Podosomes at a Glance - Journal of Cell Science - The Company of ...

Journal of Cell Science
Cell Science at a Glance 2079
Podosomes at a glance
Stefan Linder* and Petra Kopp
Institut für Prophylaxe und Epidemiologie der
Kreislaufkrankheiten, Ludwig-Maximilians-
Universität, Pettenkoferstr. 9, 80336 München,
Germany
*Author for correspondence (e-mail:
stefan.linder@med.uni-muenchen.de)
Journal of Cell Science 118, 2079-2082
Published by The Company of Biologists 2005
doi:10.1242/jcs.02390
Cells can contact the extracellular matrix
(ECM) through a variety of specialized
structures. These cell-matrix contacts
contain membrane proteins such as
integrins, which bind both matrix
components and cellular proteins, thus
bridging the substratum and the
cytoskeleton (reviewed in Adams,
2001). Matrix contacts provide the
physical linkage that enables cells to
Overlay Talin F-actin
Structure
Functions
10 µm
Adhesion
Close contact to substratum
Enrichment of adhesion-mediating integrins
Formation at substrate-attached cell side
adhere to and migrate on (or through) the
matrix. Moreover, they can also act as
localized ‘relay stations’ for important
signaling pathways. Well-known cellmatrix
contacts include focal complexes
and focal adhesions, whereas others,
such as fibrillar adhesions, podosomes
and invadopodia are just beginning to
attract widespread attention.
Focal complexes have a dash-like
appearance, a length of ~0.5 µm and
constitute some of the earliest matrix
contacts formed by a protruding cell.
They are integrin-based and enriched in
talin, paxillin and vinculin (Zamir and
Geiger, 2001). Focal complexes can
mature into focal adhesions through the
application of force – for example, during
the retraction of cellular protrusions. This
transformation is accompanied by an
increase in size, the formation of actin
Podosomes at a Glance
Stefan Linder and Petra Kopp
Plasma
membrane
Vinculin TIRF Overlay
PI3K
Src
10 µm
Human macrophage expressing YFP-vinculin
Ring structure
Integrins &
associated proteins
Podosome model
Core
F-actin &
associated proteins
Pyk2/FAK
Paxillin Talin
Dynamin MMPs CDC42
WASP/
Vinculin
α-Actinin
β2/β3 Integrin
β1 Integrin
N-WASP
jcs.biologists.org
Matrix degradation
Enrichment of matrix metalloproteinases
Colocalization with matrix degradation
F-actin Alexa 488-fibronectin Overlay
Linder and
Aepfelbacher, 2003
F-actin
Arp2/3
complex
Fimbrin
Gelsolin
Cortactin
Osiak et al., 2005
10 µm
Human umbilical vein endothelial cell (HUVEC) on labeled matrix
bundles (stress fibres), that contact the
structure, and the recruitment of zyxin
(Zaidel-Bar et al., 2004). Focal adhesions
are formed on rigid substrates and contain
high levels of phosphotyrosine but low
amounts of the actin-binding protein
tensin. On soft matrices, however, focal
adhesions can give rise to a third type of
contact, fibrillar adhesions. In contrast to
focal adhesions, fibrillar adhesions
display high levels of tensin but contain
little phosphotyrosine (Zamir et al., 1999).
In sum, these matrix contacts not only
impart close adhesion to the substratum
but also act as mechanosensors, and their
ultimate form (focal adhesion vs fibrillar
adhesion) depends strongly on matrix
rigidity (Zamir and Geiger, 2001).
Podosomes and invadopodia
Podosomes and invadopodia constitute
trailing edge
WASP/
N-WASP
Arp2/3 complex
Actin
nucleation
CDC42
F-actin
severing
+uncapping
Ring Core
Attachment
Regulation
Gelsolin PI3K
Dynamics
10 µm
Rho (Rac)
PtdIns(3,4)P2 PtdIns(3,4,5)P3 Vinculin
Talin
leading edge
Ring structure
formation
Paxillin
Integrin activation
RTK signaling
Pyk2/FAK
Src
kinase
PKC
Primary human
macrophage
expressing
GFP-actin
Dissolution ( ) and fission (O) of podosomes
© Journal of Cell Science 2005 (118, pp. 2079-2082)
(See poster insert)

Journal of Cell Science
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Journal of Cell Science 118 (10)
two forms of dot-like matrix contact that
differ from those described above
structurally and functionally (reviewed
in Linder and Aepfelbacher, 2003;
Buccione et al., 2004). Structurally, their
most distinguishing feature is their twopart
architecture: they have a core of Factin
and actin-associated proteins that is
surrounded by a ring structure consisting
of plaque proteins such as talin or
vinculin. This actin-rich core is not
present in other cell-matrix contacts.
