CNRS UMR 8542, Ecole Normale Supérieure, 46, rue d'Ulm 75230 Paris cedex, France
* Author for correspondence (e-mail: schweisg{at}wotan.ens.fr)
SUMMARY
Cell-cell signaling is a central process in the formation of multicellular organisms. Notch (N) is the receptor of a conserved signaling pathway that regulates numerous developmental decisions, and the misregulation of N has been linked to various physiological and developmental disorders. The endocytosis of N and its ligands is a key mechanism by which N-mediated cell-cell signaling is developmentally regulated. We review here the recent findings that have highlighted the importance and complexity of this regulation.
Introduction
Signal transduction by many surface receptors is tightly connected to
membrane trafficking. For many years, the internalization of receptors by
endocytosis was mostly thought to be associated with signal attenuation and
with the downregulation of cell-cell signaling. Indeed, endocytosis regulates
the steady-state level of receptors, transmembrane ligands and associated
factors at the cell surface, and can also target activated receptors for
lysosomal degradation. However, over the past decade, intensive research in
the field has provided strong evidence that endocytosis and endosomal sorting
(see Box 1) may also play an
essential role in signal transduction. For example, endocytosis may serve to
bring ligand-bound receptors to signal-transducing machinery that is localized
to specific intracellular compartments, or may regulate the transport of
active ligands from cell to cell (for a review, see
Seto et al., 2002).
Signaling by Notch (N) receptors has multiple and essential roles in many
cell fate decisions and in patterning events from worms to humans
(Lai, 2004). N receptor
signaling is regulated at multiple levels
(Schweisguth, 2004
). One of
the first indications that endocytosis plays a key role in N signaling came
from the analysis of a Drosophila temperature-sensitive mutation
called shibirets (shits), which was
later shown to encode dynamin, a GTPase required for the pinching off of
endocytic vesicles from the plasma membrane
(Chen et al., 1991
;
van der Bliek and Meyerowitz,
1991
) (see Box 1).
Mutant embryos raised at the restrictive temperature have a
Notch-like neurogenic phenotype, characterized by hypertrophy of the
nervous system at the expense of the ventral epidermis
(Poodry, 1990
). Although
coated pits formed normally in this mutant, vesicles fail to pinch off from
the cell surface. This correlation led C. Poodry to ask: `could a block in
endocytosis account for an interruption in the communication necessary for
normal epidermal and neural differentiation?'
(Poodry, 1990
). Fifteen years
of research later, the answer is clearly yes. However, the detailed molecular
consequences of a complete block of endocytosis on N signaling are not as
simple as this answer may suggest. Here, we review and discuss recent findings
on the roles of endocytosis in the regulation of N receptor signaling.
N receptor signaling: an overview
N receptors are type I transmembrane proteins that are present at the
plasma membrane as heterodimers. They consist of an ectodomain called NECD
(for Notch Extracellular Domain) and a membrane-tethered intracellular domain
(Fig. 1). The extracellular
part of N contains a variable number of Epidermal Growth Factor (EGF)-like
repeats, which are involved in ligand binding. Upon ligand binding, N
undergoes two successive proteolytic cleavages. The first cleavage at the
extracellular S2 site is ligand-induced and is mediated by extracellular
proteases of the ADAM/TACE family. S2 cleavage of N generates an activated
membrane-bound form of N. In the absence of ligand binding, the extracellular
LIN-12/Notch Repeats (LNRs) prevent S2 cleavage. The S2-cleaved,
membrane-bound form of N is further processed at the endomembrane S3 site by
the -secretase complex. This leads to the cytoplasmic release of the
intracellular domain of N, called the NICD (Notch Intracellular Domain). The
NICD localizes to the nucleus and associates with a DNA-binding protein called
CSL (for human, CBF1; Drosophila, Suppressor of Hairless; C.
elegans, Lag-1) to regulate the expression of its target genes. This
CSL-dependent signaling pathway is called the canonical N pathway
(Kopan, 2002
).
