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Molecular and Cellular Biology, October 1999, p. 7245-7254, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
The JIP Group of Mitogen-Activated Protein Kinase
Scaffold Proteins
Jun
Yasuda,
Alan J.
Whitmarsh,
Julie
Cavanagh,
Manoj
Sharma, and
Roger J.
Davis*
Howard Hughes Medical Institute, Program in
Molecular Medicine, Department of Biochemistry and Molecular Biology,
University of Massachusetts Medical School, Worcester, Massachusetts
01605
Received 7 April 1999/Returned for modification 17 May
1999/Accepted 13 July 1999
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ABSTRACT |
Activation of the c-Jun NH2-terminal kinase (JNK) group
of mitogen-activated protein (MAP) kinases is mediated by a protein kinase cascade. This signaling mechanism may be coordinated by the
interaction of components of the protein kinase cascade with scaffold
proteins. The JNK-interacting protein (JIP) group of scaffold proteins
selectively mediates signaling by the mixed-lineage kinase (MLK)
MAP
kinase kinase 7 (MKK7)JNK pathway. The scaffold proteins JIP1 and
JIP2 interact to form oligomeric complexes that accumulate in
peripheral cytoplasmic projections extended at the cell surface. The
JIP proteins function by aggregating components of a MAP kinase module
(including MLK, MKK7, and JNK) and facilitate signal transmission by
the protein kinase cascade.
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INTRODUCTION |
The response of cells to
extracellular stimuli is mediated by evolutionarily conserved signaling
mechanisms that regulate proliferation, differentiation, and survival.
These mechanisms include mitogen-activated protein kinase (MAPK) signal
transduction pathways. Several groups of MAPKs have been identified in
yeast, Drosophila melanogaster, and Caenorhabditis
elegans. In mammals, three groups of MAPKs have been described:
the extracellular signal-regulated protein kinases (ERK), the c-Jun
NH2-terminal kinases (JNK), and the p38 MAPKs. Each of
these groups of MAPKs is activated by dual phosphorylation on Thr and
Tyr by a MAPK kinase (MAPKK) which, in turn, is activated by a MAPKK
kinase (MAPKKK). Comparison of ERK, JNK, and p38 MAPKs indicates that
the biological function of each group of MAPKs is different.
The JNK group of MAPKs is activated by treatment of cells with
inflammatory cytokines or by exposure to environmental stress (11). Activated JNK phosphorylates many cellular proteins,
including components of the AP-1 transcription factor complex (c-Jun
and ATF-2). This phosphorylation leads to increased AP-1 transcription activity (11). The role of increased AP-1 transcription
activity is unclear. However, JNK signaling and AP-1 activation have
been implicated in multiple biological processes (11). For
example, genetic analysis of Drosophila demonstrated that
JNK is required for early embryonic morphogenesis (20, 26).
Genetic epistasis analysis indicated that the effect of JNK on
morphogenesis is mediated by activated Drosophila Jun
(9, 19, 25). The JNK signaling pathway is also required for
mammalian embryogenesis (6, 14, 17, 34).
Three mammalian genes encode JNK protein kinases. JNK1 and JNK2 are
expressed ubiquitously, while JNK3 is expressed primarily in the brain
(2, 7, 12, 15, 24). A role for JNK in neuronal apoptosis has
been demonstrated (31). Recent studies of knockout mice have
confirmed this observation. Targeted disruption of the Jnk3
gene causes defects in stress-induced neuronal apoptosis (36), while animals lacking both Jnk1 and
Jnk2 genes exhibit defects in developmental neuronal
apoptosis (14). JNK is also required for apoptosis of
CD4+ CD8+ double-positive thymocytes caused by
anti-CD3 in vivo (21, 22). Cellular proliferation, death,
and survival may therefore be regulated by the JNK signaling pathway in
vivo (11). The JNK signaling pathway also appears to
regulate the function of differentiated cells. For example, disruption
of the Jnk1 (4) and Jnk2 (22,
35) genes in mice causes defects in T-cell function and immune
responses. The JNK signaling pathway therefore contributes to multiple
biological processes and represents an important mechanism that is used
by cells to respond to extracellular stimulation (11).
JNK is activated by phosphorylation on Thr and Tyr by MKK4 and MKK7
(11). These MAPKKs are activated, in turn, by
phosphorylation by MAPKKKs, including ASK1, TPL2, TAK1, and members of
the MEKK and mixed-lineage protein kinase (MLK) groups of MAPKKKs
(11). Biochemical studies demonstrate that each step in the
MAPKKKMAPKKJNK signaling pathway can be reconstituted in vitro.
