Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USA
* Author for correspondence (e-mail: fgertler{at}mit.edu)
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Summary |
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Key words: Ena/VASP, VASP, Mena, Capping protein, Actin, Cell motility, Lamellipodia
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Introduction |
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The Ena/VASP family |
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Members of the Ena/VASP family share a conserved domain structure
consisting of an N-terminal Ena-VASP-homology-1 (EVH1) domain, a central
polyproline-rich core and a C-terminal EVH2 domain
(Fig. 1). The EVH1 domain binds
to proteins that contain motifs with the consensus (D/E)FPPPPX(D/E)(D/E).
Subcellular targeting of Ena/VASP proteins to focal adhesions depends upon
EVH1-mediated interactions with zyxin and vinculin, both of which contain
EVH1-binding sites (Gertler et al.,
1996; Niebuhr et al.,
1997
). Another EVH1 ligand, FYB/SLAP, recruits Ena/VASP to
immunological synapses in T-cells and to phagocytic cups in macrophages
(Coppolino et al., 2001
;
Krause et al., 2000
).
Listeria recruits Ena/VASP by displaying the bacterial ActA protein
on its surface, which harbors multiple copies of the EVH1 ligand in a classic
example of evolutionary mimicry
(Chakraborty et al., 1995
). The
central proline-rich domain contains binding sites for SH3 and WW domains as
well as for the G-actin binding protein profilin. The EVH2 domain is required
for multimerization and for F-actin binding
(Ahern-Djamali et al., 1998
;
Bachmann et al., 1999
;
Carl et al., 1999
;
Laurent et al., 1999
).
|
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What is the controversy about Ena/VASP proteins? |
---|
By contrast, the following studies were interpreted as indications of a
negative role for Ena/VASP proteins in actin-dependent cellular processes.
First, platelets isolated from VASP knockout mice exhibit increased rates of
collagen-induced platelet aggregation (an actin-dependent process) compared
with wild-type platelets (Aszodi et al.,
1999; Hauser et al.,
1999
). Second, fibroblasts devoid of Ena/VASP proteins exhibit
increased rates of cell motility (Bear et
al., 2000
). Third, Bashaw and colleagues presented genetic
evidence that Ena is required, in part, for the repulsive phenotype of the
axon guidance receptor Robo in Drosophila
(Bashaw et al., 2000
). Fourth,
neutralization of Ena/VASP function in neurons within the developing neocortex
caused the neurons to migrate significantly farther than normal neurons. The
aberrant superficial placement of Ena/VASP-inhibited neurons was cell
autonomous, and the phenotype is consistent with increased rates of neuronal
migration (Goh et al.,
2002
).
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How can these apparent discrepancies be explained? |
---|
Although all these processes are actin dependent, they are not directly
comparable. A protein that positively regulates actin polymerization might
change the geometry of the actin filament network in addition to stimulating
actin assembly. The net effect of such changes in the filamentous actin
network may not be easy to predict. The notion that the amount of actin
polymerization is positively correlated with cell motility rates is not
necessarily true. For example, although it is widely accepted that capping
protein blocks monomer addition at the barbed ends of actin filaments,
overexpression of capping protein in Dictyostelium results in faster
cell migration (Hug et al.,
1995). Therefore, here we first discuss the function of Ena/VASP
proteins in actin polymerization at a molecular level and then explain the
outcomes of the different approaches used to study Ena/VASP function in cells
and organisms.
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What is the effect of Ena/VASP proteins on actin polymerization? |
---|
So how do Ena/VASP proteins regulate actin polymerization? One clue comes
from their localization: they are concentrated in places that contain growing
free barbed ends of actin filaments, such as the distal tips of lamellipodia
or filopodia. In fact, the distribution of Ena/VASP to these structures
depends upon their interaction with growing barbed ends. Treatment of cells
with low doses of cytochalasin D, a drug that binds barbed ends and blocks
polymerization, delocalizes Ena/VASP proteins from the tips of lamellipodia
and filopodia (Bear et al.,
2002). This observation is in agreement with earlier observations
that VASP binds in vitro to F-actin
(Bachmann et al., 1999
;
Laurent et al., 1999
) but
clearly demonstrates that this binding is distinct from that of other proteins
that bind along the sides of actin stress fibers (reviewed in
Pollard and Cooper, 1986
).
Finally we reported that Ena/VASP proteins antagonize the ability of capping
protein to inhibit actin polymerization at barbed ends in vitro
(Bear et al., 2002
). These
results led us to propose that Ena/VASP proteins associate with actin
filaments at or near the barbed end and protect them from being capped by
capping protein.
This proposed function for Ena/VASP is consistent with the observed
alterations of actin geometry within the lamellipodia of cells that either
contain elevated levels of or lack Ena/VASP proteins. Ena/VASP-deficient
lamellipodia contain networks of shorter, more highly branched actin filaments
compared with control cells. By contrast, cells in which all Ena/VASP proteins
are overexpressed or constitutively targeted to the membrane contain networks
of longer, less branched actin filaments
(Bear et al., 2002). Therefore,
Ena/VASP proteins appear to support F-actin assembly within cells by acting as
`anti-capping' proteins. Ena/VASP activity also appears to reduce filament
branching. Whether this effect is due to suppression of Arp2/3 function or a
decrease in branch stability remains to be determined, although it is unlikely
that Ena/VASP proteins bind to the Arp2/3 complex.
