1 Department of Biology, Queen's University, Kingston, Ontario, Canada K7L
3N6
2 Biology Department, University of Pennsylvania, Philadelphia, PA 19104-6018,
USA
3 Banting and Best Department of Medical Research and Department of Molecular
and Medical Genetics, University of Toronto, Toronto, Ontario, Canada M5G
1L6
* Author for correspondnce (e-mail: charlie.boone{at}utoronto.ca)
![]() |
Summary |
---|
Key words: Formins, Bni1p, Cell polarity, Actin assembly, Signal transduction
![]() |
Introduction |
---|
Actin filaments are polar, having a fast-growing `barbed' end and a
slow-growing `pointed' end. Actin elongation in cells occurs largely, if not
exclusively, at the barbed end. Indeed, proteins and small molecules, such as
capping protein and cytochalasin, that cap filament barbed ends
(Caldwell et al., 1989;
Tellam and Frieden, 1982
)
block actin assembly in vivo. Thus, cells can promote actin assembly by
uncapping a filament's barbed end, by severing a filament to create a new
barbed end or by de novo nucleation of an actin filament.
For a number of filamentous actin structures, nucleation depends on
activation of the Arp2/3 complex. For example, Arp2/3 nucleates branched
networks that contain short actin filaments found in the lamellipodia of
motile cells (reviewed in Higgs and
Pollard, 2001; Pollard et al.,
2000
; Pollard et al.,
2001
). The actin branches form at 70° angles and are thought
to be optimized for mediating protrusion
(Fig. 1). The Arp2/3 complex is
also a critical component of yeast cortical actin patches, which appear to
control endocytosis (reviewed in Pruyne
and Bretscher, 2000
), and is recruited by pathogenic bacteria
(such as Listeria monocytogenes, Shigella flexneri, Salmonella
typhimurium and enteropathogenic Escherichia coli) and viruses
(such as Vaccinia), which rely on the host's actin polymerization for
movement (reviewed in Higgs and Pollard,
2001
).
|
Genetic evidence suggests that the Arp2/3 complex is not the nucleator of
all actin filaments. In budding yeast, its deletion disrupts the assembly of
cortical actin patches but does not affect the assembly of actin cables or the
actin contractile ring (Evangelista et
al., 2002; Tolliday et al.,
2002
; Winter et al.,
1999
). In Drosophila melanogaster, mutations in Arp2/3 or
its activators do not affect cytokinetic contractile rings, the
actin-dependent cytoplasmic bridges and ring canals that appear in nurse cells
early in development, the ordered actin bundles that form in nurse cells late
in development or actin bundles in bristles
(Fig. 1) (reviewed in
Miller, 2002
;
Hudson and Cooley, 2002
).
Furthermore, reduced levels of Arp2 in Caenorhabditis elegans do not
prevent cytokinesis or assembly of the cortical microfilaments needed to
establish an anterior-posterior axis
(Severson et al., 2002
). Here,
we review recent findings suggesting that nucleation of at least some of these
Arp2/3-independent structures is controlled by members of the formin family of
proteins.
![]() |
Formins: multidomain proteins controling actin assembly |
---|
|
The most highly conserved feature of formins is the two juxtaposed formin
homology domains, FH1 and FH2 (Castrillon
and Wasserman, 1994;
Wasserman, 1998
), both of
which are implicated in control of actin assembly
(Evangelista et al., 1997
;
Evangelista et al., 2002
;
Sagot et al., 2002a
;
Watanabe et al., 1999
)
(Fig. 2A). Some formins also
contain a conserved FH3 motif(s) between the RBD and the FH1 domain
(Fig. 2A); this motif
determines subcellular localization
(Petersen et al., 1998
;
Kato et al., 2001
;
Oazki-Kuroda et al., 2001; Sharpless and
Harris, 2002
). The conservation of the formin homology domains
suggests that all formins have similar molecular activities and underscores
the need to characterize their structure and function.