However, it is unclear whether these assays faithfully mimic the
activation of the JNK pathway in vivo. It is likely that the components
of the JNK protein kinase cascade may be organized into defined
signaling modules (29). For example, the MAPKKK MEKK1 binds
to JNK, MKK4, and the Ste20-related protein kinase NIK (27, 30,
32). These interactions may participate in the transmission of
signals from MEKK1 to JNK by the creation of a specific signaling
module in vivo (29). A functional signaling module could
also be created by the interaction of components of the JNK signaling
pathway with other proteins. An example is provided by the scaffold
protein JNK-interacting protein 1 (JIP1) (3), which binds
JNK, MKK7, MLKs, and the Ste20-related protein kinase HPK1
(28). The JIP1 scaffold mediates signaling to JNK by members
of the MLK group of MAPKKKs but does not participate in signaling by
the MEKK group of MAPKKKs (28).
The purpose of the study described in this report was to examine the
JIP-mediated JNK signaling module. We demonstrate that JIP1 is a member
of a group of MAPK scaffold proteins that includes JIP2. Both JIP1 and
JIP2 form homo- and hetero-oligomeric complexes with components
of the JNK signaling pathway. The JIP scaffolds facilitate JNK
activation by MLK protein kinases by aggregating components of the MAPK
cascade to form a functional JNK signaling module.
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MATERIALS AND METHODS |
Molecular cloning of JIP2.
JIP2 cDNA clones were isolated
from a human brain 
ZAPII cDNA library (Stratagene Inc.) by plaque
hybridization using a JIP cDNA fragment as a probe. The largest clone
(3,355 bp) included the complete open reading frame of human JIP2. The
sequence of JIP2 was determined by using an Applied Biosystems 373A machine.
Plasmids.
Expression vectors for JIP2 were constructed by
using the plasmids pCDNA3 (Invitrogen Inc.), pEBG (23), and
pGEX-4T-1 (Pharmacia-LKB Biotechnology Inc.) by subcloning PCR
fragments of JIP2 in the BamHI/NheI,
BamHI/NotI, and
BamHI/NotI sites, respectively. Expression vectors for MAPKs, MAPKKs, MAPKKKs, JIP1, and JIP1b have been described
previously (28).
Antibodies.
The antibodies to the Flag epitope tag (M2;
Sigma), the hemagglutinin (HA) epitope tag (12CA5; Boehringer
Mannheim), the T7-Tag epitope tag (Novagen Inc.), and glutathione
S-transferase (GST) (Pharmacia-LKB Biotechnology Inc.) were
purchased from the indicated suppliers. Antibodies to JIP1 and JIP2
were prepared by immunizing mice with purified bacterially expressed
proteins by standard techniques (8).
Immunofluorescence analysis.
Rin5F insulinoma cells were
grown on glass coverslips, washed, and then fixed and permeabilized
with methanol at 
20°C for 8 min. Indirect immunofluorescence was
performed by incubation with 10 µg of a primary monoclonal antibody
to JIP1 or JIP2/ml in 50 mM Tris-Cl (pH 7.4)-150 mM NaCl-3% (wt/vol)
bovine serum albumin for 12 h at 4°C. The secondary antibody was
ALEXA 594-conjugated anti-mouse immunoglobulin (Ig) antibody (1:200;
Molecular Probes), and nuclei were visualized by using SYTOX Green
(Molecular Probes). Confocal images were prepared with a Leica
microscope. Double-labeled immunofluorescence images were prepared with
a conventional Zeiss Axiophot microscope by using cells stained with a
fluorescein isothiocyanate-conjugated monoclonal antibody to JIP1 (2.5 µg/ml) and a monoclonal antibody to JIP2 (2.5 µg/ml) together with
a Texas red-conjugated anti-mouse Ig secondary antibody (1:100; Jackson
Immunoresearch). Nuclei were detected with
4,6-diamidino-2-phenylindole.
Biochemical assays.
Rin5F insulinoma cells and COS-7 cells
were cultured in RPMI medium and Dulbecco modified Eagle medium,
respectively, supplemented with 10% fetal calf serum (Life
Technologies Inc.). Transfection assays were performed with COS-7 cells
by the Lipofectamine method (Life Technologies Inc.). The cells were
solubilized in lysis buffer (20 mM Tris-Cl [pH 7.4], 137 mM NaCl, 2 mM EDTA, 25 mM 
-glycerophosphate, 2 mM pyrophosphate, 1 mM sodium
orthovanadate, 1 mM phenylmethylsulfonyl fluoride, 10 µg of
leupeptin/ml, 10% glycerol, 1% Triton X-100). GST fusion proteins
were isolated by incubation with glutathione-agarose (Pharmacia-LKB
Biotechnology Inc.) beads (20 µl) for 3 h at 4°C. Proteins
were immunoprecipitated by incubation for 3 h at 4°C with
antibodies bound to protein G-Sepharose (Pharmacia-LKB Biotechnology
Inc.). Immunoblot analysis was performed by using
enhanced-chemiluminescence detection (Kirkegaard & Perry). Binding
assays using purified bacterially expressed proteins were performed by
methods described previously (28). Protein kinase activity
was measured by using the in-gel method with 0.25 mg of substrate
(GST-c-Jun)/ml polymerized in the gel (28).