Consequently, actin regulatory pathways
exert a major additional influence on
podosome-type contacts. Functionally,
the ability of podosomes and
invadopodia to engage in matrix
degradation clearly sets them apart from
other cell-matrix contacts.
Podosomes are typically formed in cells
of the monocytic lineage, such as
macrophages (Lehto et al., 1982; Linder
et al., 1999), osteoclasts (Marchisio et
al., 1984) or (immature) dendritic cells
(Burns et al., 2001). However, they can
also be found or induced in a variety of
other cell types, including smooth
muscle cells (Gimona et al., 2003) and
endothelial cells (Moreau et al., 2003;
Osiak et al., 2005).
By contrast, invadopodia are found in
fibroblasts transformed with viral
oncogenes encoding protein tyrosine
kinases (Tarone et al., 1985) and in some
malignant cell types (Buccione et al.,
2004). Indeed, the first observation of
podosome-type adhesions 25 years ago
described such virally induced
invadopodia (David-Pfeuty and Singer,
1980).
Podosomes and invadopodia differ in
their respective sizes and numbers.
Typically, a cell forms dozens of
podosomes, but there are only a few
invadopodia per cell. However, what
invadopodia lack in numbers, they make
up for in size: Podosomes have a
diameter of 0.5-1 µm and a depth of 0.2-
0.4 µm, whereas invadopodia can
correspond to an array of membrane
invaginations that have a diameter of ~8
µm and also can form root-like
extensions into the matrix that are
several micrometers deep (Buccione et
al., 2004; McNiven et al., 2004).
Despite these differences, basic
similarities between the two structures,
both in composition and architecture, are
apparent. Indeed, it has been proposed
that invadopodia might develop from
podosomal precursors (Linder and
Aepfelbacher, 2003; Buccione et al.,
2004). It is therefore an attractive
speculation that podosomes and
invadopodia represent a continuum of
specialized matrix contacts comparable
to the succession of focal complexes,
focal adhesions and fibrillar adhesions
described above.
The growing list of podosomecontaining
cells may point to a
widespread ability of cells to form this
type of actin-rich structure. Furthermore,
the fact that podosomes are also formed
on soft substrates, such as endothelial
monolayers (Linder and Aepfelbacher,
2003), adds to the notion that podosomes
are physiological structures that are also
formed in the context of tissues.
Functions
The main functions of podosomes
appear to be adhesion and matrix
degradation. Moreover, podosomes have
also been implicated in cell migration
and invasion. However, much of the
evidence for these functions is still
circumstantial and needs to be rigorously
tested.
It is very possible that podosomes have
a role in adhesion, because they establish
close contact to the substratum, which
can be shown by total internal reflection
(TIRF) microscopy, are enriched in
adhesion-mediating integrins (Linder
and Aepfelbacher, 2003) and form only
at the substrate-attached cell side.
The aptly named invadopodia were
defined through their ability to perform
matrix degradation (Buccione et al.,
2004; McNiven et al., 2004). For
podosomes, the case has been less clear
cut: podosomes in osteoclasts are
enriched in matrix metalloproteases
(Sato et al., 1997; Delaissé et al., 2000),
but it was not shown until recently that,
in various cell systems, podosomes
overlap regions of matrix degradation
(Burgstaller and Gimona, 2005; Osiak et
al., 2005). It is therefore very possible
that podosomes, like invadopodia, have
an inherent ability to lyse the ECM.
Podosomes may also play an accessory
role in cell migration. They might help to
establish localized anchorage, thus
stabilizing sites of cell protrusion and
ultimately enabling productive directional
movement. The observation that
podosomes are recruited to sites of cell
protrusion, especially to the leading edge,
appears to be in line with such a concept.
Podosome-type adhesions are mainly
formed in cells that have to cross tissue
boundaries such as monocytes,
immature dendritic cells or some types
of cancer cell (invadopodia in this case).
Podosome-localized matrix degradation
at the leading edge may therefore also
confer invasive potential to cells.
Finally, podosomes are a prominent part
of the actin cytoskeleton in osteoclasts,
where they form continuous belts at the
cell periphery (Pfaff and Jurdic, 1999).
