1 The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037-1099,
USA
2 Division of Biological Sciences, Cancer Center, University of California, San
Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA
* Author for correspondence (e-mail: woodring{at}salk.edu)
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Summary |
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Key words: abl-/- arg-/- fibroblasts, F-actin, Lamellipodia, Filopodia, Focal adhesions
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Introduction |
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Recent investigations have focused on cytoskeletal structures observed in
motile cells, including those within lamellipodia, filopodia and at points of
cell adhesion (e.g. focal complexes and focal adhesions/contacts).
Lamellipodia and filopodia are protrusive structures that permit the cell to
search and explore its surrounding environment prior to navigation.
Lamellipodia are flat, broad cell-surface extensions that consist of branched
F-actin (Svitkina et al.,
1997), whereas filopodia are thin, elongated extensions that
consist of parallel bundles of F-actin
(Small et al., 1978
). F-actin
microspikes are precursors to filopodia, and the pseudopodia of migrating
cells resemble lamellipodia (Kozma et al.,
1996
; Small et al.,
2002
; Cho and Klemke,
2002
). Migrating cells extend and retract protrusions for long
periods before a protrusion is stabilized for movement
(Knight et al., 2000
).
Stabilization occurs when focal complexes are established at the leading edge,
thereby linking the extracellular matrix (ECM) to the F-actin
cytoskeleton.
The initial events of cell migration (i.e. exploration, adhesion and
polarization) require regulated assembly and disassembly of filopodia,
lamellipodia and focal adhesions/complexes. These dynamic F-actin structures
can be found in migrating cells, spreading cells and growth cones of advancing
neurons. Thus, the diverse array of stimuli that individually stimulate
chemotaxis, cell spreading and neurite extension promote the formation of
similar F-actin structures. Another type of dynamic F-actin structure is
observed during PDGF stimulation of fibroblasts: plasma membrane ruffles.
Ruffling refers to the highly dynamic curling action of the dorsal plasma
membrane where there is rapid actin polymerization and depolymerization. This
type of cell surface activity is thought to serve a role in pinocytosis and
phagocytosis (Small et al.,
2002).
Characterization of the molecular modulators that govern the formation of the different types of F-actin structure is an area of intense research. On the molecular level, the Arp2/3 complex might provide the driving force for formation of membrane protrusions by nucleating actin polymerization from the sides of existing filaments. Integrin receptors provide the adhesive connection between the F-actin cytoskeleton and the ECM. Cells must coordinate signals for actin polymerization, depolymerization, bundling, severing, capping, focal adhesion turnover and actin-myosin contraction to drive processes that require cell movement. Recent studies have implicated the c-Abl tyrosine kinase in such coordination as a regulator of F-actin-based cellular events.
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The Abl family of tyrosine kinases |
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|
In mammals the Abl family consists of two c-Abl isoforms (designated 1a and
1b in humans or I and IV in mice) and two Arg isoforms (1a and 1b). The type
1b/IV isoform of c-Abl and the 1b isoform of Arg each contain a myristoylation
site in the N-terminus, which is missing in the 1a/I isoforms owing to use of
alternative promoters. Abl homologues have been identified in
Drosophila and C. elegans
(Goddard et al., 1986;
Hoffman-Falk et al., 1983
).
The N-terminal SH3, SH2, kinase domains and the proline-rich adapter-binding
sites are highly conserved among the Abl family members
(Fig. 1). The C-terminal
regions of c-Abl and Arg contain a conserved nuclear export signal (NES) and
an F-actin-binding motif. Between the conserved N-terminal and the C-terminal
domains is a region that is divergent among Abl family members. In mouse and
human c-Abl, this region contains three nuclear localization signals (NLS)
(Wen et al., 1996
) and three
high-mobility-group-like boxes (HLB) that cooperatively bind to A/T-rich DNA
(Miao and Wang, 1996
;
David-Cordonnier et al.,
1998
). In Arg this region contains an additional F-actin-binding
domain (Wang et al., 2001
).
In Drosophila Abl this region contains an EVH1-binding domain, which
interacts with Drosophila Enabled
(Lanier and Gertler,
2000
).
