Friedrich Miescher Institute, Novartis Forschungsstiftung, PO Box 2543, CH-4002 Basel, Switzerland
* Author for correspondence (e-mail: chiquet{at}fmi.ch)
Accepted 4 April 2003
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Summary |
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Key words: Pair-rule, PML, RIP, Ten-m, Transcription
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Introduction |
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During the later stages of development, Ten-a and Ten-m/Odz are
predominantly expressed in the nervous system
(Levine et al., 1997;
Minet et al., 1999
;
Fascetti and Baumgartner,
2002
). The predominant neuronal expression is conserved in the
vertebrate homologues ten-m1, 2, 3 and 4 in the mouse
(Oohashi et al., 1999
;
Ben-Zur et al., 2000
),
neurestin in the rat (Otaki and Firestein,
1999
) and ten-m3 and ten-m4 in zebrafish
(Mieda et al., 1999
).
Most of the functional studies have been performed on the avian ten-m
family members. Three family members have been described in the chicken so far
and have been termed teneurin-1 (Minet et
al., 1999), teneurin-2 (Rubin
et al., 1999
) and teneurin-4
(Tucker et al., 2000
).
Teneurin-2 is a type II transmembrane protein containing a furin cleavage site
in the extracellular domain (Rubin et al.,
1999
). Both teneurin-1 and -2 promote neurite outgrowth in vitro
(Minet et al., 1999
;
Rubin et al., 1999
).
Teneurin-2 also acts as a homophilic adhesion protein and may play a role in
the specification of neuronal circuits in the developing visual system
(Rubin et al., 2002
). In
addition to being found in the nervous system, teneurin-2 and -4 are expressed
in two important organizing centers of limb development: the apical ectodermal
ridge and the zone of polarizing activity, respectively
(Tucker et al., 2001
;
Tucker et al., 2000
).
As all members of the teneurin family are type II transmembrane proteins
(Rubin et al., 1999;
Feng et al., 2002
), one
potential scenario by which such membrane-spanning proteins can fulfill their
role as signaling molecules is by a mechanism recently described as regulated
intramembrane proteolysis (RIP) (reviewed in
Brown et al., 2000
). RIP is a
two-step mechanism that leads to the cleavage of transmembrane proteins at and
in the lipid bilayer. The cleavage and release of the extracellular or
intraluminal parts of the protein is a prerequisite for a second cleavage,
which leads to the separation of the intracellular part from the membrane. The
latter takes place within the transmembrane domain. The resulting soluble
intracellular part translocates to the nucleus, where it participates in
transcription. RIP was first proposed as a signaling model by which the sterol
regulatory element binding protein (SREBP) regulates lipid metabolism
(Brown and Goldstein, 1997
). It
is now known to control diverse cellular and developmental processes
(Brown et al., 2000
). The
study of Notch, another protein exerting function by this mechanism, was
crucial to discover important features of RIP
(Chan and Jan, 1998
). Also
Ire1 (Niwa et al., 1999
) and
ATF6 (Haze et al., 1999
), both
of which are involved in the unfolded secretory protein pathway (endoplasmatic
reticulum stress response), signal through RIP. Amyloid precursor protein
(APP), which is thought to be involved in the Alzheimer's disease, is a
prominent example of this mechanism (Haass
and De Strooper, 1999
; Ebinu
and Yankner, 2002
). Not only does proteolysis of APP lead to the
accumulation of the toxic APP peptide underlying Alzheimer disease, but RIP
may be part of normal APP signaling (Gao
and Pimplikar, 2001
). The most recently recognized and least
described examples of RIP include CD44
(Okamoto et al., 2001
), ErbB-4
(Ni et al., 2001
;
Lee et al., 2002
), luman
(Raggo et al., 2002
) and
E-cadherin (Marambaud et al.,
2002
). These diverse examples of RIP could well be just the tip of
the iceberg of a large group of transmembrane proteins undergoing proteolytic
cleavage to initiate a signal transduction cascade.
It was the aim of the present work to determine whether a similar
proteolytic mechanism is responsible for the signaling by teneurins, thus
reconciling the enigma of Drosophila ten-m being a pair-rule gene and
a bona fide transcription regulator despite its cell-surface location. We
found that indeed the intracellular domain of teneurin-2 can be released from
the cell membrane and that it translocates to the nucleus where it is able to
influence the transcription activity of zic, a vertebrate homologue of the
Drosophila Opa (Yokota et al.,
1996).
