67
Cell polarity: Par6, aPKC and cytoskeletal crosstalk
Sandrine Etienne-Manneville and Alan Hall
Par6 and atypical protein kinase C are key players in the
establishment of cell polarity. First discovered in Caenorhabditis
elegans, the function of this protein complex is conserved in all
multicellular organisms. Recent work is beginning to throw light
on how it converts information generated by extracellular cues
into intracellular asymmetry.
Addresses
MRC Laboratory for Molecular Cell Biology, University College London,
Gower Street, London WC1E 6BT, UK

e-mail: Alan.Hall@ucl.ac.uk
Current Opinion in Cell Biology 2003, 15:67±72
This review comes from a themed issue on
Cell structure and dynamics
Edited by Michel Bornens and Laura M. Machesky
0955-0674/03/$ ± see front matter
ß 2003 Elsevier Science Ltd. All rights reserved.
DOI 10.1016/S0955-0674(02)00005-4
Abbreviations
aPKC atypical protein kinase C
CRIB Cdc42/Rac-interactive binding
JAM junctional adhesion molecule
MTOC microtubule organising centre
OPR octicosapeptide repeat
PAR partitioning-defective protein
Introduction
The generation of cell polarity is a fundamental process
controlling the behaviour of all eukaryotic cells. Asym-
metric division of cells in the embryo and chemotaxis of
phagocytic cells in the adult are two obvious examples,
but the establishment of intracellular asymmetry is also a
prerequisite to initiate the complex morphogenetic pro-
gramme that gives rise to epithelial cells and neurons.
Despite the very different biological contexts, many
features of polarity such as recognising an extracellular
cue, marking a cortical site in response to that cue and
propagating a signal from the cue to the rest of the cell, are
quite general. Evidence is beginning to accumulate that a
conserved molecular mechanism operates to regulate
polarity in a wide range of biological processes, in all
animal cells. In this review, we focus on two conserved
proteins, Par6 and atypical protein kinase C (aPKC), and
how they control polarity in different cellular contexts.
Par6 and atypical protein kinase Cs: partners
in the establishment of cell polarity
The genetic analysis of asymmetric cell division in
Caenorhabditis elegans development ®rst led to the
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identi®cation of seven proteins (partitioning-defective
protein [Par]1±6 and aPKC) as key components of the
molecular machinery required to generate cell polarity.
Recent evidence reveals that two of these proteins, Par6
and aPKC, are also essential for the establishment and
maintenance of polarity during cell morphogenesis and
directed cell migration [1].
Par6, one conserved molecule involved in different
types of cell polarisation
C. elegans Par6 was ®rst identi®ed in 1996 during a screen
for mutants with a partitioning-defective phenotype (par)
[2]. Embryogenesis in C. elegans begins with ®ve asym-
metric cell divisions that establish the fate of the six
founder cells of the embryo [3]; and in par-6 mutants, the
blastomeres are of equal size and the subsequent division
cleavages are also abnormal. An orthologue of Par6 in
Drosophila (DmPar6) is essential for the asymmetric divi-
sion of delaminating neuroblasts, a prerequisite for sub-
sequent cell fate determination to neurons or glia [4].
More recently, DmPar6 has been shown to play a role in
¯y oocyte differentiation [5]. During oogenesis, a cysto-
blast divides four times with incomplete cytokinesis, to
produce a cyst of 16 interconnected cells, from which one
posterior cell differentiates into an oocyte, while the other
15 become nurse cells. Deletion of DmPar6 causes the
development of egg chambers with 16 nurse cells and no
oocyte.
The contribution of Par6 to polarity is not restricted to
asymmetrical cell division. It is, for example, required for
the maintenance of cell morphology; and in the absence
of DmPar6, epithelial cells of embryonic Drosophila
ectoderm lose their apical±basal polarity [4]. Similarly,
in mammalian epithelial cells, Par6 is necessary for the
asymmetric distribution of membrane proteins between
the basolateral and apical surfaces [6]. Finally, Par6 is
essential for establishing cell polarity in an in vitro migra-
tion assay using primary rat astrocytes [7].
Atypical protein kinase Cs and Par3 form a complex
with Par6