|
Ligand endocytosis promotes N activation
Several lines of evidence indicate that the endocytosis of DSL ligands is
essential for N receptor activation. First, the clonal analysis of the
conditional shits mutation in Drosophila
demonstrated that dynamin-dependent endocytosis is required in both
signal-receiving cells and in signal-sending cells to promote Dl-dependent N
activation (Seugnet et al.,
1997). Dl and Ser colocalize both at the cell surface and in the
intracellular vesicles in Drosophila
(Kooh et al., 1993
;
Parks et al., 1995
). These
vesicles were first suggested to be endocytic in nature because they were not
detected in shibire mutant cells
(Kramer and Phistry, 1996
).
Moreover, antibody uptake assays in living Drosophila tissues have
shown that Dl and Ser are rapidly endocytosed
(Le Borgne et al., 2005
;
Le Borgne and Schweisguth,
2003b
). In contrast with these studies, the subcellular
localization of DSL ligands remains largely unexplored in vertebrates. In one
study, zebrafish DeltaD was shown to predominantly localize to endocytic
vesicles in neuroepithelial cells (Itoh et
al., 2003
). Importantly, the localization of Dl to endocytic
vesicles correlates well with Dl signaling in many different developmental
contexts, and endocytosis-defective Dl proteins have reduced signaling
capacity in Drosophila (Parks et
al., 2000
).
Additional evidence for the role of endocytosis in N signaling regulation
has come from genetic screens in Drosophila and zebrafish. These
screens identified epsin and two E3 ubiquitin ligases, Neuralized (Neur) and
Mind bomb (Mib in zebrafish; Dmib in Drosophila) (see
Fig. 2), as being key
regulators of ligand signaling activity. Loss of neur, mib/Dmib or
lqf (liquid facet, the Drosophila epsin gene)
activity results in phenotypes that are associated with loss of N signaling.
The accumulation of Dl at the surface of lqf mutant cells in
Drosophila probably occurs because of reduced levels of Dl
endocytosis (Overstreet et al.,
2004; Tian et al.,
2004
; Wang and Struhl,
2004
). Neur associates with Dl and promotes Dl ubiquitination and
endocytosis in both Drosophila and Xenopus
(Deblandre et al., 2001
;
Lai et al., 2001
;
Le Borgne and Schweisguth,
2003b
; Pavlopoulos et al.,
2001
; Yeh et al.,
2001
). The Neur-dependent internalization of Dl is observed in
N mutant Drosophila embryos
(Morel et al., 2003
),
indicating that the Dl-N interaction is not required for the endocytosis of
Dl. Dmib associates both with Dl and Ser, and promotes Dl and Ser endocytosis
(Le Borgne et al., 2005
;
Lai et al., 2005
), whereas
Zebrafish Mib has thus far been shown to only physically associate with and
regulate the endocytosis of Dl (Chen and
Casey Corliss, 2004
; Itoh et
al., 2003
). Interestingly, neur and Dmib are
required for distinct subsets of N signaling events in Drosophila,
indicating that these two E3 ubiquitin ligases have complementary functions.
Moreover, loss of Dmib activity can be compensated for by ectopic
Neur expression, indicating that Neur and Dmib have related molecular
activities (Le Borgne et al.,
2005
). As the regulated trafficking of DSL ligands is likely to be
governed by ubiquitin-dependent molecular interactions, it will be important
to determine whether Neur and Mib/Dmib ubiquitinate DSL ligands at common or
distinct sites, and whether they regulate the mono-, multi- and/or
poly-ubiquitination of DSL ligands (Box
2). Interestingly, Neur regulates not only the internalization of
Dl but also its degradation (Deblandre et
al., 2001
; Lai et al.,
2001
), indicating that the ubiquitination of Dl may have a dual
antagonistic role in promoting and downregulating Dl signaling activity. These
two distinct outcomes may result from the same ubiquitin modifications.
