Eu, K. W., Seow-Choen, F. et al. (2009) LARG at chromosome 11q23 has functional
characteristics of a tumor suppressor in human breast and colorectal cancer. Oncogene
28, 4189–4200
113 Montero, J. C., Seoane, S., Ocana, A. and Pandiella, A. (2011) P-Rex1 participates in
neuregulin–ErbB signal transduction and its expression correlates with patient outcome
in breast cancer. Oncogene 30, 1059–1071
114 Sosa, M. S., Lopez-Haber, C., Yang, C., Wang, H., Lemmon, M. A., Busillo, J. M.,
Luo, J., Benovic, J. L., Klein-Szanto, A., Yagi, H. et al. (2010) Identification of the
Rac-GEF P-Rex1 as an essential mediator of ErbB signaling in breast cancer. Mol. Cell
40, 877–892
115 Qin, J., Xie, Y., Wang, B., Hoshino, M., Wolff, D. W., Zhao, J., Scofield, M. A., Dowd,
F. J., Lin, M. F. and Tu, Y. (2009) Upregulation of PIP3-dependent Rac exchanger 1
(P-Rex1) promotes prostate cancer metastasis. Oncogene 28, 1853–1863
205
116 Ledezma-Sánchez, B. A., Garcı́a-Regalado, A., Guzmán-Hernández, M. L. and
Vázquez-Prado, J. (2010) Sphingosine-1-phosphate receptor S1P1 is regulated by
direct interactions with P-Rex1, a Rac guanine nucleotide exchange factor. Biochem.
Biophys. Res. Commun. 391, 1647–1652
117 Chen, K., Wang, G., Peng, L., Liu, S., Fu, X., Zhou, Y., Yu, H., Li, A., Li, J., Zhang, S.,
Bai, Y. and Zhang, Y. (2011) CADM1/TSLC1 inactivation by promoter hypermethylation
is a frequent event in colorectal carcinogenesis and correlates with late stages of the
disease. Int. J. Cancer 128, 266–273
118 Takahashi, Y., Iwai, M., Kawai, T., Arakawa, A., Ito, T., Sakurai-Yageta, M., Ito, A.,
Goto, A., Saito, M., Kasumi, F. and Murakami, Y. (2011) Aberrant expression of tumor
suppressors CADM1 and 4.1B in invasive lesions of primary breast cancer. Breast
Cancer, doi:10.1007/s12282-011-0272-7
119 Masuda, M., Kikuchi, S., Maruyama, T., Sakurai-Yageta, M., Williams, Y. N., Ghosh,
H. P. and Murakami, Y. (2005) Tumor suppressor in lung cancer (TSLC)1 suppresses
epithelial cell scattering and tubulogenesis. J. Biol. Chem. 280, 42164–42171
120 Masuda, M., Maruyama, T., Ohta, T., Ito, A., Hayashi, T., Tsukasaki, K., Kamihira, S.,
Yamaoka, S., Hoshino, H., Yoshida, T. et al. (2010) CADM1 interacts with Tiam1 and
promotes invasive phenotype of human T-cell leukemia virus type I-transformed cells
and adult T-cell leukemia cells. J. Biol. Chem. 285, 15511–15522
121 Qin, Y., Capaldo, C., Gumbiner, B. M. and Macara, I. G. (2005) The mammalian Scribble
polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J.
Cell Biol. 171, 1061–1071
122 Garcı́a-Mata, R., Dubash, A. D., Sharek, L., Carr, H. S., Frost, J. A. and Burridge, K.
(2007) The nuclear RhoA exchange factor Net1 interacts with proteins of the Dlg family,
affects their localization, and influences their tumor suppressor activity. Mol. Cell. Biol.
27, 8683–8697
123 Muders, M. H., Dutta, S. K., Wang, L., Lau, J. S., Bhattacharya, R., Smyrk, T. C., Chari,
S. T., Datta, K. and Mukhopadhyay, D. (2006) Expression and regulatory role of
GAIP-interacting protein GIPC in pancreatic adenocarcinoma. Cancer Res. 66,
10264–10268
124 Favre-Bonvin, A., Reynaud, C., Kretz-Remy, C. and Jalinot, P. (2005) Human
papillomavirus type 18 E6 protein binds the cellular PDZ protein TIP-2/GIPC, which is
involved in transforming growth factor β signaling and triggers its degradation by the
proteasome. J. Virol. 79, 4229–4237
125 Muders, M. H., Vohra, P. K., Dutta, S. K., Wang, E., Ikeda, Y., Wang, L.,
Udugamasooriya, D. G., Memic, A., Rupasinghe, C. N., Baretton, G. B. et al. (2009)
Targeting GIPC/synectin in pancreatic cancer inhibits tumor growth. Clin. Cancer Res.
15, 4095–4103
126 Ligensa, T., Krauss, S., Demuth, D., Schumacher, R., Camonis, J., Jaques, G. and
Weidner, K. M. (2001) A PDZ domain protein interacts with the C-terminal tail of the
insulin-like growth factor-1 receptor but not with the insulin receptor. J. Biol. Chem.
276, 33419–33427
127 Wu, D., Asiedu, M. and Wei, Q. (2009) Myosin-interacting guanine exchange factor
(MyoGEF) regulates the invasion activity of MDA-MB-231 breast cancer cells through
activation of RhoA and RhoC. Oncogene 28, 2219–2230
128 te Velthuis, A. J., Sakalis, P. A., Fowler, D. A. and Bagowski, C. P. (2011) Genome-wide
analysis of PDZ domain binding reveals inherent functional overlap within the PDZ
interaction network. PLoS ONE 6, e16047
129 Junqueira, D., Cilenti, L., Musumeci, L., Sedivy, J. M. and Zervos, A. S. (2003) Random
mutagenesis of PDZOmi domain and selection of mutants that specifically bind the Myc
proto-oncogene and induce apoptosis. Oncogene 22, 2772–2781
Received 20 May 2011/5 July 2011; accepted 14 July 2011
Published on the Internet 28 September 2011, doi:10.1042/BJ20110903
c The Authors Journal compilation c 2011 Biochemical Society