Their probable roles in adhesion and
matrix degradation suggest an important
role in bone homeostasis. Moreover, their
fusion was believed to form the boneremodeling
organelle of osteoclasts, the
so-called sealing zone, a tightly adherent
structure surrounding the space into
which lytic enzymes and protons are
secreted (Lakkakorpi and Väänänen,
1996). However, recent data suggest that
both types of organelle are formed
independently (Saltel et al., 2004).
Furthermore, on mineralized bone, their
physiological substrate, osteoclasts form
only sealing zones, but not podosomes
(Saltel et al., 2004). The proposed role
for podosomes – as opposed to sealing
zones – in bone homeostasis is therefore
again open for debate.
Structure and components
Podosomes comprise a core of F-actin
and actin-associated proteins embedded
in a ring structure of integrins and
integrin-associated proteins (see poster,
middle and right). Ring and core are
probably linked by bridging molecules
such as α-actinin, and the whole structure
is surrounded by a cloud of mostly
monomeric actin molecules (Destaing et
al., 2003). Many podosome components
show a distinct localization to either the
core or ring structure. Typical core
components are F-actin, actin regulators
such as members of the Wiskott-Aldrich
Syndrome protein (WASP) family, the

Journal of Cell Science
Cell Science at a Glance 2081
Arp2/3 complex, gelsolin and cortactin,
whereas adhesion mediators such as
paxillin, vinculin or talin, and kinases
such as PI3K or Pyk2/FAK preferentially
associate with the ring structure (Linder
and Aepfelbacher, 2003; Buccione et al.,
2004).
Podosomes are anchored in the
extracellular matrix through integrins.
These are distributed over the whole
outer surface of the podosome, but show
an isotype-specific localization: β1
integrins localize mostly to the core,
whereas β2 and β3 integrins localize to
the ring.
Regulation
Podosomes are influenced by a variety of
cellular signaling pathways. Major
modes of podosome regulation include
signaling by Rho family GTPases, actin
regulatory pathways, protein tyrosine
phosphorylation, and the influence of the
microtubule system.
Rho GTPases
The RhoGTPases RhoA, Rac1 and
CDC42 have all been shown to regulate
podosome turnover in various cell types.
Their influence on podosomes is
undisputed; however, their particular
mode of action may depend on the cell
type. For example, both dominant active
and inactive mutants of these GTPases
can interfere with podosome formation
or localization in dendritic cells (Burns
et al., 2001), while expression of
dominant active CDC42 leads to
podosome formation in aortic
endothelial cells (Moreau et al., 2003).
In any case, podosome turnover appears
to need subcellular fine tuning of the
GTP/GDP cycles of these cellular master
switches (Linder and Aepfelbacher,
2003). Accordingly, active Rho has been
localized to invadopodia in transformed
fibroblasts (Berdeaux et al., 2004).
Actin regulation
The most prominent feature of
podosomes is their F-actin-rich core,
which is also necessary for the stability
of the whole structure (Lehto et al.,
1982). Members of the WASP family, as
well as actin-nucleating Arp2/3 complex
are both strongly enriched in the
podosome core. Absence of these
components, either induced artificially
(Linder et al., 2000a) or in disease
(Linder et al., 1999; Burns et al., 2001)
(reviewed in Calle et al., 2004), results
in disruption of podosomes. Another
prominent podosome component
involved in actin regulation is gelsolin. It
probably contributes to actin turnover
through its ability to both sever and cap
actin filaments (Chellaiah et al., 1998).
Tyrosine phosphorylation
It was noted early on that podosome-type
adhesions can be induced by
transformation of cells with viruses
whose oncogenes encode tyrosine
kinases such as v-Src (Tarone et al.,
1985; Marchisio et al., 1987). Indeed,
one of the best ways to visualize
podosomes is by staining phosphorylated
tyrosine (Linder and Apfelbacher, 2003),
which is highly enriched in some types of
adhesive structure. Not surprisingly,
cellular tyrosine kinases such as Src and
Csk play major roles in podosome
regulation (Howell and Cooper, 1994),
and tools for podosome manipulation
include Src kinase inhibitors, which
disrupt podosomes (Linder et al., 2000b),
and vanadate, a phosphotyrosine
phosphatase inhibitor, which is able to
induce podosome formation (Marchisio
et al., 1988).