The mammalian c-Abl can shuttle between the nuclear and cytoplasmic
compartments because of its NLS and NES
(Taagepera et al., 1998)
(Fig. 1). The oncogenic Bcr-Abl
and v-Abl proteins do not enter the nucleus despite the fact that they each
contain the three nuclear localization signals
(Van Etten et al., 1989
;
McWhirter and Wang, 1991
;
Vigneri and Wang, 2001
).
Nuclear c-Abl plays a role in transcription regulation, particularly in
response to DNA damage (Shaul,
2000
; Wang,
2000a
; Puri et al.,
2002
; Barilá et al.,
2003
), and activation of the nuclear pool of c-Abl can induce
apoptosis (Vigneri and Wang,
2001
; Wang,
2000a
). Cytoplasmic c-Abl is activated by growth factors and cell
adhesion, localizing to dynamic regions of the cytoskeleton, including
membrane ruffles, the leading edges and F-actin protrusions found in actively
spreading fibroblasts or the neurites of cortical neurons. Here, we focus on
current understanding of the role of cytoplasmic c-Abl in F-actin
dynamics.
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Regulation of c-Abl tyrosine kinase |
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|
|
The disruption of the inactive conformation can be achieved by displacement
of the N-terminus, SH3 or SH2 domains, as suggested by the crystal structure
of c-Abl and in vitro experiments (Nagar
et al., 2003; Hantschel et
al., 2003
; Tanis et al.,
2003
; Brasher and Van Etten,
2000
). The association of substrates with the SH3 or SH2 domain of
c-Abl (e.g. binding of a phosphotyrosine ligand to the SH2 domain or a PXXP
ligand to the SH3 domain) might increase the catalytic activity in situ to
allow substrate phosphorylation without the need for Y412 phosphorylation.
Indeed, a substrate-dependent mechanism for activation of c-Src has been
proposed (Hanks and Polte,
1997
; Hubbard,
1999
; Alexandropoulos and
Baltimore, 1996
). A similar in situ activation of c-Abl kinase may
explain the inability to detect pY412 on endogenous c-Abl.
The tyrosine kinase activity of c-Abl is under stringent control within the
cell (Smith and Mayer, 2002).
Table 1 summarizes stimuli that
have been reported to activate cytoplasmic c-Abl in cells. Many of the stimuli
cause very low to moderate levels of kinase stimulation, which may reflect a
localized transient activation of a subset of the total c-Abl. c-Abl is likely
to be held in an inactive conformation through intramolecular and
intermolecular restraints (Fig.
2). Current evidence suggests the involvement of the SH3 domain,
the proline rich SH2-CAT linker, and the extreme N-terminus, including the
myristate group, in retaining the kinase domain in a repressed state
(Barilá and Superti-Furga,
1998
; Pluk et al.,
2002
; Hantschel et al.,
2003
; Nagar et al.,
2003
). Inhibitor proteins that selectively bind to inactive c-Abl
may further enforce the repressed kinase conformation. Several c-Abl
inhibitors have been reported, including Pag/Msp23, AAP1, Abi, RB and F-actin
(Dai and Pendergast, 1995
;
Pendergast et al., 1991
;
Prospéri et al., 1998
;
Shi et al., 1995
;
Welch and Wang, 1993
;
Woodring et al., 2001
;
Zhu and Shore, 1996
). The
inhibition of c-Abl kinase by Abi and Pag is accompanied by tyrosine
phosphorylation of Abi and Pag, indicating that these proteins might also be
substrates of c-Abl, and the inhibition may be the result of competition with
the substrates used in the kinase reactions. By contrast, Rb binds directly to
the ATP-binding lobe of c-Abl to inhibit catalytic activity without itself
becoming phosphorylated (Welch and Wang,
1993
; Woodring et al.,
2001
). F-actin can also inhibit the activity of purified c-Abl
protein, and this depends on the direct interaction between F-actin and the
F-actin-binding motif at the extreme C-terminus of c-Abl
(Woodring et al., 2001
).