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Materials and Methods |
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The following DNA constructs were used: pFR-luc (luciferase reporter
plasmid; Stratagene), pSV-ß-Galactosidase (Promega), pBD-NFB
(encodes BDAD), pCMV-AD and pCMV-BD (Stratagene), p-CMX-PML and p-CMX-PML-RAR
(expression plasmids encoding PML or PML-RAR fusion protein, respectively,
kindly provided by Ronald M. Evans, San Diego)
(Kakizuka et al., 1991
;
Lin and Evans, 2000
), pEF-zic1
(expression plasmid encoding myc-tagged zic-1, a generous gift from Jun Aruga,
Saitama, Japan) (Aruga et al.,
1996
), pXP2-APOE189 (luciferase reporter plasmid under
the control of an apolipoprotein E promoter; kindly provided by Francisco
Zafra, Madrid) (Salero et al.,
2001
).
Teneurin-2 constructs
Eight different teneurin-2 constructs were used in this study
(Fig. 1). They are named
according to the teneurin-2 protein domains contained within their coding
regions. Two of them (constructs TE and TEY) were described before
(Rubin et al., 2002).
Construct I represents the soluble intracellular domain of teneurin-2. It
encodes the first 372 amino acids of the teneurin-2 sequence as described
previously (Rubin et al.,
1999
), followed by a VSV tag for detection. Construct IT contains,
in addition to the intracellular domain, amino acids 373-406, including the
membrane-spanning domain and 10 extracellular amino acids followed by an HA
tag for detection. In four constructs teneurin-2 was coupled to the
Gal4-binding domain (BD) and the NF
B activation domain (AD), generating
BDAD-teneurin-2 fusion proteins (see Fig.
1). These constructs were cloned by multiple PCR. The product of
the PCRs comprised bases 675-1118 of pCMV-BD, coding for BD, bases 703-1267 of
pCMV-AD coding for AD and bases 1-630 of teneurin-2 coding for the first 210
amino acids of the intracellular domain of teneurin-2 until the BlpI
site. These fragments were connected by the method of SOE
(Horton, 1995
), and the
resulting construct was cloned into the BamHI/BlpI site of
the preexisting pcDNA3 vectors containing teneurin-2 constructs of different
lengths (Rubin et al.,
2002
).
|
Transient transfections
HT1080 fibrosarcoma and COS-7 green monkey kidney cells were routinely
maintained in DMEM medium supplemented with 10% FCS. For transient
transfections, the cells were seeded in six-well plates or 35 mm dishes
containing four internal wells (Greiner). 12 hours later they were transfected
with the indicated expression vectors (1 µg of each vector) by using
FUGENE-6 (3 µl, 6 µl or 9 µl for one, two to three or four different
plasmids, respectively; Roche). 24 hours after transfection the cells were
rinsed in PBS and processed for either measuring luciferase and
ß-galactosidase activities, western blotting or immunofluorescence.
Where indicated the cells were treated with the following substances at least 5 hours after transfection: ALLN (25 µg/ml; N-acetyl-leu-leu-norleu-AL; Sigma); tunicamycin (2 µg/ml; Sigma) or lactacystin (10 µM; Sigma) for 4 or 8 hours prior to harvesting.
Stable cell lines
Construct I was subcloned into the ecdyson-inducible expression vector pIND
(Invitrogen) and transfected into EcR-293 cells (Invitrogen) according to the
supplier's manual, resulting in the cell line EcR-293-I. Clones were tested
for the inducible expression of construct I after the addition of increasing
concentrations of ponasterone (1-10 µg/ml; Invitrogen) by immunoblotting
using anti-VSV antibodies.
Clones of HT1080 cells stably expressing TEY (TEY cells) or TE (TE cells)
on their surfaces, respectively, have been described previously
(Rubin et al., 2002).
Luciferase and ß-galactosidase assays
The cells were lysed by adding reporter lysis buffer (Promega). Appropriate
dilutions of the lysed cell suspension were then pipetted into
MicroliteTM luciferase plates (Dynex Technologies), and the luciferase
activity was measured in a Microlumat (LB96P, EG+G Berthold) by automatic
injection of luciferin substrate solution (2 mM luciferin, 100 mM ATP in 250
mM glycin pH 7.8, 150 mM MgSO4). All luciferase activities were
normalized with respect to the transfection efficiency by co-transfecting a
ß-galactosidase vector. To determine ß-galactosidase activity the
diluted cell suspensions were incubated with the substrate solution (4.5 mM
2-nitrophenyl-b-D-galactopyranoside in 0.2 M Na-phosphate, 2 mM
MgCl2, 0.1 mM ß-mercaptoethanol) for 30 minutes at 37°C.