Immunolocalisation studies have revealed that Par6 loca-
lises to the anterior periphery of asymmetric dividing cells
in the C. elegans zygote, along with Par3, another Par gene
product, and PKC3, the single aPKC in worms [8]. This
observation led to the subsequent identi®cation of these
two molecules as binding partners for Par6.
The ®rst PDZ domain of the highly conserved Par3
protein interacts with the single PDZ domain of Par6
(Figure 1) [9]. Furthermore, Par6 co-immunoprecipitates
Current Opinion in Cell Biology 2003, 15:67±72
68 Cell structure and dynamics
Figure 1
(a)
Inactive Par6 complex
Activation by
Par6
Cdc42
1 2 3
aPKC Par3
(b)
Inactive Par6 Activation by
(closed conformation) aPKCs or Cdc42
CRIB motif
Kinase domain
PDZ domain
OPR motif
Phosphorylation site
Par6 complexes and their regulation. The major domains responsible for the interaction of Par6 with its different binding partners are indicated in
colour. Two mechanisms of regulation of Par6 have been proposed: (a) Par6±aPKCs±Par3 form a stable complex. Upon Cdc42±GTP binding to Par6,
aPKC is activated and can, in turn, phosphorylate proteins, including Par3. This may lead to the dissociation of the three molecules. (b) Par6 is present
in an inactive conformation. The binding of activated Cdc42 or aPKC leads to a change in the conformation of Par6, allowing it to interact with Par3.
with the two human atypical PKCs, PKCz and PKCl from
mammalian cell extracts [9,10]. The association of these
molecules is direct and mediated by the amino-terminal
domain of Par6, which binds to the amino-terminal
domain of aPKC. Critical residues appear to lie in octi-
cosapeptide repeat (OPR) motifs, present in both Par6
and aPKC [11] (Figure 1). In fact, mutation of two
conserved aspartate residues within the OPR domain
of PKCz abolishes its binding to Par6. OPR is present
in other PKCs and in several target proteins for Rho
GTPases, and is likely to represent an important new
protein±protein interaction domain.
Like Par6, Par3 and aPKCs are essential for polarisation of
the C. elegans embryo [2,12]. The Drosophila orthologues
Bazooka (Par3) and DaPKC are similarly required for
generation of asymmetric division of neuroblasts, and
they co-localise with DmPar6 at the apical cortex [5].
Bazooka and DaPKC are also required for oocyte differ-
entiation, and co-localise at sites of germ cell intercon-
nections during oocyte differentiation [13] (Figure 2b).
The Par6±Par3±aPKC complex is also conserved in Xeno-
pus, where it localises to the animal pole of oocytes [14,15].
In epithelial cells, Par6, Par3 and aPKC co-localise at cell±
cell contacts and play a crucial role in the establishment of
Current Opinion in Cell Biology 2003, 15:67±72
Cdc42–GTP
1 2 3
+
Phosphorylation
of Par3?
P P P
Activation of a PKC
Cdc42–GTP
aPKC
Active Par6
(open conformation)
1 2 3 Par3
Formation of a Par6–Par3 complex
Current Opinion in Cell Biology
cell polarity (reviewed in [1]). Finally, during astrocyte
migration, Par6 and PKCz are both found at the leading
edge of migrating cells [7] and their activities are
required for cell polarisation, although in this case
Par3 does not appear to co-localise with Par6 or PKCz
(S Etienne-Manneville, unpublished data; Figure 2b).
It can be concluded, therefore, that Par6, Par3 and aPKC
are highly conserved within multicellular organisms and are
involved in many widely differing aspects of cell polarity.
Regulation of Par6 and atypical protein
kinase C by Cdc42
A key step towards understanding how cell polarity is
regulated came with the observation, by three different
groups, that Par6 is a direct target for two small GTPases,
Cdc42 and Rac (Figure 1). Cdc42, in particular, has been
shown previously to play a pivotal role in regulating
polarity, not only in animal cells but also in yeast [16±
19]. An orthologue for Par6 has not been found in Sac-
charomyces cerevisiae, and it may be that in this organism
Cdc42 in¯uences cell polarity in other ways. Neverthe-
less, con®rmation that Cdc42, Par6 and aPKC are all
required for asymmetric cell division in the C. elegans
zygote, has recently been obtained using an RNA inter-
ference (RNAi) approach [20].
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 Cell polarity: Par6, aPKC and cytoskeletal crosstalk Etienne-Manneville and Hall 69