|
The proline-rich FH1 domain binds to the G-actin-binding protein profilin
(Chang et al., 1997;
Evangelista et al., 1997
;
Imamura et al., 1997
;
Watanabe et al., 1997
). The
formin-profilin interaction, which can deliver ATP-bound actin monomers to the
growing barbed ends of actin filaments (reviewed in
Carlier and Pantaloni, 1997
;
Theriot and Mitchison, 1993
;
Wear et al., 2000
), is
essential for at least some formin functions (see below). SH3 and WW domains
(Chan et al., 1996
;
Kamei et al., 1998
;
Tong et al., 2002
;
Vallen et al., 2000
) also
associate with the FH1 domain of formins. For example, the SH3 domain of yeast
Hof1p, a protein that participates in cytokinesis, binds to the FH1 domain of
Bnr1p in a Rho-dependent manner (Kamei et
al., 1998
; Vallen et al.,
2000
). Similarly, the SH3 domain of the mammalian nonreceptor
tyrosine kinase Src binds to mammalian diaphanous (mDia)-related formins
(DRFs; see below) (Tominaga et al.,
2000
). The mDia-Src interaction appears to mediate mDia-dependent
signaling to serum response factor (SRF), a transcription factor that
regulates growth-factor-induced genes and muscle-specific genes
(Tominaga et al., 2000
).
Further analysis (Copeland and Treisman,
2002
) has revealed that fragments of mDia1 containing only the FH2
domain stimulate actin assembly by causing a decrease in the pool of G-actin,
which leads to activation of SRF indirectly. Thus, the FH1 domain appears to
function as a scaffold that enables formins to recruit proteins that modulate
its intrinsic actin assembly activity.
The FH2 domain represents a unique and defining feature of formin proteins,
sharing no obvious sequence similarity with any other domain or polypeptide.
It controls actin nucleation in vitro
(Pruyne et al., 2002;
Sagot et al., 2002b
) and actin
assembly in vivo (Copeland and Treisman,
2002
; Evangelista et al.,
2002
; Pruyne et al.,
2002
; Sagot et al.,
2002a
; Sagot et al.,
2002b
). The domain was originally thought to encompass 100
residues (Castrillon and Wasserman,
1994
; Wasserman,
1998
), but sequence alignment
(http://pfam.wustl.edu/index.html)
of multiple newly discovered formins indicates that the region of sequence
similarity is much larger and covers almost 500 residues, which encompass the
C-terminal Dia-autoregulatory (DAD) domain (see below). The FH2 domain remains
to be fully characterized, so we do not yet know whether it is composed of
multiple subdomains that have independent actin assembly roles. In the case of
mDia1, deletion analysis has demonstrated that the N-terminal and C-terminal
regions of the FH2 domain are both required for efficient actin assembly in
vivo (Copeland and Treisman,
2002
). Consistent with this observation is the finding that
deletion of the C-terminal region of Bni1p encompassing the DAD domain results
in a 50% loss of activity (M.E. and C.B., unpublished). Thus most of the FH2
may be dedicated to an actin assembly role.
Some evidence, nevertheless, suggests that particular subdomains of the FH2
domain may have distinct actin assembly functions. For example, the N-terminal
region of the Bni1p FH2 domain binds translation elongation factor 1A (eF1A)
(Umikawa et al., 1998;
Liu et al., 2002
). Since eF1A
can bundle actin filaments (Demma et al.,
1990
), this interaction may facilitate the organization of growing
filaments or regulate actin assembly in some other fashion. Overexpression of
eF1A in yeast induces filament assembly resembling that associated with
activated forms of Bni1p (Munshi et al.,
2001
). Deletion of the eF1A-binding site within Bni1p leads to a
defect in actin assembly in vivo (Umikawa
et al., 1998
); however, to determine whether this effect is due to
a defect in eF1A interaction or in nucleation, the mutant protein should be
assessed for actin nucleation activity in vitro (discussed below).