Nucleotide sequence accession number.
The sequence of JIP2
has been deposited in GenBank under accession no. AF136382.
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RESULTS |
Molecular cloning of JIP2.
The JIP1 protein has been
identified as a putative scaffold that binds components of the JNK
signaling pathway (28). We investigated whether additional
members of the JIP group are expressed by mammalian cells. These
studies led to the molecular cloning of human JIP2 (Fig.
1A). The JIP2 gene is
composed of 12 exons and is located on human chromosome 22q13 (Fig.
1B). Sequence analysis of JIP2 cDNA clones demonstrated the presence of
a JNK binding domain (JBD) in the NH2-terminal region and
both an SH3 domain and a PTB domain in the COOH-terminal region (Fig.
1C). This domain structure is similar to that of JIP1. However, unlike
JIP1, we obtained no evidence for the expression of alternatively
spliced variants of JIP2 with a deletion in the PTB domain.
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FIG. 1.
JIP2 is a member of the JIP group of scaffold proteins.
(A) The structure of the JIP group of scaffold proteins is illustrated
schematically. The JBD, the SH3 domain, and the PTB domain are
indicated. Comparison of the NH2-terminal region of JIP2
(residues 1 to 603) with the corresponding region of JIP1 indicates
41% identity and 46% similarity (Line-up Program, Wisconsin package,
version 9.1; Genetics Computer Group). The SH3 domains of JIP2
(residues 604 to 665) and JIP1 are 66% identical and 80% similar. The
PTB domains of JIP2 (residues 683 to 812) and JIP1b are 64% identical
and 74% similar. (B) The human JIP2 gene consists of 12 exons and is
located on chromosome 22q13 (GenBank accession no. U62317). The
structure of the gene is illustrated schematically. Solid boxes, coding
regions; open boxes, noncoding regions of exons 1 and 12. (C) The
primary sequence of human JIP2 deduced from the sequence of cDNA clones
is presented in single-letter code and compared to the sequences of
JIP1 and JIP1b. Periods, residues that are identical to JIP2 residues;
dashes, deletions; pound signs (#), termination codons. The JBD, the
SH3 domain, and the PTB domain are indicated. The sequences of JIP1,
JIP1b, and JIP2 have been deposited in GenBank under accession no.
AF003115, AF054611, and AF136382, respectively. (D) The expression of
JIP2 mRNA was examined by Northern blot analysis of different human
tissues (Clontech Inc.) using JIP2 cDNA as a probe. (E) Comparison of
the tissue distribution of the expression of the human JIP1
and JIP2 genes. Immobilized human mRNA was hybridized with
human JIP1 and JIP2 cDNA probes labeled with 32P by random
priming. The data were quantitated by PhosphorImager analysis and are
presented graphically. The data are normalized to the expression in the
whole brain (arbitrarily set at 1.0). JIP1 and JIP2 are represented by
open and filled bars, respectively.
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Northern blot analysis of the expression of JIP2 in human tissues
demonstrated that transcripts were detected in the brain
but not in the
other tissues examined (Fig.
1D). This selective
expression of JIP2 in
the brain differs from JIP1, which is expressed
more widely throughout
the body (
3). To directly compare the
distribution of these
JIP proteins, we examined the amounts of
JIP1 and JIP2 mRNAs in
different human tissues. This analysis
demonstrated that both JIP1 and
JIP2 are expressed throughout
the nervous system (Fig.
1E). JIP1 was
also expressed in many
additional tissues. A low level of JIP2
expression was also detected
in a limited number of human tissues,
including the uterus, prostate,
colon, testis, ovary, pancreas,
adrenal gland, thyroid gland,
and salivary
gland.
The JIP2 scaffold binds components of the JNK cascade.
JIP1
selectively binds components of the JNK signaling pathway
(28). We therefore examined the interaction of JIP2 with MAPKKKs, MAPKKs, and MAPKs.
The interaction of JIP1 and JIP2 with MAPKKKs was examined in
coimmunoprecipitation assays (Fig.
2).