Figure 2

(a) Drosophila epidermal cells Mammalian epithelial cell

Apical

⇒ Maintenance of Tight junctions ⇒ Formation of

Adherens junctions
adherens junctions adherens junctions tight junctions

N N

Basal

(b) (i) (ii) (iii)

⇒ Posterior positionning
Anterior Posterior of the MTOC Direction of migration
Leading edge Rear

N
Dynein
Dynein

Oocyte Nurse cells ⇒ Re-orientation of the MTOC

⇒ Asymmetric
spindle positionning
Current Opinion in Cell Biology

Multiple roles of Par6 complexes. (a) In epithelial cells, Par6 co-localises with aPKCs and Par3 at cell±cell contacts. The trimolecular complex is
involved in the formation of tight junctions in mammalian epithelial cells and in the maintenance of cell±cell contacts and adherens junctions of
Drosophila epithelium. N, nucleus. (b) During asymmetric division or migration, Par6 complexes are involved in the organisation of the microtubule
cytoskeleton and the localisation of the MTOC. (i) Polarisation of the C. elegans embryo. Par6, Par3 and PKC3 co-localise at the anterior pole and
control the forces exerted on the anterior aster allowing the asymmetric positioning of the spindle. (ii) Differentiation of Drosophila oocytes. DmPar6,
Bazooka and DaPKC co-localise around the ring canal in a region where microtubules can also been found. The three proteins are involved in the
posterior positioning of the MTOC in the germarial cyst, leading to the differentiation of the oocyte. (iii) Polarisation of migrating astrocytes. Par6 and
PKCz co-localise at the leading edge of migrating cells and are involved in the reorientation of the MTOC. The blue lines/dots indicate the localisation
of the Par6±aPKC complex. In the C. elegans embryo and Drosophila egg chamber, Par3 co-localises with this complex. Microtubules are green, the
MTOC red and dynein localisation violet. Arrows indicate forces that might act on microtubules and lead to MTOC positioning.

Many Ð but not all Ð target proteins for Rac and Cdc42
contain a consensus sequence, the CRIB (Cdc42/Rac-
interactive binding) motif. Par6 has a partial CRIB motif,
which also requires a part of the neighbouring PDZ
domain to form a recognition site for Cdc42. What are
the consequences of GTPase binding? The binding of
activated Cdc42 to two other target proteins, Wiscott±
Aldrich syndrome binding protein (WASP) and p65Pak, is
known to induce a conformational change that then
allows these targets to participate in additional protein±
protein interactions. Whether this is true for Par6 is not
known, but its interaction with PKCz, at least, appears to
be independent of active Cdc42. The biochemical rela-
tionship between Par6, Par3, aPKC and Cdc42 remains
confusing. Experiments carried out using transfected
cells suggest that Par6 can mediate stimulation of aPKCs
in response to activated (GTP-bound) Cdc42 or Rac [10]
(Figure 1a). In agreement with this, initiation of migration
in astrocyte monolayers leads to the Cdc42-dependent
activation of PKCz [7]. Another potential consequence of
Cdc42 binding to Par6 is to allow binding to Par3 [11];
however, this is predicted to lead to a completely differ-
ent outcome in terms of PKCz activity, since Par3 has
been reported to bind to and inhibit its kinase domain
[21] (Figure 1a).
One recurrent observation is that Par6 and aPKCs pre-
cisely co-localise, and that this is essential for the estab-
lishment of polarity. In the C. elegans zygote, Par6 and
PKC3 co-localise with Par3 at the anterior pole of the
zygote, and Par6 depletion leads to a mislocalisation of
both PKC3 and Par3. Interestingly, aPKCs and Par3 are
both required for the correct localisation of Par6 [8], an
observation con®rmed in Drosophila. This suggests a
pathway of positive-feedback loops that are likely to
involve Cdc42. This strongly suggests that here, at least,
the interaction of Par6 with activated Cdc42 leads to the
recruitment of Par6 and its binding partners, Par3 and
aPKCs (Figure 1a). The situation in other systems is not
so clear. In epithelial cells, for example, Par6 localises
with Par3 and PKCz to tight junction, but there are con-
¯icting reports concerning the role of Cdc42 in this [11,22].