Microtubules
Microtubules are closely associated with
podosomes. Moreover, they have been
shown to stabilize podosome patterns
such as the marginal belts in osteoclasts
(Babb et al., 1997), to influence the
fusion and fission rates of podosome
precursors in murine macrophages
(Evans et al., 2003) and to regulate
podosome formation in human
macrophages (Linder et al., 2000b).
A model for podosome formation
Analysis of podosome-inducing pathways
has been performed in a variety of
cell types. From these data we can
propose the following simplified model
for podosome formation: The key signal
for initiation is attachment of the cell to
the substrate, because podosomes are
only observed in adherent cells. This
leads to clustering and activation of
integrins and signaling by receptor
tyrosine kinases. One of the most
upstream signals is probably PKC
activity. This is underscored by the fact
that podosome formation can be induced
by PKC-activating agents, such as
phorbol esters (Gimona et al., 2003).
An important subsequent switch is
activation of Src. Downstream, a variety
of pathways are initiated, most notably
PI3K signaling (Chellaiah et al., 1998),
which leads to the formation of the
phosphatidylinositols PtdIns(3,4)P2 and
PtdIns(3,4,5)P3, and activation of focal
adhesion kinase (FAK) or its
haematopoietic relative Pyk2. 3�
phosphoinositide signaling is also
influenced by the RhoGTPases Rho and
(probably) Rac (Chellaiah et al., 2001;
Sechi and Wehland, 2000).
CDC42, another RhoGTPase, is crucial
for the local initiation of actin filament
formation, which gives rise to the
formation of the actin-rich core
structure. This is achieved by releasing
the autoinhibition of N-WASP or its
relative WASP, which in turn activates
actin-nucleating Arp2/3 complex
(Linder et al., 1999; Linder et al., 2000a;
Burns et al., 2001). Turnover of corelocalized
actin filaments is probably
facilitated by gelsolin (Chellaiah et al.,
1998) and the GTPase dynamin
(McNiven et al., 2004; Buccione et al.,
2004). Additionally, dynamin may also
play a role in podosome-localized matrix
degradation by facilitating matrix
metalloprotease release.
It is unclear how core- and ringformation
are coordinated. However,
similarly to core molecules, central
components of the ring structure, such as
talin and vinculin, are also influenced by
phosphoinositides (Sechi and Wehland,
2000), and activation of paxillin through
integrin-related signaling (Pfaff and
Jurdic, 2001) may constitute one of the
earliest signals in ring formation.
Dynamics
Podosomes are highly dynamic
organelles with a half-life of 2-12
minutes. Moreover, their inner dynamic
is even faster: F-actin in the core turnes
over 2-3 times during the life span of a
podosome (Destaing et al., 2003).
Individual podosomes are motile within

Journal of Cell Science
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Journal of Cell Science 118 (10)
a certain radius, but movement of larger
podosome groups is achieved through
assembly at the front and disassembly at
the rear. This is especially visible in
migratory cells where podosomes are
recruited to the leading edge.
Podosomes can assemble de novo or by
branching off precursor clusters, which
undergo constant fusion and fission
(Evans et al., 2003) (see poster, lower
right). ‘Regular’ podosomes are mostly
found in the inner regions of the cell,
while the larger precursor clusters
localize to the cell periphery or the
leading lamella of migrating cells.
Disease
Podosomes are assembled from
molecules that have multiple functions
in the cell, such as actin and Src kinases.
Inhibitors of podosome assembly
therefore also have profound effects
on other parts of the cytoskeleton.
Similarly, the absence of podosomes in
diseases based on defects in a podosome
component(s) may only constitute a side
effect. The podosome aficionado should
therefore take care to ascertain whether
a lack of podosomes causes or is simply
symptomatic of a particular phenotype.
Podosome-associated diseases include
Wiskott-Aldrich Syndrome (WAS) and
chronic myeloid leukemia (CML).
WAS-patient macrophages (Linder et
al., 1999) and dendritic cells from CML
patients (Dong et al., 2003) both display
pronounced defects in podosome
formation and chemotaxis.
We thank Bettina Ebbing for help with TIRF
microscopy, Alexander Bershadsky for the gift of
YFP-vinculin, Peter C. Weber and Jürgen
Heesemann for continuous support and Barbara
Böhlig for expert technical assistance. Work from
our lab is supported by the Deutsche
Forschungsgemeinschaft (GRK 438, SFB 413), the
Friedrich Baur Stiftung and the August Lenz
Stiftung. We apologize to all whose work was not
mentioned owing to space limitations.
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