To stop the enzymatic reaction, 1 M Na2CO3 was added and
the OD was measured at 405 nm in a microplate reader (BioRad).
Western blotting
Teneurin-2 constructs I, IT and ITE were extracted by adding SDS sample
buffer containing 20% ß-mercaptoethanol directly to the cells. Extraction
of the nuclear constructs BDAD and BDAD-I was achieved by performing nuclear
fractionation. The transfected cells were harvested by scraping off the cell
layer in lysis buffer [10 mM HEPES pH 7.5, 0.5% triton X-100, 300 mM sucrose,
100 mM NaCl, 2 mM MgCl2, protease inhibitors (CompleteTM,
Roche Diagnostics)] on ice and subsequent centrifugation for 10 minutes at 420
g in an Eppendorf centrifuge. The resulting pellet was
resuspended in lysis buffer and centrifuged again. The final pellet was then
dissolved in SDS sample buffer containing 20% ß-mercaptoethanol, 6 M urea
and protease inhibitors (CompleteTM). Before loading on an 8% SDS-PAGE
gel, DTT was added to a final concentration of 10 mM.
The transmembrane constructs BDAD-ITE and BDAD-ITEY were extracted from the cells by the following procedure. The cells were extracted on ice by a hypotonic buffer (2 mM Na-phosphate buffer pH 7.5, 20 mM KCl, 1 mM ß-mercaptoethanol), scraped off and centrifuged for 10 minutes at 6800 g at 4°C in an Eppendorf centrifuge. The resulting pellet was reconstituted in detergent buffer [50 mM Tris pH 8, 1% NP40, 150 mM NaCl, 5 mM EDTA, 6 M urea, protease inhibitors (CompleteTM)], incubated for 20 minutes at 37°C and centrifuged for 10 minutes at 17,900 g. SDS sample buffer containing 20% ß-mercaptoethanol, 6 M urea and protease inhibitors (CompleteTM) was added to the supernatant and incubated for 1 hour at 52°C. After DTT was added (10 mM), the samples were loaded on a 6% SDS-PAGE gel.
The gels were transferred to PVDF membranes. The proteins were detected by anti-Gal4 antibody (BDAD and BDAD-I) or by anti-teneurin-2 serum (BDAD-ITE and BDAD-ITEY), horseradish-peroxidase-coupled secondary antibodies and ECL SuperSignal® (Pierce).
Immunofluorescence
The cells grown on 35 mm four-well staining dishes (Greiner) were fixed
with 4% PFA for 30 minutes at room temperature and, where indicated,
permeabilized with 0.1% triton X-100 for 5 minutes. Incubation with primary
antibodies was performed for 60 minutes and that with secondary antibodies for
30 minutes, both at room temperature, and the cells were washed in PBS after
each incubation. Finally, the specimens were mounted in Moviol and examined
and photographed using a Zeiss Axiophot microscope (Carl Zeiss Ltd.) connected
to a 3CCD camera (Sony).
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Results |
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Functional interaction of teneurin-2 with zic
In Drosophila, ten-m was postulated to modulate the activity of
Opa protein (Baumgartner et al.,
1994). It was therefore of interest to investigate whether the
zinc finger transcription factor zic, a vertebrate homologue of Opa, would
influence or would be influenced by the intracellular domain of
teneurin-2.
When both proteins were expressed in COS-7 cells by transient transfections
we observed a marked downregulation of the intracellular domain I of
teneurin-2 compared with its usual expression level
(Fig. 3A). On the other hand,
co-transfection of the two constructs did not have an effect on the level of
zic (Fig. 3C). In contrast to
its effect on teneurin-2, zic did not downregulate another co-transfected
transcription factor BDAD (Gal4 DNA-binding domain fused to the NFB
activation domain) in an analogous analysis
(Fig. 3B,D). The zic-induced
downregulation of the intracellular domain I of teneurin-2 was counteracted by
the addition of the proteasome inhibitor lactacystin
(Fig. 3A). Thus the nuclear
intracellular domain of teneurin-2 seems to be subject to degradation by the
proteasome pathway. By immunofluorescence staining of the transfected cells we
observed that zic-transfected cells revealed a relatively diffuse nuclear
staining (Fig. 3E,F) and in
nuclei containing high amounts of zic protein, the punctate staining of
teneurin-2 I disappeared and became diffuse
(Fig. 3F). Thus, the presence
of zic prevented the association of the teneurin-2 intracellular domain with
PML bodies and made it amenable to proteasome-mediated degradation.