Alternatively, the rate of degradation following endocytosis may depend on the
number, or type, of ubiquitination events (mono versus polyubiquitnination)
that are catalyzed by Neur and Mib/Dmib. A biochemical analysis should resolve
these issues. Finally, and most importantly, clonal analysis in
Drosophila and transplantation studies in zebrafish have indicated
that neur, Mib/Dmib and lqf act non-autonomously to promote
N activation (Bingham et al.,
2003
; Itoh et al.,
2003
; Le Borgne et al.,
2005
; Le Borgne and
Schweisguth, 2003a
; Le Borgne
and Schweisguth, 2003b
; Li and
Baker, 2004
; Overstreet et
al., 2004
; Pavlopoulos et al.,
2001
; Tian et al.,
2004
; Wang and Struhl,
2004
). Thus, these data suggest that the endocytosis of Dl and Ser
in signal-sending cells is strictly required for N activation in many, if not
all, N-mediated decisions in Drosophila. Whether this applies to
other organisms is discussed below.
|
The observation that the endocytosis of a transmembrane ligand in a signal-sending cell is associated with receptor activation in a signal-receiving cell is seemingly paradoxical. Indeed, endocytosis removes the ligand from the cell surface where it interacts with its receptor. Several models have been proposed to resolve this paradox (Fig. 3).
|
Other models postulate that the DSL ligands are produced as inactive or
poorly active ligands and that endocytosis is a prerequisite for the surface
expression of active DSL ligands. One such model is based on the observation
that Dl and Ser accumulate in large endocytic vesicles that may correspond to
multi-vesicular bodies (MVBs). In this model, endocytosis is required to
produce Dl-containing exosomes extracellular vesicles that are
produced from the fusion of a MVB with the plasma membrane
(Le Borgne and Schweisguth,
2003a). These vesicles would be the active form of the DSL ligand.
Consistent with this model, an active form of Dl that co-eluted with
full-length Dl was detected in the culture medium of Dl-expressing S2 cells
(Mishra-Gorur et al., 2002
).
This model is, however, not supported by the observation that loss of
hrs activity, which inhibits the formation of MVBs, does not
significantly impair Dl signaling activity
(Jekely and Rorth, 2003
).
Another model proposes that endocytosis allows the DSL ligands to undergo
post-translational modification in the sorting and/or recycling endosomes, to
produce fully active ligands (Wang and
Struhl, 2004). This model is supported by the analysis of chimeric
Dl proteins. It had been previously shown that a truncated Dl lacking its
intracellular domain (ICD) cannot signal
(Sun and Artavanis-Tsakonas,
1996
). Replacing its ICD with a 21 amino acid peptide from the Low
Density Lipoprotein receptor (LDLR), which is known to promote LDLR
internalization and recycling, restored signaling (although not to control
levels) (Wang and Struhl,
2004
). Replacing the Dl ICD with a monoubiquitin can, likewise,
promote both Dl endocytosis and N signaling
(Wang and Struhl, 2004
).
Interestingly, the expression of the Dl-LDLR chimera protein suppressed the
lqf phenotype, whereas the Dl-ubiquitin chimera did not. The LDLR
peptide differs in its ability to promote recycling to the cell surface,
perhaps highlighting an essential role for Lqf in recycling
(Wang and Struhl, 2004
). The
use of these and similar chimeric proteins will hopefully tease apart each
step in the trafficking of the DSL ligand from the cell surface, through the
endosomes and back to the cell surface, and also shed light on when and where
DSL activation occurs and the genes involved in this activation.
Is ligand endocytosis always required for N activation?
The range of combined neur and Dmib mutant phenotypes
strongly suggest that the endocytosis of DSL ligands is required for all, or
most, N-mediated fate decisions in Drosophila
(Le Borgne et al., 2005). The
neurogenic phenotype observed in lqf mutant clones further
strengthens the notion that the endocytosis of DSL ligands is required for N
activation. However, this strict in vivo requirement for ligand endocytosis is
not observed in transfected Drosophila S2 cells. Indeed, the
activation of N receptor signaling that occurs upon the aggregation of N- and
Dl-expressing S2 cells does not appear to require the endocytosis of Dl. This
is because the formalin fixation of Dl-expressing S2 cells prior to cell
aggregation does not block the activation of the E(spl)-m3 N target
gene in N-expressing S2 cells. Thus, Dl molecules immobilized at the cell
surface are still able to activate N, implying that endocytosis is not
essential for N activation in this assay
(Mishra-Gorur et al.,
2002
).