The inactive conformation of c-Abl must be relieved to allow substrate
phosphorylation. This may occur through several mechanisms, such as
displacement of the SH3 domain from the SH2-CAT linker, phosphorylation of
regulatory residues, displacement of the myristate group from the C-lobe of
the kinase domain, loss of association to an inhibitor protein or gain of
association of an activator protein (Fig.
2). Substrates may transiently disrupt the repressed c-Abl
conformation as discussed above. Alternatively, `trans-activators' of c-Abl
that relieve the inactive conformation may exist. Several SH2/SH3 adapter
proteins activate c-Abl tyrosine kinase when co-expressed
(Table 1), although it is
unclear whether this occurs through direct stable interaction
(Juang and Hoffmann, 1999;
Shishido et al., 2001
;
Smith et al., 1999
). Taken
together, the current evidence suggests that c-Abl activity is regulated by
multiple different mechanisms. The complexity in c-Abl kinase regulation may
allow it to function as an integrator of multiple signals
(Wang, 2000b
).
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Reciprocal regulation of c-Abl and F-actin |
---|
Several reports indicate that c-Abl can regulate F-actin structures within
the cellular cytoskeleton. For example, c-Abl is involved in membrane
ruffling, filopodia formation, neurite extension and cell migration. The
catalytic activity of c-Abl is required in order for c-Abl to modulate the
F-actin cytoskeleton (Kain and Klemke,
2001; Plattner et al.,
1999
; Woodring et al.,
2002
; Zukerberg et al.,
2000
). In contrast, Arg may act locally by directly binding to
F-actin since it can assemble F-actin into tight bundles in vitro
(Wang et al., 2001
). It is
currently unknown whether Arg also contributes to F-actin dynamics through its
kinase activity and whether c-Abl can also bundle F-actin in vivo. The c-Abl
FABD can bundle F-actin in vitro (Van
Etten et al., 1994
). Loss of both c-Abl and Arg causes a more
severe phenotype than does either alone
(Koleske et al., 1998
),
suggesting that the disorganized F-actin structure found in
abl-/- arg-/- neural epithelium
results from the loss of the dual mechanisms by which c-Abl and Arg modify the
F-actin cytoskeleton.
c-Abl increases the number of F-actin microspikes and filopodia on
spreading fibroblasts and neurons. Treatment of cells with an Abl kinase small
molecule inhibitor [STI571, also referred to as imatinib mesylate or
GleevecTM (Schindler et al.,
2000)] largely blocks this effect (see below).
FABD c-Abl
increases the number of F-actin microspikes in suspended cells; its effect is
constitutive and independent of ECM stimulation
(Woodring et al., 2002
).
These combined data suggest that there is a reciprocal relationship between
c-Abl and F-actin. Although increased c-Abl activity can increase the number
of F-actin microspikes/filopodia and contribute to membrane ruffling and
neurite extension, the mechanism may be self-limiting because association of
c-Abl with F-actin can decrease c-Abl activity and thus reduce the number of
F-actin-rich protrusions.
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Localization of c-Abl to dynamic F-actin structures |
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|
PDGF stimulation of NIH3T3 cells expressing the c-Abl biosensor shows a
striking accumulation of c-Abl activity within membrane ruffles
(Ting et al., 2001). This
suggests that c-Abl is active in these highly dynamic actin structures and is
consistent with the previously reported data indicating that the
membrane-localized pool of c-Abl is activated upon PDGF stimulation
(Plattner et al., 1999
). FRET
studies in live spreading cells show c-Abl activity is elevated within
membrane protrusions, particularly at the tips of lamellipodial and filopodial
structures (P. J. Woodring, S. A. Johnson, K. Shah et al., unpublished).
Indeed, immunofluorescence experiments on fixed cells indicate that c-Abl
protein is localized within membrane protrusions
(Frasca et al., 2001
;
Greaves, 2002
;
Woodring et al., 2002
). Use
of the FRET biosensor to detect the localization of active c-Abl in live cells
may thus provide important insights into the spatiotemporal localization of
active c-Abl during dynamic F-actin-based processes.