A distinct class of formins, the DRFs
(Table 1, asterisk), has been
defined on the basis of their ability to interact with the activated GTP-bound
form of a Rho-type GTPase through an N-terminal Rho-binding domain (RBD)
(Evangelista et al., 1997;
Habas et al., 2001
;
Imamura et al., 1997
;
Kohno et al., 1996
;
Watanabe et al., 1997
)
(Fig. 2B). Because the formin
RBD domains do not share significant sequence similarity, DRFs have been
classified by a functional definition. Rho-GTP binding to the RBD domain
alleviates auto-inhibition by a DAD domain
(Fig. 2B), which mediates an
intramolecular interaction with the RBD, producing an inactivated state
(Alberts, 2001
;
Watanabe et al., 1999
). This
regulatory activity was originally characterized in mDia1
(Watanabe et al., 1999
), and a
consensus DAD domain is a general feature of DRFs
(Alberts, 2001
). This type of
regulation resembles that associated with Cdc42-GTP-dependent activation of
the actin regulator N-WASP (Rohatgi et
al., 1999
). Because a number of formins whose activation has not
been characterized contain sequences resembling the DAD domain (e.g. S.
pombe For3), they may also be DRFs.
Some formins may be regulated by other signaling pathways or different
mechanisms. If these other formins retain an intramolecular mode of
regulation, then any protein that binds or modifies either the N-terminal
regulatory region or the corresponding DAD-like negative regulatory domain
could potentially activate nucleation. For example, mammalian Delphilin links
the glutamate receptor 2 (GluR
), involved in postsynaptic
transmission, to the actin cytoskeleton
(Miyagi et al., 2002
).
Delphilin is a unique formin because it contains an N-terminal PDZ domain,
which binds GluR
2 (Miyagi et al.,
2002
). In this case, the GluR
2 receptor may also regulate
the activity of Delphilin in a manner analagous to Rho-GTP-mediated regulation
of DRFs. In response to Wnt-activated Frizzled (Fz) receptor signaling, the
human formin Daam1 forms a complex with Dishevelled (Dvl) and activated RhoA
(Habas et al., 2001
). Finally,
the plant formin AHF1 contains an N-terminal transmembrane domain, which has
the potential to localize or regulate its function
(Banno and Chua, 2000
).
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Formins directly assemble Arp2/3-independent actin structures |
---|
More recent work has established a direct role for budding yeast formins
(Bni1p and Bnr1p) in the assembly of actin cables
(Evangelista et al., 2002;
Pruyne et al., 2002
;
Sagot et al., 2002a
;
Sagot et al., 2002b
). Deletion
of BNI1 or BNR1 has no effect on cell viability, but
deletion of both genes is lethal (Imamura
et al., 1997
), indicating that the roles of yeast formins overlap.
Creation of fast-acting, temperature-sensitive (ts) mutations in the FH2
domain of BNI1 in a bnr1
background has allowed
investigation of the roles of these formins in vivo
(Evangelista et al., 2002
;
Sagot et al., 2002a
). At
permissive temperature, bnr1
bni1-ts double mutants
show wild-type actin cables and polarized cortical patches
(Fig. 3). After a shift to the
restrictive temperature, the actin cables disappear rapidly, but there is no
change in the structure or polarization of actin patches
(Fig. 3). Similarly, in fission
yeast, the formin For3 appears to play a major role in actin cable formation
(Feierbach and Chang, 2001
).
Analysis of an arp3
deletion mutant revealed that it exhibits
defective actin patch assembly but normal actin cable assembly
(Winter et al., 1999
;
Evangelista et al., 2002
).
Thus, in yeast, Arp2/3 appears to be dedicated to actin patch assembly whereas
formins are dedicated to actin cable assembly.
|
In C. elegans (Severson et
al., 2002), RNAi-induced reduction in the levels of either
profilin or the formin CYK-1 results in cytokinesis and anterior-posterior
polarity defects. In contrast, the Arp2/3 complex is dispensable for both of
these processes but is required for other actin-based processes such as
gastrulation and epidermal enclosure. Thus, in C. elegans, the Arp2/3
complex and formins might also assemble distinct actin structures.