Box 2. Ubiquitin as an endocytosis signal
Ubiquitin is a highly conserved 76-amino acid polypeptide that is
covalently linked to its protein substrates via an isopeptide bond between its
carboxy-terminal glycine and the
|
Studies in cultured mammalian cells may help solve this apparent paradox.
Soluble, non-membrane bound ligands have been shown to retain signaling
activity in some, but not all, cultured cell assays
(Hicks et al., 2002;
Li et al., 1998
;
Ohishi et al., 2002
;
Shimizu et al., 2000
;
Shimizu et al., 2002
;
Vas et al., 2004
;
Wang et al., 1998
). The
antibody-induced oligomerization of soluble ligands, which were produced as
fusions with human IgG Fc, has been reported to increase the signaling
activity of these ligands, suggesting that ligand clustering promotes
signaling (Hicks et al., 2002
;
Shimizu et al., 2002
). The
immobilization of soluble ligands on beads or on a plastic surface also
appeared to increase their activity
(Maekawa et al., 2003
;
Ohishi et al., 2002
;
Varnum-Finney et al., 2000
;
Vas et al., 2004
).
Importantly, free soluble ligands can antagonize the activity of immobilized,
soluble ligands, as well as that of membrane-bound ligands in cells assays
(Hicks et al., 2002
;
Shimizu et al., 2002
;
Small et al., 2001
;
Trifonova et al., 2004
;
Vas et al., 2004
). These
observations are similar to those made in transgenic flies expressing secreted
versions of Dl and Ser, which indicate that soluble ligands act as N
antagonists in vivo (Hukriede et al.,
1997
; Sun and
Artavanis-Tsakonas, 1997
). These results can be interpreted as
follows: secreted ligands can compete with membrane-bound ligands for N
binding, but are very poor activators of N. Thus, soluble ligands may only be
able to activate N in specific cultured cell assays in which their competition
with endogenous ligands is reduced.
By contrast, ligand endocytosis may be largely dispensable for the
activation of the C. elegans N family receptors GLP-1 and LIN-12.
First, the ICD of LAG-2 can be replaced with a ß-galactosidase fusion
protein with no discernable consequences on GLP-1 and LIN-12 signaling
(Fitzgerald and Greenwald,
1995; Henderson et al.,
1994
). Second, the C. elegans genome contains five genes
that encode putative ligands for GLP-1 and LIN-12 that are predicted to be
secreted. At least one of these predicted secreted ligands, DSL-1, acts as a
bona fide ligand for LIN-12 (Chen and
Greenwald, 2004
). [It will be interesting to examine the
evolutionary conservation of genes encoding secreted DSL ligands, and it is
noteworthy that a secreted version of human Jagged1 can be generated by
alternative splicing (Aho,
2004
).] Finally, there is no clear mib homolog in the
C. elegans genome, and RNAi-mediated inactivation of the putative
neur homolog (F10D7.5) does not reveal that it is specifically
required for LIN-12 and/or GLP-1 activation
(http://www.wormbase.org/db/gene/gene?name=neuralized).
Together, these results indicate that ligand endocytosis is not strictly
required for the activation of the GLP-1 and LIN-12 receptors in C.
elegans, which contrasts with the strict requirement for endocytosis in
Drosophila. However, a lack of requirement does not necessarily imply
an absence of function, and it is conceivable that endocytosis modulates
ligand activity in C. elegans too. Consistent with this speculation
is that epsin activity is required for GLP-1 signaling in the C.
elegans gonad (Tian et al.,
2004
). Whether C. elegans epsin regulates the signaling
activity of a transmembrane ligand for GLP-1 or another process remains to be
determined.