|
To examine the potential effect of the teneurin-2 I on the transcriptional
activity of zic, stably transfected EcR-293 cell lines were produced. In these
EcR-I cells teneurin-2 I was only expressed upon addition of ponasterone
(Fig. 4A). EcR-I cells were
transiently transfected with zic and a luciferase reporter construct under the
control of the apolipoprotein E (ApoE) promotor known to be activated by zic
(Salero et al., 2001). Whereas
the ApoE-luciferase reporter construct alone did not show any activity, the
presence of zic led to a dramatic increase in luciferase acitivity
(Fig. 4B). After the induction
of teneurin-2 I by ponasterone we observed a marked reduction in the
expression level of the reporter gene only in EcR-I cells
(Fig. 4B) and not in EcR
control cells (Fig. 4C). This
result suggested that the intracellular domain of teneurin-2 did have an
inhibiting effect on the transcriptional activity of zic, and this effect was
more pronounced in the presence of the proteasome inhibitor ALLN, which
stabilizes teneurin-2 I (Fig.
4A).
|
Release of the intracellular domain from the plasma membrane
To be a functional regulator of transcription, wild-type transmembane
teneurin-2 would have to be specifically cleaved in or at the plasma membrane,
possibly upon a signal by ligand binding. In turn its intracellular part must
be released and translocated to the nucleus in a manner similar to that
established for proteins regulated by RIP (reviewed in
Brown et al., 2000;
Ebinu and Yankner, 2002
). To
test this hypothesis we developed a sensitive method to detect the released
intracellular domain of teneurin-2 in the nucleus. We expressed fusion
proteins of full-length teneurin-2 (or of smaller transmembrane versions
truncated in their extracellular domain) fused to a Gal4 DNA-binding domain
(BD) and a NF
B activation domain (AD; see
Fig. 1). If cleavage and
translocation to the nucleus occurred, BDAD-I could be detected by binding to
specific Gal4 recognition sequences in the promotor of the cotransfected
luciferase reporter plasmid, and subsequent initiation of luciferase gene
expression activated by AD could be monitored.
Fig. 5 illustrates the correct expression of the transfected fusion proteins. BDAD and BDAD-I, serving as positive controls in this experiment, were detectable on a western blot of nuclear extracts by anti-Gal4 antibodies (Fig. 5A), and their accumulation in the nucleus was confirmed by immunofluorescence staining of permeabilised cells (Fig. 5B). At the same time BDAD-ITE and BDAD-ITEY could be identified as part of the plasma membrane by western blots of membrane fractions and by immunofluorescence of non-permeabilized cells (Fig. 5A,B).
|
For analysis of the luciferase activity induced by the teneurin-2 fusion
constructs, HT1080 cells were cotransfected with the respective
BDAD-teneurin-2 constructs, the luciferase reporter plasmid, as well as a
ß-galactosidase construct for normalization of transfection efficiencies.
As displayed in Fig. 6A,
BDAD-ITE, BDAD-IT and BDAD-I did indeed lead to an induction of luciferase
activity above the negative control (BD construct). However, BDAD-ITEY, being
the largest fusion protein, did not lead to a significantly enhanced activity.
This might partly be explained by the fact that the larger the transmembrane
construct the lower the expression level. Alternatively, cleavage of the
shorter constructs might be constitutive, whereas cleavage of the full-length
construct might have to be specifically induced. This is the case for Notch:
processing of Notch expressed on the cell surface is specifically activated by
binding to its ligand Delta (Kidd et al.,
1998; Schroeter et al.,
1998
; Struhl and Adachi,
1998
). Teneurin-2 has recently been shown to bind homophilically
by its extracellular domain (Rubin et al.,
2002
). We therefore speculated that this interaction could induce
cleavage and translocation of the intracellular domain of the BDAD-teneurin-2
fusion proteins, which in turn would be represented by enhanced luciferase
activities.
|
|
The induction of luciferase activity following transfection of BDAD-ITEY could again be markedly upregulated by the addition of protease inhibitors, such as ALLN and lactacystin (Fig. 7A). Thus, also the cleaved intracellular domain is subject to rapid degradation by the proteasome pathway. This was confirmed when the ITE protein of transfected cells was analysed on a western blot. The addition of ALLN led to the stabilization of two particular cleavage products, of which one matched the size of the entire intracellular domain and one was a fragment thereof (Fig. 7B, arrow and arrowhead).
|
Taken together, we conclude that the activity of the luciferase reporter gene originated from cleavage of the BDAD-teneurin-2 fusion proteins at (or in the vicinity of) the membrane. However, cleavage of full-length teneurin-2 led to a significant induction of the luciferase gene only when processing was upregulated by homophilic binding of the extracellular C-terminal part of teneurin-2. Furthermore, the cleaved intracellular domain is subject to rapid degradation by the proteasome pathway.