![]() |
Formin FH2 domain: nucleation and polarization of actin filaments |
---|
Polymerization induced by Bni1p is inhibited by cytochalasin B, which
indicates that the nucleated filaments grow predominantly from the
fast-growing barbed end (Pruyne et al.,
2002; Sagot et al.,
2002b
). Electron microscopy has shown that these filaments are
long and unbranched (Pruyne et al.,
2002
; Sagot et al.,
2002b
) and that Bni1p associates specifically with the barbed end
(Pruyne et al., 2002
). Indeed,
a Bni1p construct containing just the FH1 and FH2 domains (Bn1p FH1-FH2) can
associate with the barbed end of pre-existing filaments and slow but not block
their elongation (Pruyne et al.,
2002
). These findings suggest that Bni1p is an
actin-filament-capping protein, but, unlike traditional capping proteins,
which bind to the barbed end and prevent filament elongation, Bni1p appears to
bind to the barbed end of filaments and regulate the rate at which they
grow.
Since Bni1p localizes to discrete regions of the growing cell cortex, such
as the tip of a developing bud, its ability to bind to the barbed ends of
filaments indicates that it may be able to tether the filaments it nucleates
and polarize them towards itself (Fig.
4). Indeed, the unidirectional movement of cable-dependent myosin
V motors indicates that cable filaments are polarized with their barbed ends
towards the growing cortex (Schott et al.,
2002). In vivo analysis of cable dynamics has shown that actin
cables assemble from these sites, indicating that the anchorage of actin
cables occurs at their growing ends (Yang
and Pon, 2002
). Because myosin V cargo includes secretory
vesicles, mRNA and a molecular complex that associates with cytoplasmic
microtubules (Beach et al.,
1999
; Bertrand et al.,
1998
; Hoepfner et al.,
2001
; Miller et al.,
2000
; Pruyne et al.,
1998
; Rossanese et al.,
2001
; Schott et al.,
2002
; Takizawa et al.,
2000
; Theesfeld et al.,
1999
; Yin et al.,
2000
; Zahner et al.,
1996
) (Fig. 4),
mutations in the BNI1 gene lead to defects in polarized secretion,
mRNA localization, spindle orientation and nuclear positioning
(Evangelista et al., 2002
;
Fujiwara et al., 1999
;
Lee et al., 1999
;
Sagot et al., 2002a
). Thus,
the ability of Bni1p, possibly aided by other proteins, to bind to the growing
barbed end of an actin cable filament provides a simple yet elegant way of
orienting actin cables, which directs myosin motors and their associated cargo
towards the growing bud tip (Fig.
4).
|
![]() |
Mechanism for FH2-mediated actin nucleation |
---|
|
It is interesting to compare features of spontaneous and Arp2/3-induced
actin nucleation with that induced by formins. In spontaneous nucleation, the
pre-nucleus (a form that can elongate like an actin filament) is an actin
trimer, which forms very slowly at physiological actin concentrations. In
Arp2/3-induced nucleation, the actin-related proteins Arp2 and Arp3 are
thought to acquire an arrangement similar to that of two actin subunits (along
the short-pitch helix) of an actin filament (reviewed in
Pollard and Beltzer, 2002).
Addition of a single G-actin molecule to the Arp2/3 complex forms a nucleus
that can elongate with kinetics of an actin filament barbed end
(Fig. 5A); the resultant
filament is capped by the Arp2/3 complex at its pointed end
(Fig. 5B).
In Bni1p FH2-induced nucleation, the pre-nucleus is an actin dimer (Fig. 5A), which is probably formed by sequential monomer addition. Like capping protein and cytochalasin, Bni1p also associates with the barbed end of the filament (Fig. 5B); however, it slows but does not block barbed end elongation, acting like a `leaky capper'. The underlying mechanism remains a mystery, but perhaps the FH2 domain wobbles towards the barbed end in a processive manner as the filament is elongating.
Arp2/3-dependent nucleation is regulated by various factors, including WASP
family members and cortactin (reviewed in
Higgs and Pollard, 2001). As
noted above, at least some formins are activated by Rho GTPases.
Formin-induced nucleation may be further modulated by post-translational
modification of formin or its binding partners. For example, mouse formin I
(Vogt et al., 1993
) and yeast
Bni1p (Goehring et al., 2003
),
are phosphoproteins in vivo and could be regulated by phosphorylation.