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c-Abl transduces extracellular signals to F-actin |
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|
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Cell spreading and migration |
---|
During the initial 20-30 minutes of fibronectin stimulation, when c-Abl
activity is the highest, the nuclear pool of c-Abl in 10T1/2 fibroblasts
re-localizes transiently to focal adhesions
(Lewis et al., 1996). This
transient re-localization also occurs in NIH3T3 cells, where a fraction of the
cellular Abl associates with the focal adhesion proteins paxillin and Grb2
(Lewis and Schwartz, 1998
;
Renshaw et al., 2000
).
Although it was thought that this translocation could play a role in the
reactivation of c-Abl, further experimentation showed that the nuclear pool of
c-Abl could be reactivated independently of shuttling out of the nucleus
(P.J.W. and J.Y.J.W., unpublished). Thus, there is likely to be another
rationale for the recruitment of c-Abl to focal adhesions during cell
attachment and spreading. Some cell types do not maintain a substantial pool
of c-Abl in the nucleus. For example, when c-Abl is re-expressed in the
abl-/- arg-/- MEFs, it is present
mostly in the cytoplasm. When these cells are replated onto fibronectin, c-Abl
is localized throughout the cytoplasm to cytoskeletal structures, including
focal adhesions, cell membranes and filopodia
(Greaves, 2002
;
Woodring et al., 2002
).
Therefore, c-Abl is correctly positioned to regulate the reorganization of the
cytoskeleton at sites of membrane protrusion and at focal adhesions when
integrins are engaged.
c-Abl increases the number of F-actin microspikes and filopodia
During cell spreading over fibronectin-coated surfaces, c-Abl promotes an
increased number of F-actin microspikes and filopodia, allowing them to
persist for longer periods of time on the surface of cells relative to cells
lacking c-Abl (Woodring et al.,
2002). These structures are likely to serve a sensory function,
being used by the cell to pick up spatial information about the nearby
environment during the spreading process. This suggests that c-Abl prolongs
the exploratory phase of cell spreading. The c-Abl-reconstituted fibroblasts
not only have more filopodia but also are less polarized during the early
phases of cell spreading (M. Sheetz, personal communication). MEFs treated
with STI571 or lacking c-Abl and Arg (or c-Abl alone) have reduced numbers of
microspikes and filopodia during cell spreading and appear to flatten out
isotropically using lamellipodial structures. Reduced numbers of filopodia are
also observed in primary cultured embryonic cortical neurons treated with
STI571 or neurons isolated from mice lacking c-Abl
(Woodring et al., 2002
).
Intriguingly, expression of kinase-deficient c-Abl or STI571 treatment of PC12
cells decreases the number of filopodia and increases formation of
lamellipodia-like structures, which suggests that particular F-actin
structures result from active versus inactive c-Abl (P.J.W. and T.H.,
unpublished). Together, these data suggest a role for c-Abl in cell
exploration during cell spreading or navigation over the ECM.
Rate of cell migration is reduced by c-Abl
Random cell migration towards fibronectin is also affected by c-Abl
activity, although it is unclear how c-Abl alters the F-actin cytoskeleton
during cell movement (Frasca et al.,
2001; Kain and Klemke,
2001
). Immortalized abl-/-
arg-/- MEFs are modestly impaired in their ability to
move, whereas abl-/- arg-/- mouse
embryos show significant defects in the actin latticework
(Koleske et al., 1998
). This
is probably due to activation of compensatory mechanisms in the immortalized
MEFs.
A fraction of the cellular Abl or Arg is concentrated at the tips of
extending pseudopods in the stimulated metastatic thyroid cancer cell line
Ca18/3 (Frasca et al., 2001)
and in Swiss 3T3 fibroblasts (Wang et
al., 2001
), respectively. In stimulated Ca18/3 cells, MEFs or
COS-7 cells overexpressing c-Abl, the rate of haptotaxis towards fibronectin
is reduced by c-Abl. Wild-type MEFs treated with STI571 and MEFs lacking c-Abl
and Arg fill in a wounded area more rapidly than do untreated wild-type MEFs
(Kain and Klemke, 2001
). These
results were somewhat unexpected given the positive role that c-Abl plays in
filopodia formation, membrane ruffling and neurite extension, but might
reflect the activation of alternative or additional signaling pathways that
occur during the longer time course of cell migration. Another interpretation
is that c-Abl may extend the time it takes for a cell to migrate because c-Abl
prolongs the exploratory phase of cell movement.