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How does the effect of Ena/VASP proteins on actin polymerization lead to differences in whole cell behavior? |
---|
What is the potential significance of Ena/VASP influencing cell motility rates by regulating barbed end elongation? Protruding lamellipodia contain a high density of barbed ends, which in turn could promote recruitment of Ena/VASP proteins. At one extreme, excess Ena/VASP anti-capping activity would create a network of long actin filaments that would presumably be too flexible to counteract the forces of membrane tension. At the other extreme, the absence of Ena/VASP activity would favor the formation of networks of short and therefore stiff filaments that permit protrusions to persist longer and potentially increase the probability that they are stabilized further by the formation of cell substratum attachments (Fig. 2).
|
The activity of Ena/VASP proteins is regulated by phosphorylation, and
members of this family appear to interact with a variety of signaling
molecules (Gertler et al.,
1996; Halbrugge et al.,
1990
; Loureiro et al.,
2002
). Therefore, Ena/VASP may integrate multiple signaling
pathways responding to the extracellular environment at the very tip of
protruding lamellipodia. Signals that increase Ena/VASP activity would promote
the formation of ruffles, thereby increasing the membrane surface area while
causing cells to slow down. Such a mechanism might permit cells to explore the
environment and to regulate their `motility machinery' accordingly.
This might also help to explain the different results that were obtained in T-cells and macrophages. Membrane extensions are formed during T-cell activation and phagocytosis but the actin ultrastructure of these protrusions is less well studied than that of lamellipodia of fibroblasts. Perhaps, these membrane extensions resemble ruffles more than lamellipodia. Any actin-based process that depends on relatively long and unbranched actin filaments would probably be positively influenced by Ena/VASP activity. Neuronal growth cones, which extend many long filopodia composed of bundled, unbranched actin filaments, may be particularly dependent on Ena/VASP activity.
How can we reconcile the results of studies on platelets that were interpreted to indicate a negative regulatory function of Ena/VASP proteins on the actin cytoskeleton? Platelet activation and aggregation is a complex process involving the formation of filopodia, lamellipodia and finally contraction of the platelets, each of which may depend upon Ena/VASP function. Since only the total rate of aggregation was measured, the effect of the absence of VASP on the speed of lamellipodia and filopodia protrusions might be obscured. Analysis of the actin ultrastructure of the processes of phagocytosis, T-cell polarization, platelet aggregation and growth cone guidance might help to answer this question.
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How are Ena/VASP proteins recruited to the tips of lamellipodia and filopodia? |
---|
The EVH1 domain might act to refine the distribution of Ena/VASP within
lamellipodia to the very tip. Although other EVH1-binding proteins such as
zyxin do not localize to lamellipodia
(Rottner et al., 2001), we
have recently identified a novel EVH1-binding protein that is concentrated in
lamellipodial and filopodial tips and therefore could participate in anchoring
and/or regulating Ena/VASP activity at the tips of these structures (M.K. and
F.G., unpublished).
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What is the significance of profilin binding to Ena/VASP? |
---|
First, the anticapping activity appears to be sufficient for Ena/VASP
function in regulating random fibroblast migration and lamellipodial dynamics.
Deletion of the polyproline-rich region of Mena, which contains the
profilin-binding sites, has no effect on the ability of Mena to rescue the
hypermotile phenotype of Ena/VASP deficient cells
(Loureiro et al., 2002). What
then is the potential function of Ena/VASP-profilin complexes? Unlike
lamellipodial dynamics, Listeria motility appears to require the
polyproline region of Ena/VASP proteins for optimal intracellular motility
(Geese et al., 2002
). Since
profilin recruitment to the bacterial surface correlates with motility rates,
it is possible that Ena/VASP proteins act as adaptors to recruit profilin to
the bacterial surface (Geese et al.,
2000
).
Skoble and colleagues have noted that Listeria expressing a mutant
ActA protein lacking the G-actin binding site require Ena/VASP to support
Arp2/3-dependent actin nucleation on the bacterial surface
(Skoble et al., 2001). It is
possible that Ena/VASP recruits profilin to supply polymerization-competent
monomers to support Arp2/3-dependent nucleation on the bacterial surface,
although the high intracellular concentration of profilin (20 µM) makes it
unclear why such a mechanism would be necessary (for reviews, see
Schluter et al., 1997
;
Sun et al., 1995
).
Interestingly, Listeria apparently do not utilize the anticapping
activity of Ena/VASP proteins because deletion of motifs essential for this
activity has no effect on the ability of the proteins to support
Listeria motility but does eliminate their function within
lamellipodia (Geese et al.,
2002
; Loureiro et al.,
2002
).
It is unclear which physiological processes use the Ena/VASP-profilin
interaction in addition to, or instead of, the anticapping activity of these
proteins. The affinity of Ena/VASP proteins for profilin is in the nanomolar
range, and the polyproline-binding activity of profilin is required for
profilin function, at least in yeast
(Lambrechts et al., 2000;
Lu and Pollard, 2001
). The
phenotype of Mena knockout mice is exacerbated by a reduction in the
gene dosage of profilin from two to one
(Lanier et al., 1999
).
Although this type of genetic evidence does not prove that Ena/VASP proteins
and profilin function in a biochemical complex, it does indicate that Mena and
profilin participate in some overlapping pathways. Besides random fibroblast
migration there are other cellular actin-dependent processes, such as
filopodia dynamics, phagocytosis, axon guidance or vesicle movement that might
require recruitment of profilin through Ena/VASP proteins. Further analysis
will be required to identify cellular processes that depend upon
Ena/VASP-profilin complexes.
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Concluding Remarks |
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