The JIP proteins did
not bind members of the MEKK group, for example,
MEKK1 and MEKK4
(Fig.
2A). However, a very small amount of
coimmunoprecipitation
of MEKK3 was detected in experiments using JIP1
but not JIP2 (Fig.
2A). Furthermore, a very small amount of
coimmunoprecipitation
of the MAPKKK ASK1 with both JIP1 and JIP2 was
detected (data
not shown). In contrast, three different MLKs (DLK,
MLK2, and
MLK3) coimmunoprecipitated with JIP1 and JIP2 (Fig.
2A).
Reciprocal
precipitation-immunoblot analysis confirmed the interaction
between
the JIP proteins and MLKs (Fig.
2B). These data demonstrated
that
both JIP1 and JIP2 selectively interact with the MLK group of
MAPKKKs. The COOH-terminal region of JIP1 (
28) or JIP2 (Fig.
2B) was sufficient for the observed interaction with MLK3.
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FIG. 2.
Selective binding of JIP1 and JIP2 to the mixed-lineage
group of MAPKKKs. (A) Epitope-tagged JIP1 or JIP2 was expressed in
cells together with epitope-tagged MAPKKKs. Control experiments were
performed by transfection of the empty expression vector instead of the
JIP expression vector. The expression of JIP and MAPKKK proteins was
examined by immunoblot analysis of the cell lysates. The MAPKKK
proteins were immunoprecipitated with the M2 monoclonal antibody to the
Flag epitope. The presence of JIP proteins in the immunoprecipitates
(IP) was examined by immunoblot analysis using a monoclonal antibody
that binds the T7-Tag epitope. Coimmunoprecipitation was not observed
in experiments using MEKK1, MEKK3, or MEKK4. In contrast, JIP1 and JIP2
coimmunoprecipitated with the MLKs DLK, MLK2, and MLK3. (B) The
COOH-terminal regions of JIP1 (residues 283 to 660) and JIP2 (residues
499 to 824) were expressed in cells as GST fusion proteins together
with epitope-tagged MLK. Control experiments were performed by
transfection with the GST expression vector pEBG. The amounts of the
GST proteins and MLK in the cell lysates were examined by protein
immunoblot analysis. The GST fusion proteins were precipitated from
cell lysates with glutathione-agarose, and MLK present in the pellet
was detected by protein immunoblot analysis.
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Coimmunoprecipitation assays were performed to investigate the
interaction of JIP proteins with MAPKKs (Fig.
3). No evidence
for interaction with JIP1
or JIP2 was obtained in experiments
using activators of the ERK (MEK1)
or p38 MAPK (MKK3 and MKK6)
pathways (Fig.
3A). Similarly, MKK4, an
activator of JNK, did
not coimmunoprecipitate with the JIP proteins.
However, both JIP1
and JIP2 were found to coimmunoprecipitate with the
JNK activator
MKK7 (Fig.
3A). The interaction of MKK7 with the JIP
proteins
was confirmed by reciprocal precipitation-immunoblot analysis
(Fig.
3B). Thus, both JIP1 and JIP2 selectively bind the MAPKK
isoform
MKK7. The COOH-terminal region of JIP1 (
28) or JIP2
(Fig.
3B) was sufficient for the observed interaction with MKK7.
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FIG. 3.
Selective binding of JIP1 and JIP2 to the MAPKK MKK7.
(A) Epitope-tagged JIP1 and JIP2 were expressed in cells together with
epitope-tagged MEK1, MKK3, MKK4, MKK6, or MKK7. Control experiments
were performed by transfection of the empty expression vector instead
of the JIP expression vector. The expression of JIP and MAPKK proteins
was examined by immunoblot analysis of the cell lysates. The MAPKK
proteins were immunoprecipitated, and the presence of JIP1 and JIP2 in
the immunoprecipitates (IP) was examined by immunoblot analysis using a
monoclonal antibody that binds the T7-Tag epitope. (B) The
COOH-terminal regions of JIP1 (residues 283 to 660) and JIP2 (residues
499 to 824) were expressed in cells as GST fusion proteins together
with epitope-tagged MKK7. Control experiments were performed by
transfection with the GST expression vector pEBG. The amounts of the
GST proteins and MKK7 in the cell lysates were examined by protein
immunoblot analysis. The GST fusion proteins were precipitated from
cell lysates with glutathione-agarose, and MKK7 present in the pellet
was detected by protein immunoblot analysis using an antibody to the
Flag epitope.
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To test the interaction of the JIP proteins with MAPKs, we performed
coimmunoprecipitation assays with JNK, ERK, and p38 MAPK
(Fig.