Prospective c-Abl effectors during cell spreading and migration
Although still in early stages of investigation, the targets of c-Abl
downstream of integrins may include focal adhesion proteins (e.g. paxillin,
p130Cas and CrkII) and/or proteins found in filopodial structures (e.g. Dok1,
Abi and PSTPIP). c-Abl can phosphorylate paxillin
(Lewis and Schwartz, 1998;
Escalante et al., 2000
),
p130Cas (Mayer et al., 1995
)
and CrkII (Feller et al.,
1994a
; Feller et al.,
1994b
; Ren et al.,
1994
) in vitro, and all four proteins localize to focal adhesions
(Zamir and Geiger, 2001
).
Although the integrin-induced tyrosine phosphorylation of paxillin
(Nakamura et al., 2000
;
Turner, 2000
;
Schaller, 2001
) and p130Cas
(O'Neill et al., 2000
;
Vuori et al., 1996
) is
associated with enhanced rates of fibroblast spreading and migration, tyrosine
phosphorylation of CrkII may negate these effects by disrupting Abl:Crk:Cas or
Abl:Crk:paxillin complexes (Mayer et al.,
1995
; Escalante et al.,
2000
; Kain and Klemke,
2001
). This raises the interesting possibility that c-Abl may both
activate and inactivate cytoskeletal rearrangements at focal adhesions during
cell spreading and migration.
Anti-pY221 CrkII antibodies reveal that CrkII is a specific substrate of
Abl kinases (Kurokawa et al.,
2001) and that the phosphorylation of Y221 in CrkII is reduced in
fibroblasts lacking c-Abl and Arg (Kain
and Klemke, 2001
). The pY221-induced conformational change in
CrkII is thought to inactivate the adapter by sterically blocking the
accessibility of its N-terminal SH3 domain
(Escalante et al., 2000
;
Feller et al., 1994a
;
Hashimoto et al., 1998
;
Rosen et al., 1995
). A
tyrosine phosphorylation-dephosphorylation cycle is critical for the function
of CrkII in the activation of Rac, a GTPase that in its GTP-bound form
stimulates lamellipodia formation and membrane ruffling
(Abassi and Vuori, 2002
). It is
thought that CrkII affects the localization and activation of Rac through its
SH3-domain-dependent interactions with Rac-specific GEFs, such as C3G or
DOCK180 (Feller, 2001
).
Further investigation is necessary to determine what this means for the
integrity of focal adhesions and the actin cytoskeleton.
Dok1 is also a substrate for c-Abl in spreading cells (P. J. Woodring, S.
A. Johnson, K. Shah et al., unpublished). It localizes to the tips of
filopodia during cell spreading. Furthermore, MEFs lacking Dok1 have fewer
filopodia and cells co-expressing Dok1 and c-Abl have more filopodia.
Fibronectin stimulation induces tyrosine phosphorylation of Dok1
(Noguchi et al., 1999). One
residue that is specifically targeted by c-Abl is Y361 of Dok1 (P. J.
Woodring, S. A. Johnson, K. Shah et al., unpublished), a site that has been
implicated in the recruitment of Nck
(Master et al., 2001
;
Murakami et al., 2002
;
Noguchi et al., 1999
;
Shah and Shokat, 2002
;
Tang et al., 1997
). In
addition to Dok1, three other c-Abl targets have been reported to be localized
to filopodia: PSTPIP (Spencer et al.,
1997
), Mena/VASP (Lanier and
Gertler, 2000
) and the Abi proteins
(Stradal et al., 2001
). While
PSTPIP and Abi appear to be substrates for c-Abl in cells, tyrosine
phosphorylation of Mena and VASP has not been detected in mammalian systems
under physiological conditions (Gertler et
al., 1996
). Nevertheless, since VASP does co-immunoprecipitate
with c-Abl in an adhesion-dependent manner, VASP protein complexes may target
c-Abl to F-actin structures (Howe et al.,
2002
). These data suggest that c-Abl uses multiple modulators to
affect filopodia during cell spreading and migration.