www.current-opinion.com Current Opinion in Cell Biology 2003, 15:67±72

70 Cell structure and dynamics
Towards an understanding of the molecular
mechanisms controlling cell polarity
Par6±aPKC±Par3 regulates tight-junction formation,
leading to epithelial cell polarity
In epithelial cells, the basolateral and apical domains are
segregated by tight junctions, which is essential for estab-
lishing and maintaining their polarised morphology. A
key event during the formation of tight junctions is the
recruitment of the Par6±aPKC±Par3 trimolecular com-
plex from the cytoplasm to sites of cell±cell contacts [6].
The tight-junction-associated protein JAM (junctional
adhesion molecule), which is recruited at the very initial
phase of cell±cell contact, contains a Par3-binding domain
necessary for the co-recruitment of Par6 and aPKC and for
the development of tight junctions [23,24]. Whether the
presence of JAM at the plasma membrane is suf®cient to
promote the recruitment of Par6-containing complexes is
still unclear. As described above, it seems highly likely
that Par6 complexes are carefully regulated; and, indeed,
phosphorylation of Par3 by aPKCs at Ser827 is observed
during the initial phase of tight-junction formation [25].
Cdc42 is an obvious candidate for regulating the activity
of the Par6/aPKC-containing complex, but it has been
reported by one group to be dispensable for tight-junction
formation [11]. Gao et al. [11] found that expression of a
truncated or mutated Par6 that can no longer interact
with aPKC slows down tight-junction assembly and the
establishment of transepithelial resistance in MDCK
cells. They postulate that aPKC activates Par6, leading
to its binding to Par3 and recruitment into junctions
(Figure 1b).
This model does not account for the presence, in the
cytosol, of a pre-formed Par6±Par3±aPKC complex before
the formation of cell±cell contact [6], and it is not clear
how aPKCs are activated if not by Cdc42. An earlier study
concluded, however, that Cdc42 is required for tight-
junction function in MDCK cells [22].
Since inhibition of the Par complex delays, but does not
completely block, tight-junction formation, nor does it
disrupt pre-existing junctions, the complex may be a
facilitator, rather than an essential component of the
junction. In agreement with this, overexpression of
Par3 promotes cell±cell-contact-induced tight junctions
[25], which would be consistent with it being a limiting
factor in these cells. Interestingly, Par3 expression levels
are upregulated as a consequence of E-cadherin-
mediated adhesion [26].
The Drosophila embryonic epithelium does not contain
the typical characteristic tight junctions seen in mamma-
lian cells. Nevertheless, a DmPar6±Bazooka±DaPKC
complex is required for epithelial polarity, and DmPar6
concentrates in apicolateral spots that are probably func-
tionally analogous to tight junctions (Figure 2a). No
Current Opinion in Cell Biology 2003, 15:67±72
orthologue of JAM has been described in Drosophila
and the mechanism by which the Par6 complex is
recruited to cell±cell junctions in this organism remains
to be determined.
Par6±aPKC±Par3 regulates cell polarity in asymmetric
cell division and in cell migration
It is clear that zygote development depends on the
asymmetric distribution of protein and mRNA cell-fate
determinants. In C. elegans, the antero±posterior axis is
established after fertilisation by the point of sperm entry,
which becomes the embryo's posterior pole. The sperm
polarises the cytoskeleton and directs cytoplasmic ¯ow,
and it appears that components of the sperm's microtu-
bule organising centre (MTOC) generate signals to initi-
ate the asymmetric localisation of Par proteins (Figure 2b)
[27,28]. One possibility is that entry of the sperm aster
activates Cdc42 at the posterior pole, leading to the
recruitment and activation of Par6, Par3 and PKC3.
Par proteins control the pulling forces applied to the
anterior and posterior asters, which determine the poster-
ior displacement of the spindle; and in Par mutants, the