4). These experiments demonstrated that
ERK and p38 MAPK
did not interact with JIP1 or JIP2 proteins. In
contrast, both
JIP proteins coimmunoprecipitated with JNK (Fig.
4A).
Reciprocal
precipitation-immunoblot analysis confirmed that JNK
interacts
with JIP proteins (Fig.
4B). These data demonstrate that JIP1
and JIP2 selectively bind the JNK group of MAPKs. The
NH
2-terminal
region of JIP1 (
28) or JIP2 (Fig.
4B) was sufficient for the
observed interaction with JNK.
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FIG. 4.
Selective binding of JIP1 and JIP2 to the JNK group of
MAPKs. (A) Epitope-tagged (T7-Tag) JIP1 and JIP2 were expressed in
cells with the HA-tagged MAPKs ERK2, p38 , and JNK22. Control
experiments were performed by transfection of the empty expression
vector instead of the JIP expression vectors. The MAPKs were
immunoprecipitated with an antibody to HA. The presence of JIP in the
immunoprecipitates (IP) was detected on immunoblots probed with an
antibody to T7-Tag. The amounts of JIP and MAPKs in the cell lysates
were examined by protein immunoblot analysis. (B) The
NH2-terminal regions of JIP1 (residues 1 to 282) and
JIP2 (residues 1 to 229) were expressed in cells as GST fusion proteins
together with epitope-tagged JNK11 or JNK22. Control experiments
were performed by transfection with the GST expression vector
pEBG instead of the JIP expression vector. The amounts of the GST
fusion proteins and JNK in the cell lysates were examined by protein
immunoblot analysis. The GST fusion proteins were precipitated from
cell lysates with glutathione-agarose, and JNK present in the pellet
was detected by protein immunoblot analysis using an antibody to the HA
epitope. (C) Comparison of the binding of 10 human JNK isoforms to JIP1
and JIP2. The JNK protein kinases were prepared by in vitro translation
in the presence of [35S]methionine. The JNK proteins were
incubated with GST-JIP1, GST-JIP2, or GST immobilized on
glutathione-agarose beads. The beads were washed with lysis
buffer. Bound JNK was detected by sodium dodecyl sulfate-polyacrylamide
gel electrophoresis and autoradiography. The amount of JNK bound
was quantitated by PhosphorImager analysis. The data are presented
graphically as relative binding by defining the amount of JNK11
binding to JIP1 as 1.0.
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Comparison of JIP1 and JIP2 indicates that these proteins exhibit
similar binding properties in assays using MAPKKKs and MAPKKs
(Fig.
2
and
3). In contrast, the interaction with MAPKs appears
to differ
between JIP1 and JIP2. While both JIP proteins selectively
bind
JNK, a greater amount of JNK binding to JIP1 than to JIP2
was
detected (Fig.
4A and B). To quantitate this difference and
to examine
the relative binding to different JNK isoforms, we
performed assays
using JNK prepared by in vitro translation in
the presence of
[
35S]methionine. The binding of JNK isoforms to
immobilized recombinant
JIP1 and JIP2 was examined (Fig.
4C).
These experiments demonstrated
that 10 different JNK isoforms bound to
both JIP proteins. However,
differences in binding were detected.
First, the amount of JNK
binding to JIP1 was markedly greater than the
binding to JIP2.
Second, some JNK isoforms (e.g., JNK1
1) were found
to bind JIP
more strongly than other JNK isoforms (e.g., JNK2
2).
These data
indicate that JIP proteins interact with JNK and can
distinguish
between JNK
isoforms.
To test whether the interaction of JIP2 with JNK, MKK7, and MLK3 might
be direct, we investigated the binding of JIP2 to these
protein kinases
using purified bacterially expressed recombinant
proteins. This
analysis demonstrated that JIP2 binds to JNK, MKK7,
and MLK3 (Fig.
5). Similarly, purified recombinant JIP1
binds
to purified recombinant JNK, MKK7, and MLK3 (
28).
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FIG. 5.
JIP2 binds JNK, MKK7, and MLK3 in vitro. Purified
bacterially expressed GST and GST-JIP2 fusion proteins were immobilized
on glutathione-agarose and incubated with purified bacterially
expressed JNK2, MKK7, or MLK3 (residues 1 to 204). Bound JNK2,
MKK7, and MLK3 were detected by immunoblot analysis.
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JIP2 regulates signal transduction by the JNK signaling
pathway.