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Plasma membrane ruffling |
---|
PDGF-induced plasma membrane ruffling is increased by c-Abl
The activation of c-Abl contributes to the morphological response
associated with treatment of cells with PDGF: plasma membrane ruffling. MEFs
lacking c-Abl contain four- to fivefold fewer dorsal/circular membrane ruffles
when stimulated by PDGF (Plattner et al.,
1999). Expression of wild-type c-Abl or c-Abl lacking the nuclear
localization sequences, but not kinase-deficient c-Abl, in
abl-/- arg-/- MEFs rescues the effect
of PDGF, indicating that c-Abl substrates are involved in membrane ruffling
(Furstoss et al., 2002
;
Plattner et al., 1999
).
Prospective c-Abl effectors during plasma membrane ruffling
Although downstream effectors of c-Abl in membrane ruffling remain to be
fully characterized, several prospective candidates are worthy of mention:
WAVE1, adapter proteins (CrkII, Nck and Abi1/2) and PSTPIP. Membrane ruffling
activity involves the activation of the Rac GTPase
(Hall, 1992;
Nobes and Hall, 1995
;
Ridley et al., 1992
), which is
also activated at the leading edge of migrating cells
(Kraynov et al., 2000
). As
mentioned above, CrkII might play a role in the recruitment of Rac to the
membrane. Through relieving the trans-inhibition of WAVE1, activated Rac can
stimulate Arp2/3-mediated actin polymerization. WAVE1 translocates to cell
membranes upon PDGF stimulation and is found at the membrane in a complex
containing c-Abl and other signaling proteins
(Westphal et al., 2000
).
Furthermore, the complex of proteins that co-purifies with WAVE1 includes Abi2
and the Nck-binding proteins PIR121 and Nap125
(Eden et al., 2002
). Although,
it is unclear whether c-Abl signals to the WAVE1 complex, it is interesting to
note that Abi proteins are substrates of c-Abl and are localized to the tips
of lamellipodia in metastatic cells
(Stradal et al., 2001
). Also,
Nck, which can associate with c-Abl
(Feller et al., 1994a
;
Ren et al., 1994
), relieves
the trans-inhibition of WAVE1 (Eden et
al., 2002
) and activates WASp
(Benesch et al., 2002
;
Rivero-Lezcano et al., 1995
;
Rohatgi et al., 2001
). The
importance of Nck1 and Nck2 in activating F-actin polymerization is supported
by the observation that nck1-/-
nck2-/- MEFs cannot form actin pedestals when infected
with enteropathogenic Escherichia Coli
(Gruenheid et al., 2001
).
PSTPIP is a cytoskeletal protein that becomes tyrosine phosphorylated in an
Abl-dependent manner upon PDGF stimulation
(Cong et al., 2000). c-Abl
appears to associate with PSTPIP through its SH2 and SH3 domains
(Cong et al., 2000
;
Cote et al., 2002
). PSTPIP can
interact with WASp (Cote et al.,
2002
) and co-localizes with several types of F-actin structures
including cortical actin and actin in lamellipodia, elongated filopodia,
stress fibers and the cleavage furrow of cytokinetic cells
(Spencer et al., 1997
).
PSTPIP may recruit PTP-PEST, a tyrosine phosphatase, to regulate F-actin
dynamics by reversing the effects of tyrosine-phosphorylated proteins
(Cong et al., 2000
). Although
PSTPIP is clearly a substrate of c-Abl, the physiological function of
pY-PSTPIP is currently unknown. Further investigation is necessary to
determine whether PSTPIP, Nck, WAVE1, Abi and/or CrkII are essential
downstream targets of c-Abl in the PDGF-induced membrane ruffling
response.