Finally, the existence of secreted ligands in C. elegans but not in Drosophila may reflect differences in developmental strategies. Indeed, anchoring a ligand to the cell surface restricts receptor activation to the few cells that are in direct contact with the signal-sending cell. This might ensure the tight spatial control of N activation. By contrast, secreted ligands may activate N in distant cells and have long-range effects. Thus, one may predict that the ability of a cell to respond to diffusible signals may be tightly regulated in organisms expressing secreted ligands. Indeed, both transcriptional and post-transcriptional mechanisms ensure that GLP-1 and LIN-12 are tightly developmentally regulated in C. elegans. Conversely, the ability of a cell to respond to membrane-bound signals may not need to be tightly regulated in organisms with membrane-anchored ligands. This developmental strategy is observed in Drosophila: N is broadly expressed in the embryo and the imaginal tissues, whereas the transcription of the Dl, Ser and neur genes is tightly regulated.
Is N endocytosis required for S2 and/or S3 cleavage?
The strong correlation of endocytosis with DSL activity, as discussed
above, does not alone account for the neurogenic shits
phenotype. Indeed, clonal analysis of the conditional
shits mutation has indicated that dynamin-dependent
endocytosis is also required in signal-receiving cells for N signal
transduction (Seugnet et al.,
1997).
Two observations have recently indicated that a regulatory step exists
between the S2 and S3 cleavages of N. First, soluble Delta1 can bind to Notch2
at the surface of mammalian cultured cells and promote its S2 cleavage, but it
cannot promote intracellular S3 cleavage nor the release of the Notch2 ICD and
the subsequent activation of Notch2 reporter constructs
(Shimizu et al., 2002).
Second, although two distinct extracellular proteases, TACE and Kuzbanian
(Kuz), can cleave an engineered form of N at the extracellular S2 site in
Drosophila cells, only the S2-cleaved forms of N generated by Kuz are
efficiently cleaved by the
-secretase complex
(Lieber et al., 2002
).
A recent study has indicated that regulating the cleavage of N may involve
its endocytosis. First, a truncated form of Notch1 (N1), N1E, that is
similar to the S2-cleaved form of N1, could be endocytosed in 3T3 cells in an
antibody-uptake assay (Gupta-Rossi et al.,
2004
). Second, inhibiting endocytosis using dominant-negative
forms of either Dynamin2 or Eps15 blocked the
-secretase processing of
N1
E (Gupta-Rossi et al.,
2004
). N1
E was mono-ubiquitinated at a conserved lysine
residue, the mutation of which reduced both N internalization and S3 cleavage
(Gupta-Rossi et al., 2004
).
These data suggest that S2-cleaved N is endocytosed prior to S3 cleavage and
raise the possibility that endocytosis is required following S2 cleavage for N
signal transduction. Although this possibility remains to be tested in a
ligand-mediated signaling event, results from a sensitive assay for S3
cleavage of Drosophila N do not support this hypothesis
(Struhl and Adachi, 2000
) [see
discussion in Gupta-Rossi et al.
(Gupta-Rossi et al., 2004
)].
It will thus be important to test the functional importance of this
mono-ubiquitination for N signaling and, of course, to identify the E3
ubiquitin ligase(s) involved in this modification of N. Finally, we note that
this model raises the possibility that endocytosis may be similarly required
for the intracellular cleavage of Delta/Jagged by the
-secretase
complex (Bland et al., 2003
;
Ikeuchi and Sisodia, 2003
;
Kiyota and Kinoshita, 2004
;
LaVoie and Selkoe, 2003
;
Six et al., 2003
).