The binding to MLKs, MKK7, and JNK suggests that JIP2 may
act as a scaffold protein. We therefore examined the effect of JIP2 overexpression on the JNK signal transduction pathway. Initial studies
of the effect of JIP2 overexpression indicated that JIP2, like JIP1,
acted as a powerful inhibitor of JNK signaling. For example, studies of
the chimeric transcription factor GAL4-ATF-2 demonstrated that both
JIP1 and JIP2 inhibited JNK-dependent reporter gene expression by more
than 90% (data not shown). This inhibition of JNK signaling by
JIP proteins (3) is probably mediated by the
sequestration of limiting components of the JNK signaling pathway
into separate complexes by the overexpressed scaffold protein
(28).
To test the effect of JIP2 under conditions where sequestration of
limiting components of the JNK signaling pathway does not
occur, we
coexpressed JIP proteins with components of the JNK
signaling pathway
(Fig.
6). JNK activity was measured in an
in
vitro protein kinase assay using recombinant c-Jun as the substrate.
This analysis demonstrated that MLK3 caused JNK activation. Expression
of JIP1 and JIP2 enhanced the activation of JNK caused by MLK3.
Similar
data were obtained in experiments using JNK1, JNK2, or
JNK3. Together,
these data demonstrated that JIP2 increases JNK
activation by the MLK
signaling pathway. The effect of JIP2 in
increasing JNK activation was
similar to that caused by JIP1.
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FIG. 6.
JIP1 and JIP2 enhance JNK activation by MLK3.
Epitope-tagged (HA) JNK11 (A), JNK22 (B), and JNK32 (C) were
each expressed alone or coexpressed with JIP1 and/or JIP2. JNK activity
was examined by using c-Jun as a substrate. The effect of coexpression
with MLK3 was examined. The amounts of JIP, MLK, and JNK expressed were
examined by immunoblot analysis.
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Coexpression of JIP1 with JIP2 did not cause further enhancement of JNK
activation beyond that caused by either JIP1 or JIP2
alone (Fig.
6).
Since the binding of JNK to JIP1 was markedly
greater than the binding
of JNK to JIP2 (Fig.
4), the similar
effects of JIP1 and JIP2 on JNK
activation (Fig.
6) suggest that
the function of JIP proteins to
potentiate MLK-stimulated JNK
activation may be catalytic and may not
require the formation
of stable complexes with
JNK.
JNK scaffold complexes are formed by JIP1 and JIP2.
JIP1 and
JIP2 are individually capable of forming scaffold complexes for the
MLKMKK7JNK signaling pathway. However, both JIP1 and JIP2 are
expressed in the brain (Fig. 1). This coexpression of JIP1 and JIP2
raises questions about whether the JIP1 and JIP2 scaffold complexes are
independent or whether these complexes may interact. To examine this
question, we performed coimmunoprecipitation analysis of JIP1 and JIP2
(Fig. 7). These experiments demonstrated that JIP1 interacts with JIP2. Furthermore, both JIP1 and JIP2 were
observed to self-associate. These data indicated that JIP1 and JIP2 can
form both homo-oligomers and hetero-oligomers. Deletion analysis
demonstrated that the COOH-terminal regions of JIP1 and JIP2 were
sufficient for the formation of hetero-oligomeric complexes (Fig.
8).
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FIG. 7.
JIP proteins form homo- and hetero-oligomeric scaffold
complexes. Epitope-tagged JIP1 and JIP2 proteins (Flag and T7-Tag) were
expressed in COS-7 cells. The expression of epitope-tagged JIP proteins
was examined by immunoblot analysis of cell lysates with antibodies to
Flag and T7-Tag. Coimmunoprecipitation analysis was performed by
immunoblot analysis (T7-Tag antibody) of immunoprecipitates (IP)
prepared by using the M2 monoclonal antibody to the Flag epitope.
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FIG. 8.
The interaction of JIP1 and JIP2 is mediated by the
COOH-terminal region. Epitope-tagged JIP1 was expressed in COS-7 cells
together with GST or GST-JIP2 fusion proteins. The expression of JIP1
was detected by immunoblot analysis using an antibody to the T7 epitope
tag. GST and GST-JIP2 fusion proteins were detected by immunoblot
analysis using an antibody that binds GST. The interaction of JIP1 with
JIP2 was examined by isolation of GST and GST-JIP2 complexes using
glutathione-agarose and immunoblot analysis of the bound T7-tagged
JIP1. Deletion analysis demonstrated that the COOH-terminal regions,
but not the NH2-terminal regions, of JIP1 and JIP2 were
sufficient for the formation of hetero-oligomeric complexes.
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To examine whether JIP1 and JIP2 form oligomeric complexes in vivo, we
prepared antibodies to JIP1 and JIP2 (Fig.
9A). These
antibodies detect endogenous
JIP1 and JIP2 proteins expressed
by cultured cells (Fig.
9B).