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Neurite extension |
---|
Murine c-Abl stimulates neurite outgrowth
Although growing evidence indicates that murine c-Abl also functions
positively in neurite outgrowth, the mechanisms do not appear to be conserved
between D-Abl and murine c-Abl. Expression of murine c-Abl in
Drosophila D-Abl-null mutants does not restore proper neuronal
navigation (Henkemeyer et al.,
1990). This might be due to different substrate specificities of
D-Abl and c-Abl, and/or structural differences, which include the absence of
binding sites for Ena/VASP in murine c-Abl
(Fig. 1). Although
Drosophila Abl and the murine c-Abl are not strictly homologous and
may use different mechanisms, both do appear to function in modulation of
neuronal F-actin dynamics.
Key observations regarding c-Abl and Arg in neurulation were first made
with abl-/- arg-/- mouse embryos
(Koleske et al., 1998).
Pathological and histological analysis of embryonic day 9-11
abl-/- arg-/- mice revealed
significant deficiencies in neurulation. In these mice the neuroepithelium was
buckled and highly disordered. The actin latticework at the apical surface is
also disrupted and ectopic actin-rich deposits occur at the basolateral
surface. This suggests a role for c-Abl and Arg in regulating the actin
cytoskeleton in both neurons and neuroepithelial cells. It is not known
whether it is the loss of c-Abl/Arg kinase activity, their adapter function or
both that is responsible for these defects. A subsequent report has suggested
that c-Abl activity is important for embryonic neuronal growth
(Zukerberg et al., 2000
).
c-Abl protein localizes to the cell body, neurite extensions, the growth
cone and excitatory synapses of rodent embryonic cortical and hippocampal
neurons (Zukerberg et al.,
2000; Moresco et al.,
2003
). Arg is also found in neurons; it is especially abundant in
brain regions containing high concentrations of synapses, which may explain
the behavioral abnormalities observed in arg-/- mice
(Koleske et al., 1998
).
Expression of active c-Abl in rodent embryonic neurons stimulates neurite
outgrowth on laminin (Zukerberg et al.,
2000
; Woodring et al.,
2002
). Moreover, the overall length of neurons is decreased by
inhibition of c-Abl, and these neurons contain fewer filopodial exploratory
structures. The stimulus for c-Abl in neurite extension may be either the ECM
protein laminin or an autocrine regulatory factor. A recent report also
reveals another role for c-Abl and Arg activity in neurons: modulation of
synaptic transmission induced by paired-pulse stimulation
(Moresco et al., 2003
).
Further research is necessary to determine whether modulation of F-actin by
Abl and Arg can contribute to regulating neuronal synapses.
Prospective c-Abl effectors during neurite extension
Cables is a protein that simultaneously interacts with c-Abl and Cdk5, a
serine/threonine kinase essential for regulating neuronal migration and
neurite outgrowth through the phosphorylation of specific substrates
(Zukerberg et al., 2000). In
the Cdk5-cables-c-Abl complex, c-Abl is proposed to phosphorylate Y15 on Cdk5
to stimulate its kinase activity. Antisense RNA to cables and expression of
dominant negative Cdk5 each inhibit embryonic neurite outgrowth, while
overexpression of activated c-Abl lengthens neurites. It will be interesting
to determine whether cables and Cdk5 also play a role in the stimulatory
effects of c-Abl on embryonic neuronal filopodia
(Woodring et al., 2002
).
Additionally, c-Abl directly associates with neuronal receptors including TrkA
receptors (Brown et al., 2000
;
Koch et al., 2000
;
Yano et al., 2000
), EphB
receptors (Yu et al., 2001
)
and the N-methyl-D-aspartic acid receptor
(Glover et al., 2000
). The
Abl-interacting Abi proteins are also expressed in developing neurons
(Courtney et al., 2000
) and
overexpression of Abi together with Mena can stimulate the tyrosine
phosphorylation of Mena (Tani et al.,
2003
). However, the biological significance of these interactions
remains elusive.