Why would endocytosis of N be required for S3-cleavage? One model is that
the -secretase is prevented from contacting its substrate at the plasma
membrane, such that endocytosis is required to bring S2-cleaved N from the
plasma membrane, where it is produced, to an intracellular compartment
containing biologically active
-secretase. Whether the S3 cleavage of N
takes place at the plasma membrane or in an intracellular membrane compartment
is an unsolved issue. Although a large pool of active
-secretase
complexes is known to reside in lipid rafts within the endosomal pathway
(Pasternak et al., 2004
;
Vetrivel et al., 2004
), it is
difficult to exclude the presence of a minor pool at the cell surface that
would be specifically involved in N S3 cleavage
(Tarassishin et al., 2004
).
Further analysis of the compartment in which S3 cleavage of N occurs in vivo
is required.
How is N targeted for lysosomal down-regulation?
The studies reviewed above have indicated that endocytosis positively regulates N signaling. Endocytosis also appears to regulate the steady-state level of N at the cell surface by targeting N for lysosomal degradation. Results from several recent studies indicate that more than one mechanism may contribute to the downregulation of N.
Biochemical studies have indicated that murine N1 is targeted to the
lysosomal compartment for degradation by Cbl
(Jehn et al., 2002). N1
contains a YxxxP binding site for Cbl, which is a RING finger E3 ubiquitin
ligase that regulates the internalization of various transmembrane receptors.
Cbl co-immunoprecipitates with N1 in C2C12 cells, and this association
increases upon treatment of C2C12 cells with the lysosomal inhibitor
chloroquine. Immunoprecipitation experiments using an antiubiquitin antibody
also revealed that full-length N1 is either mono-ubiquitinated or is
associated with a ubiquitinated complex in C2C12 cells. Consistent with this
observation, N intracellular and extracellular epitopes colocalize with Hrs in
Drosophila, suggesting that N is endocytosed into Hrs-positive
endosomes prior to S2 cleavage (Fehon et
al., 1990
; Wilkin et al.,
2004
). Moreover, N accumulates together with many other
non-degraded ubiquitinated proteins into large vesicles in hrs mutant
cells (Jekely and Rorth,
2003
). Together, these results suggest that Cbl may be involved in
the lysosomal degradation of N1 in mammals
(Jehn et al., 2002
).
Interestingly, Cbl-C, which is one of the three human Cbl family members,
binds to AIP4/Itch, an E3 ubiquitin ligase of the Nedd4 family. These two
interacting E3 ubiquitin ligases cooperate to regulate the internalization of
the EGF receptor (Courbard et al.,
2002; Waterman and Yarden,
2001
). AIP4/Itch binds to and promotes the ubiquitination of N1 in
cultured cells (Qiu et al.,
2000
). Moreover, mammalian Numb, an inhibitor of N signaling that
has been implicated in the endocytosis of N
(Berdnik et al., 2002
;
Santolini et al., 2000
), has
been shown to interact with AIP4/Itch and to promote the AIP4/Itch-dependent
ubiquitination and degradation of N1
(McGill and McGlade, 2003
)
(Fig. 4A). Although there is no
genetic evidence that Cbl regulates N signaling in Drosophila
(Pai et al., 2000
), two Nedd4
family members, Nedd4 and Suppressor of deltex [Su(dx); the putative
Drosophila homolog of AIP4/Itch], appear to target N for degradation
(Cornell et al., 1999
;
Fostier et al., 1998
;
Sakata et al., 2004
;
Wilkin et al., 2004
). Nedd4
associates with full-length N in transfected Drosophila cells, and in
vitro binding studies have indicated that Nedd4 binds the PPSY endocytic motif
of N via its WW domain. Likewise, Su(dx) also interacts with full-length N via
its WW domain (Qiu et al.,
2000
; Wilkin et al.,
2004
) (Fig. 2A).
Additionally, ubiquitination of full-length N is abolished upon mutation of
the PPSY motif or upon the RNAi-mediated downregulation of Nedd4 activity in
S2 cells (Sakata et al.,
2004
). While these data suggest that Su(dx) and Nedd4 may target N
for degradation, loss of Nedd4 and/or Su(dx) activity has surprisingly little
effect on the accumulation and/or localization of endogenous N, or on the
level of N signaling (Cornell et al.,
1999
; Fostier et al.,
1998
; Sakata et al.,
2004
; Wilkin et al.,
2004
). This might be due to functional redundancy between Nedd4,
Su(dx) and Dsmurf, the three Nedd4 family members in Drosophila.