Reciprocal immunoprecipitation-immunoblot
analysis of cell extracts
demonstrated coprecipitation of JIP1
and JIP2 (Fig.
9B). These data
confirm the observation made with
transfected recombinant JIP proteins
in cultured cells by demonstrating
an interaction between the
endogenous JIP proteins in vivo.
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FIG. 9.
Identification of endogenous oligomeric JIP complexes.
(A) Characterization of monoclonal antibodies to JIP1 and JIP2. COS-7
cell lysates containing T7-Tag-labeled JIP proteins were examined by
protein immunoblot analysis using antibodies to the T7-Tag and
monoclonal antibodies to JIP1 and JIP2. (B) JIP1 and JIP2 interact in
vivo. Extracts were prepared from Rin5F insulinoma cells and examined
by protein immunoblot analysis by probing with murine antibodies to
JIP1 and JIP2. The endogenous JIP1 and JIP2 proteins were detected in
the cell lysates and in immunoprecipitates (IP) prepared by using
antibodies to JIP1 and JIP2.
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Subcellular localization of JIP scaffold complexes.
We
investigated the subcellular localization of JIP proteins using
monoclonal antibodies to JIP1 and JIP2. Confocal immunofluorescence microscopy demonstrated that both JIP1 and JIP2 were located in the
cytoplasm and were largely excluded from the nucleus (Fig. 10A). This distribution of JIP proteins
was unaffected when JNK was activated following treatment of the cells
with interleukin-1 or exposure to UV-C radiation (data not shown).
Comparison of JIP1 and JIP2 indicated that the patterns of expression
of these proteins differed. Immunofluorescence analysis demonstrated a punctate appearance of JIP1 in the cytoplasm and an accumulation of
JIP1 in cell surface projections (Fig. 10A). A similar punctate expression of JIP2 was observed, but more extensive cytoplasmic accumulation of JIP2 than JIP1 was detected.
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FIG. 10.
Cytoplasmic location of endogenous JIP proteins. (A)
The endogenous JIP1 and JIP2 proteins expressed by Rin5F insulinoma
cells were detected by confocal immunofluorescence analysis using
monoclonal antibodies to JIP1 and JIP2 (red). The nucleus was detected
by staining DNA with SYTOX green. (B) Double-label immunofluorescence
analysis of JIP1 (green) and JIP2 (red) was performed by conventional
microscopy. The nucleus was detected by staining DNA with
4,6-diamidino-2-phenylindole (blue).
|
|
To compare the distribution of JIP1 and JIP2, we performed double-label
immunofluorescence analysis (Fig.
10B). JIP1 and JIP2
colocalized in
the peripheral cell surface projections where most
of the JIP1 protein
was detected. In addition, the punctate cytoplasmic
distributions of
JIP1 and JIP2 were similar. However, the majority
of JIP2 was found in
cytoplasmic structures that did not appear
to contain JIP1. Thus, some
JIP2 molecules colocalize with JIP1
(Fig.
10B). This conclusion is
consistent with the observation
that a fraction of the total JIP2
molecules coimmunoprecipitated
with JIP1 (Fig.
9B). Together, these
data indicate that the JIP1
and JIP2 scaffolds exist in vivo as both
homo- and hetero-oligomeric
complexes.
| |
DISCUSSION |
Two members of the JIP group have been identified: JIP1 (1,
3, 13) and JIP2 (Fig. 1). These JIP proteins are related in
structure (Fig. 1), but the genes that encode these proteins are not
closely linked in the genome. The human JIP1 gene is located on human chromosome 11 (11p11.2-p12), while a JIP1
pseudogene is located on human chromosome 17 (17q21) (16).
In contrast, the JIP2 gene is located on human chromosome 22 (22q13) (Fig. 1). Comparison of the expression of the JIP1
and JIP2 genes indicates that both JIP proteins are widely
expressed in many regions of the brain (Fig. 1). In addition,
expression of JIP1 and JIP2 was detected in other tissues.
The JIP1 and JIP2 proteins interact with multiple components of the JNK
signaling pathway, including the JNK group of MAPKs, the MAPKK isoform
MKK7, and members of the MLK group of MAPKKKs (Fig. 2 to 4). Functional
analysis demonstrated that these complexes cause marked potentiation of
JNK activation (Fig. 6). These data suggest that the JIP1 and JIP2
proteins act as molecular scaffolds that mediate the activation of the
JNK signaling pathway in vivo.