Formin-interacting proteins that might participate in the assembly reaction
include Bud6p/Aip3p (Amberg et al.,
1997
), a protein that is required for Bni1p-induced cable
formation in vivo (Evangelista et al.,
2002
; Sagot et al.,
2002a
) and in two-hybrid studies interacts with a Bni1p C-terminal
region that overlaps with the FH2 domain
(Evangelista et al., 1997
),
and the actin-bundling protein eF1A (Demma
et al., 1990
), which interacts with the N-terminal region of the
FH2 domain (Umikawa et al.,
1998
; Liu et al.,
2002
). We anticipate that in vitro actin assembly reactions with
full-length formin proteins purified from eukaryotic cells and formin-binding
proteins will provide further insight into the regulation of formin-induced
actin assembly.
![]() |
The role of profilin in Bni1p-induced nucleation |
---|
![]() |
Formins may nucleate different actin bundle structures |
---|
A general requirement for formins in cytokinesis indicates that formins
might control the formation of the actin contractile ring (reviewed in
Frazier and Field, 1997;
Wasserman, 1998
;
Zeller et al., 1999
). C.
elegans studies using RNAi to reduce the levels of formin CYK-1, for
example, show that formins might have a direct role in this process, whereas
Arp2/3 is dispensable (Severson et al.,
2002
). This finding has been corroborated in Drosophila:
mutations in fly Arp2/3 or its activators are not required for formation of
the cytokinetic contractile rings (Hudson
and Cooley, 2002
). Assembly of the budding yeast actin contractile
ring involves Rho1-dependent stimulation of formin proteins and profilin
(Tolliday et al., 2002
). In
fission yeast, the formin Cdc12 is a component of the cell division ring
(Chang et al., 1997
) and is
required for the formation of the leading F-actin cable that forms the actin
contractile ring (Arai and Mabuchi,
2002
). However, in this case, Cdc12 and the Arp2/3 complex appear
to collaborate in the continual synthesis of actin filaments required for
cytokinesis (Pelham and Chang,
2002
). Formation of some actin structures may therefore require
coordinated nucleation by both formins and Arp2/3.
![]() |
Roles for formins in microtubule organization |
---|
In mammalian cells, mDia formins modulate microtubule function and
organization (Isizaki et al., 2001; Kato
et al., 2001; Palazzo et al.,
2001
). Overexpression of an activated form of mDia1 induces
bipolar elongation of HeLa cells and alignment of microtubules and F-actin
bundles with the long axis of the cell
(Ishizaki et al., 2001
).
Interestingly, mutation of conserved residues within the FH2 domain abolishes
this phenotype. Furthermore, microinjection of serum-starved NIH 3T3 cells
with DNA encoding a constitutively active form of mDia2 or DNA encoding the
DAD autoinhibitory domain, which leads to activation of endogenous mDia1,
stimulates the formation of stable microtubules oriented towards the wound
site (Palazzo et al., 2001
).
In addition, mDia2 colocalizes with a subset of microtubules in some cells and
binds directly to microtubules in vitro
(Palazzo et al., 2001
).
Finally, mDia1 localizes to the mitotic spindle in HeLa cells in an
FH3-domain-dependent manner (Kato et al.,
2001
). Thus, there is a clear functional link between mDia and
regulation of the microtubule cytoskeleton; however, whether the effects on
microtubules depend on actin nucleation by formins remains to be
clarified.
![]() |
Outlook |
---|
Additional actin nucleators may be identified with the use of conditional
mutants in which both Arp2/3 complex and formin function are defective. The
VASP/Mena family of proteins (Krause et
al., 2003), for example, may function as actin nucleators in vivo;
these proteins resemble formins because they can nucleate actin filaments in
vitro (Huttelmaier et al.,
1999
; Walders-Harbeck et al.,
2002
), albeit inefficiently, and bind the barbed ends of actin
filaments (Bear et al., 2002
).
Moreover, the Listeria protein ActA, which activates the Arp2/3
complex, has Arp2/3-independent nucleating activity that requires VASP
(Fradelizi et al., 2001
;
Skoble et al., 2001
). Human
zyxin is another potential nucleator, since it appears to be able to generate
new actin structures independently of the Arp2/3 complex
(Fradelizi et al., 2001
). A
major challenge is to link each filamentous actin structure to a specific
nucleation system.
![]() |
Acknowledgments |
---|
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