Nevertheless, overexpression of Su(dx) or Nedd4 mimic a partial loss of N
activity (Mazaleyrat et al.,
2003
; Sakata et al.,
2004
; Wilkin et al.,
2004
). Furthermore, the overexpression of both Su(dx) and N leads
to the accumulation of N in intracellular vesicles that also contain Rab7-GFP,
a late endosomal marker (Wilkin et al.,
2004
). By contrast, the overexpression of a truncated version of
Su(dx), in which the HECT (Homologous to E6-AP C Terminus) catalytic domain
has been removed, leads to the accumulation of overexpressed N in a distinct
intracellular compartment that contains Rab11-GFP, a marker for the recycling
endosome (Wilkin et al.,
2004
). Inhibition of Su(dx) activity, therefore, appears to
promote the sorting of endocytosed N to the recycling endosome. Thus, Su(dx)
and Nedd4 may act to direct N for degradation by regulating the endosomal
sorting of N following its endocytosis from the plasma membrane.
|
Does endosomal sorting regulate CSL-independent N signaling?
Thus far, we have only considered the role of endocytosis in ligand- and CSL-dependent N signaling. However, there is evidence, both in Drosophila and vertebrates, that N also promotes distinct cellular responses in a CSL-independent manner. Although this CSL-independent activity of N is not well characterized, several studies have suggested that it may involve the activity of the RING finger type E3 ubiquitin ligase Deltex (Dx).
Dx was first characterized as a positive regulator of N in
Drosophila (Busseau et al.,
1994; Matsuno et al.,
1995
; Xu and
Artavanis-Tsakonas, 1990
), and was later found to also regulate N
signaling in mammals (Izon et al.,
2002
; Kishi et al.,
2001
; Matsuno et al.,
1998
). Dx binds N (Diederich
et al., 1994
; Matsuno et al.,
1995
) and has E3 ubiquitin ligase activity in vitro
(Takeyama et al., 2003
). Loss
of dx activity in Drosophila leads to a slight reduction in
the expression of N target genes during wing development. Conversely,
overexpression of Dx results in the cell-autonomous, N-dependent, activation
of N target genes that has been reported to be independent of CSL
(Hori et al., 2004
). Genetic
analysis of truncated N alleles in Drosophila has also suggested that
N signals in a CSL-independent manner via Dx
(Ramain et al., 2001
).
Moreover, the activity of a N-regulated enhancer, the vestigial
boundary enhancer, is not significantly affected in cells that are mutant for
both Ser and Dl and that overexpress Dx. This indicates that
Dx potentiates a signaling activity of N that is ligand-independent in
Drosophila (Hori et al.,
2004
). This conclusion is further supported by results from
transfection studies in S2 cells. These studies show that the expression of a
mutant version of Nedd4, Nedd4C974FS, in which the catalytic
cysteine used for ubiquitin transfer is mutated, promotes the
ligand-independent activation of a N target gene, and that this effect is
potentiated by the concommitant expression of Dx
(Sakata et al., 2004
). These
results were interpreted as showing that Nedd4C974FS inhibits the
targeting of N for degradation, and that Dx enhances the ligand-independent
signaling activity of this pool of stabilized N, at least in S2 cells
(Sakata et al., 2004
).