The JIP scaffold proteins were found to self-associate to form
intermolecular complexes (Fig. 7). Coimmunoprecipitation studies demonstrated the presence of both homo- and hetero-oligomeric complexes. These oligomeric JIP complexes may contribute to the scaffold function of JIP proteins by aggregating components of the JNK
signaling pathway to create a functional protein kinase cascade. This
oligomeric structure of JIP is analogous to the Ste5p scaffold protein
in yeast, which also forms oligomeric complexes containing more than
one Ste5p molecule (5, 10, 33).
Previous studies of overexpressed epitope-tagged JIP1 indicate that it
is located exclusively in the cytoplasm (3). Similarly, overexpressed epitope-tagged JIP2 was also detected in the cytoplasm (data not shown). Together, these observations suggest that the endogenous JIP proteins expressed by cells may also be located in the
cytoplasm. To examine this question, we prepared monoclonal antibodies
to JIP1 and JIP2 and examined the distribution of the endogenous
JIP proteins in cultured cells (Fig. 10). These data confirmed that
both JIP proteins were detected in the cytoplasm. Interestingly,
the majority of the JIP1 protein accumulated in peripheral cytoplasmic
projections that extend from the cell surface. The JIP2 protein
colocalized in these cell surface projections but was also found to
accumulate in a cytoplasmic compartment that did not include JIP1. It
is tempting to speculate that the observed cell surface location of JIP
proteins may represent a site of action of these scaffold proteins in
vivo, as described for the yeast scaffold protein Ste5p
(18).
In a recent study, JIP1 was implicated in the expression of the
Glut2 and insulin genes (1). Further
studies are required to determine whether there is a similar role for
JIP2. The JIP1 function of regulating Glut2 and
insulin gene expression was proposed to be mediated by
nuclear JIP1 (1). Our immunofluorescence analysis of
endogenous JIP proteins did not detect significant amounts of nuclear
JIP1 or JIP2. We cannot eliminate the possibility that JIP proteins
might accumulate in the nucleus under some experimental conditions.
However, it is possible that the effect of JIP1 on Glut2 and
insulin gene expression may be indirectly mediated by changes in JNK activity (or some other JIP-regulated activity).
The JIP group of MAPK scaffold proteins includes at least two members.
Both JIP1 and JIP2 strongly potentiate JNK activation by the MLK/MKK7
signaling pathway. The function of the JIP scaffold proteins appears
similar to that of the Ste5p scaffold, which mediates activation of the
Ste11p (MAPKKK), Ste7p (MAPKK), and Fus3p (MAPK) signaling pathway in
yeast (for a review, see reference 29). The results
of the present study demonstrate that JIP proteins exist as oligomers
in vivo and are detected in peripheral cell surface projections. These
properties are similar to those of the yeast Ste5p scaffold, which also
functions as an oligomer (5, 10, 33) and is present in
pheromone-induced cell projections (18). Together, these
data suggest that mammalian JIP and yeast Ste5p may function by
analagous mechanisms that involve the selective aggregation of MAPK
pathway components in a discrete cellular compartment.
The JIP scaffold proteins interact with MLKs, MKK7, and JNK.
Interactions with other components of the JNK signaling pathway, including MKK4 and members of the MEKK group of MAPKKKs, were not
observed. This selectivity indicates that JIP scaffold complexes represent only one mechanism of JNK activation. Signals mediated by
MEKK protein kinases and MKK4 function independently of the JIP
scaffold complexes (29). These signals may be mediated by other scaffold complexes. Alternatively, JNK may be activated by a
mechanism involving intermolecular associations between signaling components, as described recently for signaling mediated by MEKK1 (27, 30, 32). The concept that scaffold-dependent and
scaffold-independent signaling pathways can coexist has been
established by studies of MAPK signaling in yeast (for a review, see
reference 29). An important goal for future research
will be to define the relative roles of these alternative mechanisms
that mediate JNK activation. The analysis of mice with targeted
disruptions of genes that encode components of the JNK signaling
pathway will facilitate the genetic dissection of these processes.
| |
ACKNOWLEDGMENTS |
We thank our colleagues for providing essential reagents, L. Gangwani for assistance with monoclonal antibody production, W. E. Theurkauf for assistance with confocal microscopy, T. Barrett and
A. Quail for DNA sequence analysis, and K. Gemme for administrative assistance.
J.Y. was supported, in part, by the Foundation for Promotion of Cancer
Research in Japan. R.J.D. is an investigator of the Howard Hughes
Medical Institute. This study was supported by a grant from the
National Cancer Institute.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Howard Hughes
Medical Institute, Program in Molecular Medicine, University of
Massachusetts Medical School, 373 Plantation St., Worcester, MA 01605. Phone: (508) 856-6054. Fax: (508) 856-3210. E-mail:
roger.davis{at}umassmed.edu.
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Abstract
Introduction