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Discussion |
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The genetics in Drosophila imply that ten-m and opa interact to
induce the transcription of the same downstream target genes
(Baumgartner et al., 1994).
Furthermore it is known that opa is expressed throughout the segments and
ten-m only in the part of the segment where the downstream genes are induced
(Baumgartner et al., 1994
). On
the basis of our results we therefore speculate that opa could act as a
transcriptional repressor and that the repressor function is interfered with
by ten-m. Thus, both ten-m and opa are required to determine localized
transcription of their target genes in segmental stripes. Also, in
vertebrates, functional interaction in vivo of zic proteins with teneurin
family members is not unlikely, since they may be co-expressed in many tissues
and both appear to be involved not only in regulating neuronal development but
possibly also limb pattern formation (Aruga
et al., 2002a
; Rubin et al.,
2002
; Nagai et al.,
1997
; Tucker et al.,
2001
).
For the transmembrane protein teneurin-2 to function as a transcription
regulator the release of the intracellular domain is indispensable. To date,
two types of proteolytic mechanisms have been shown to account for such a
release of the intracellular domains involved in transcription control, namely
regulated intramembranous proteolysis RIP by either -secretase or S2P
(site-2-protease) or regulated ubiquitin/proteasome-dependent processing RUP
(Hoppe et al., 2001
). In the
case of teneurin-2, RUP is unlikely to be responsible for the cleavage since
proteasome inhibitors enhance the presence of the cleaved intracellular
domain. However, levels of the intracellular domain of teneurin-2 seem to be
tightly controlled by degradation through the proteasome pathway. Under
conditions where the intracellular domain of teneurin-2 is localized in PML
bodies the teneurin-2 protein is stable. In contrast, conditions leading to a
diffuse nuclear expression, as is the case for the teneurin-2 I BDAD fusion
protein or the soluble intracellular domain in the presence of zic, result in
the degradation of the protein, which can be inhibited by the proteasome
inhibitors ALLN and lactacystin. These findings are intriguing in the light of
recent discoveries concerning the regulation of transcription by ubiquitin,
which causes a rapid turnover of the ubiquitinylated transcription factors
(Molinari et al., 1999
;
Salghetti et al., 2001
;
Conaway et al., 2002
).
Interestingly, one of the first proteins discovered to function through RIP,
SREBP, is also subject to rapid degradation by the ubiquitin-proteasome
pathway (Hirano et al., 2001
).
The same is true for Notch, which is the most intensely studied example of a
membrane-anchored transcription factor functioning through RIP. Cleaved
fragments of Notch could not be identified at first owing to rapid
downregulation in proteasomes simultaneously with a low sensitivity in the
detection methods (Chan and Jan,
1998
; Annaert and De Strooper,
1999
; Kopan and Goate,
2000
; Schroeter et al.,
1998
). The same problem might be responsible for our inability to
directly detect the cleaved intracellular domain of teneurin-2 in the nucleus
by immunohistochemistry.
Cleavage of Notch is induced by interaction with its heterophilic ligand
Delta (for a review, see Artavanis-Tsakonas
et al., 1999). In the case of teneurin-2 we found that homophilic
interactions can induce the release of the intracellular domain. This is
interesting considering our previous observation that neurons making up
functional circuits in the avian visual system express the same type of
teneurin molecule (Rubin et al.,
2002
). Therefore, promotion of the release of the intracellular
domain of teneurin-2 could be the mechanistic basis by which growing axons
realize that they have reached a proper target, namely another neuron
expressing teneurin-2. Since homophilic interaction leads to only a moderate
activation of the release of the intracellular domain, we cannot exclude the
possibility that more potent mechanisms exist by interaction with yet-to-be
identified heterophilic ligands. The released intracellular domain could then
turn on a gene expression program to stabilize the connection to differentiate
and to build synapses. In this respect teneurin-2 would counteract the action
of zic, which by itself was shown to promote the expansion of neuronal
progenitors (Aruga et al.,
2002b
). This would fit our present observation that transcription
from at least one zic target gene, namely ApoE, is downregulated by
teneurin-2.
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Acknowledgments |
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