Consistent with this model, the overexpression of Dx leads to the
stabilization of N in intracellular vesicles in vivo
(Hori et al., 2004
),
indicating that Dx antagonizes the degradation of N that is thought to be
promoted by Su(dx) and Nedd4. These studies suggest that Dx acts
antagonistically to Nedd4 family members to protect N from being sorted to an
endocytic degradation pathway. Thus, Su(dx)/AIP4/Itch, Nedd4 and, possibly,
Dsmurf would regulate the endosomal sorting of N towards lysosomal
degradation, whereas Dx would target N towards an undefined intracellular
compartment, possibly the Rab11-positive recycling endosome, from which N
signals in a ligand- and/or a CSL-independent manner
(Fig. 4B). Confirmation of this
model will require the molecular characterization of the ligand- and
CSL-independent signaling activity of N, the biochemical identification of the
forms of N that are endocytosed and sorted by the E3 ubiquitin ligases
involved in these sorting events, and a more precise description of the
compartment in which these sorting events takes place. Although these studies
have been extremely useful at identifying a novel level of N signaling
regulation, we note that the analysis of N endosomal sorting relies partly on
experiments in which N, the E3 ubiquitin ligases that regulate N trafficking,
and the small GTPases used as endosomal markers are overexpressed
(Wilkin et al., 2004
). Thus,
an important challenge in the field is to develop tools that give access to
the dynamics of N sorting in more physiologically relevant situations.
What is the role of Numb and Wasp in N signaling?
One important issue in the field is whether all N signaling events
similarly require endocytosis, or whether the regulation of N signaling by
endocytosis is context dependent. Results from the study of N-mediated binary
fate choices following asymmetric cell division clearly favor the second
possibility. Two regulators of N signaling, Neur and Numb, act as cell-fate
determinants in Drosophila (Le
Borgne and Schweisguth, 2003b;
Rhyu et al., 1994
). Numb is a
conserved membrane-associated protein that acts upstream of the S3 cleavage to
antagonize N signaling (Guo et al.,
1996
). Numb binds both NICD and the ear domain of
-adaptin
(Berdnik et al., 2002
;
Guo et al., 1996
;
Santolini et al., 2000
). The
latter is one of the subunits of the AP2 complex that, either directly or
indirectly, links cargos recruited for endocytosis to the clathrin coat of the
transport vesicles. Numb-mediated inhibition of N appears to require
-adaptin function, suggesting that Numb may be directly involved in
targeting N for endocytosis (Berdnik et
al., 2002
). Alternatively, or perhaps additionally, Numb may act
by preventing the plasma membrane accumulation of Sanpodo (Spdo), a four-pass
transmembrane protein that physically associates with both Numb and N, and
that is strictly required for N signaling in many, if not all, Numb-mediated
cell fate decisions (Dye et al.,
1998
; O'Connor-Giles et al.,
2003
; Skeath and Doe,
1998
). However, whether Numb directs N and/or Spdo towards
endocytosis remains to be demonstrated
(Fig. 5).
|
Conclusions and perspectives
Recent studies have begun to unravel the key role of endocytosis and
endosomal sorting in the regulation of N receptor signaling. Many important
questions, however, remain. Is the internalization of N (or of its ligands)
clathrin-dependent? Or do alternative endocytic routes exist? What are the
different compartments through which N and its DSL ligands traffic? What are
the forms of N targeted for endocytosis and endosomal sorting? What are the
membrane domains in which the S2 and S3 cleavages occur? Are different forms
of N targeted to distinct endocytic compartments? What are the signals used
for constitutive and regulated endocytosis, and what are the ones used to
regulate the endocytosis of the different forms of N? In the case of
ubiquititination signals, are N and its DSL ligands mono- and/or
multi-ubiquitinated? When and where in the cell do ubiquitination and
processing of N take place relative to each other? How is endosomal sorting
regulated? Is the activity of the various E3 ubiquitin ligases known to
regulate N developmentally regulated? Does activation of N, in turn, regulate
the activity of the endocytic and sorting machineries? Some of the answers to
these questions will certainly come from a combination of biochemical, genetic
and in vivo imaging approaches, as illustrated by the recent elegant studies
on endocytosis in yeast (Kaksonen et al.,
2003).
ACKNOWLEDGMENTS
We thank E. C. Lai for communicating unpublished data. We thank T. Klein, A. Martinez-Arias and the anonymous referees for their help in improving this review.
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