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Future prospects |
---|
Paradoxically, c-Abl seems to have a negative role in cell migration but
positively contributes to filopodia formation, membrane ruffling and neurite
extension. The Ena/VASP proteins exhibit a similar paradox: they decrease cell
motility yet positively regulate actin polymerization
(Bear et al., 2002;
Krause et al., 2002
). Although
Ena/VASP proteins increase the lamellipodial protrusion rate, they also
inhibit cell motility. Directed cell movement involves the coordination of
several events. Individual cycles of protrusion and retraction are only one
parameter. Thus, c-Abl may decrease overall cell migration by a mechanism
independent of its positive effect on filopodia and membrane ruffling.
Alternatively, c-Abl may decrease overall cell migration by inducing
persistence of membrane protrusions that do not facilitate cell movement. For
example, protrusions may not be stabilized for movement or may be stimulated
globally instead of locally at the leading edge. Another possible explanation
could relate to experimental design. At present, the effect of c-Abl on
F-actin is determined in response to a single stimulus, such as PDGF or the
ECM. However, processes such as cell migration are simultaneously regulated by
a variety of diverse signals in vivo. Because c-Abl is responsive to a
plethora of signals, its physiological effect on F-actin may not be
represented by the results obtained thus far in isolated experimental
systems.
In consideration of cellular signaling networks, regulation of
F-actin-dependent processes is not the only function of c-Abl. Activated
nuclear c-Abl kinase can inhibit differentiation or induce apoptosis in
response to DNA damage (Puri et al.,
2002; Wang,
2000a
). The question, therefore, arises as to why a single
tyrosine kinase is equipped to perform such a diverse array of biological
functions? Two models can account for the multi-functionality of c-Abl
(Wang, 2000b
). The first
proposes that c-Abl possesses cytoplasmic and nuclear functions, which are
distinct and unrelated. This model considers the regulation of
F-actin-dependent processes to be the function of cytoplasmic c-Abl, which has
no relationship to the regulation of differentiation and apoptosis by the
nuclear c-Abl. Recently, it was shown that c-Abl does not enter the nucleus of
differentiated myocytes while it undergoes nuclear-cytoplasmic shuttling in
undifferentiated myoblasts (Puri et al.,
2002
). This supports the idea that c-Abl in terminally
differentiated myocytes may have a cytoplasmic function that is independent of
its nuclear localization. The second model proposes that the cytoplasmic and
the nuclear functions of c-Abl are coordinated. In this model, the
participation of c-Abl in F-actin-dependent processes is hypothesized to have
a direct bearing on the nuclear c-Abl function. Results from three recent
studies provide some evidence to support the second model. Activation of
caspases by apoptotic stimuli leads to the cleavage of cytoplasmic c-Abl,
producing a truncated protein that lacks the FABD and NES of c-Abl. The
caspase-dependent cleavage of c-Abl allows the nuclear accumulation of c-Abl
to promote cell death (Barilá et
al., 2003
). The FABD-truncated Abl may also induce cytoskeletal
rearrangements associated with apoptosis. Consistent with this idea, is the
finding that CrkII phosphorylation by c-Abl may contribute to the cytoskeletal
alterations that occur during apoptosis
(Kain et al., 2003
). Tyrosine
phosphorylation of CrkII-Y221 by c-Abl disrupts the Cas-Crk complex. The loss
of Cas-Crk coupling induced by c-Abl inhibits cell migration and promotes
apoptosis (Kain and Klemke,
2001
; Klemke et al.,
1998
; Cho and Klemke,
2000
). In addition, Truong and colleagues observed that DNA damage
cannot activate nuclear c-Abl tyrosine kinase in cells that are deprived of
the ECM signal (T. Truong, G. Sun, M. Doorly, J. Y. J. Wang and M. A.
Schwartz, unpublished). They found that the stable adhesion of fibroblasts to
fibronectin decreases migration and promotes DNA-damage-induced apoptosis by
allowing the activation of c-Abl and p53. These cultured-cell-based results
are intriguing but future work will be required to determine whether cell
migration and DNA damage response are indeed coordinately regulated through
c-Abl in animal models.
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Acknowledgments |
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