positioning of the mitotic spindle is defective [29]
(Figure 2b). The microtubule network has also been
implicated in Drosophila oocyte differentiation, where
the MTOC localises at the posterior pole within the
future oocyte, allowing oocyte speci®cation factors to
be transported towards that pole via a microtubule-
dependent mechanism [30] (Figure 2b). Microtubules
project through a region between germ cells where
Bazooka and DaPKC concentrate [13]. Moreover,
Bazooka and aPKC are required for the posterior estab-
lishment of the MTOC in germarial cyst cells and there-
fore in the localisation of speci®cation factors [13].
During astrocyte cell migration, analysed in an in vitro
scratch-healing assay, the activity of Par6 and PKCz direct
the reorientation of the MTOC to a position in front of the
nucleus, facing the direction of migration [7] (Figure 2).
The microtubule cytoskeleton is absolutely required for
orientation of the MTOC, and it is thus tempting to
speculate that Par6 regulates the activity of the plus ends
of microtubules at the cortex. In fact, there is strong
evidence that the microtubule motor protein dynein is
required for the establishment of MTOC polarity in
migrating cells as well as during Drosophila oocyte differ-
entiation [7,31,32] (Figure 2b). Inhibition of DaPKC,
for example, perturbs dynein accumulation, which
normally occurs at the posterior of the oocyte [13,33].
When associated with the plasma membrane, dynein Ð
minus-end-directed motor protein Ð could provide a
pulling force on microtubules to promote the transloca-
tion of the MTOC within a cell. Interestingly, in yeast a
dynein motor has been implicated in the sliding of
microtubules along the bud neck using a similar sort of
mechanism.
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 Cell polarity: Par6, aPKC and cytoskeletal crosstalk Etienne-Manneville and Hall 71
An alternative and surprising suggestion Ð that aPKC
interacts with and phosphorylates glyceraldehyde 3-phos-
phate dehydrogenase to promote microtubule binding
to the plasma membrane Ð has also been proposed
[34].
Some aspects of asymmetric cell division are, however,
clearly microtubule independent, suggesting that Par
proteins could also be involved in other aspects of cell
regulation. Cdc42 RNAi and some Par mutants in C.
elegans evoke changes in actin micro®lament organisation
[20]. In ®broblasts, aPKCs have been reported to med-
iate the Cdc42-induced disruption of stress ®bres [35] and
Par6 and aPKC both co-localise in Rac-induced mem-
brane ruf¯es [36]. In addition to aPKCs, Par3 can mediate
actin rearrangements; and when overexpressed in MDCK
cells, Par3 leads to some interesting changes in cell
behaviour [26]: the cells have increased ruf¯ing activity,
which is microtubule-, Rac- and actin-dependent, and are
unable to respond normally to cell±cell contact. It has
been reported that inhibition of PKCz gives a similar
phenotype [37].
Conclusions and perspectives
There has been signi®cant progress in identifying key
molecules involved in the establishment of cell polarity.
Although this came from work on asymmetric cell divi-
sion, it is clear that the same molecules are involved in the
control of polarity in a wide variety of biological contexts,
including morphogenesis and cell migration. The exact
biochemical role of the Par6±PKCz±Par3 complex is still
unclear, and how this links to the microtubule and actin
cytoskeletons is an important and pressing issue. Cdc42,
too, is central to polarity in all eukaryotic cells, including
yeast, and the mechanism by which it is spatially acti-
vated is likely to provide important insights into how cells
interpret extracellular directionality cues.
Acknowledgements
We are grateful for support from Cancer Research UK and the Medical
Research Council. S Etienne-Manneville is supported by an EMBO long-
term fellowship.
References and recommended reading
Papers of particular interest, published within the annual period of
review, have been highlighted as:
 of special interest
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