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(Received for publication, June 12, 1997, and in revised form, August 11, 1997)
From the Department of Pathology, Division of Molecular and
Cellular Pathology, the University of Alabama at Birmingham,
Birmingham, Alabama 35294
ABSTRACT c-Jun NH2-terminal protein kinase
(JNK), a distant member of the mitogen-activated protein (MAP) kinase
family, regulates gene expression in response to various extracellular
stimuli. JNK is activated by JNK-activating kinase 1 (JNKK1), a dual
specificity protein kinase that phosphorylates JNK on threonine 183 and
tyrosine 185 residues. Here we show that JNKK2, a novel member of the
MAP kinase kinase family, was phosphorylated and activated by MEKK1, a
MAP kinase kinase kinase in the JNK signaling cascade. JNKK2 activity
was also stimulated by constitutively active forms of Rac and Cdc42Hs,
members of the Rho small GTP-binding protein family. Unlike JNKK1 that
activates both JNK and p38 MAP kinases, JNKK2 stimulated only JNK.
Transient transfection assays demonstrated that JNKK2 potentiated the
stimulation of c-Jun transcriptional activity by MEKK1. The existence
of multiple JNK-activating kinases may contribute to the specificity of
the JNK signaling cascade.
INTRODUCTION The mitogen-activated protein
(MAP)1 kinase is an essential
part of the signal transduction machinery and occupies a central position in cell growth, differentiation, and transformation (1-3). To
date, several mammalian MAP kinases have been identified, including extracellular signal-regulated protein kinase (ERK) (4, 5), c-Jun
NH2-terminal protein kinase (JNK, also known as
stress-activated protein kinase, SAPK) (6-8), and p38 (also known as
Mkp2/CBSP) (9-11). Each MAP kinase belongs to a distinct MAP kinase
module which consists of a MAP kinase kinase kinase, a MAP kinase
kinase (MKK), and a MAP kinase. The MAP kinase kinases in the ERK
signaling cascade are MAPK/ERK kinase (MEK) 1 and 2 (12-14), and the
MAP kinase kinase kinases include Raf-1, Mos, and MEK kinase (MEKK) 1 (15-19). In the JNK signaling cascade, the MAP kinase kinase is
JNK-activating kinase (JNKK) 1 (also known as SAPK/ERK kinase, SEK, and
MKK4) (20-22), and the MAP kinase kinase kinases are the MEKKs
(23-25). In the p38 signaling cascade, the MAP kinase kinases include
JNKK1, MKK3, and MKK6 (20, 22, 26, 27). The MAP kinase kinase kinases
for p38 may include MEKK1, TAK1, and Ask (28-30). These individual MAP
kinase modules may provide a structural basis for different signaling
cascades to relay extracellular stimuli to specific effectors.
A challenge in understanding the mammalian MAP kinase cascade is how
signaling specificity is achieved. Despite the MAP kinase modules,
cross-talk still exists. The cross-talk may allow the cells to
coordinate the activity of different signaling cascades to produce a
specific physiological response. However, it also makes the signaling
cascades prone to lack of specificity. Other mechanisms are needed to
ensure the specificity of each MAP kinase cascade, including
subcellular localization, specific associated proteins, high enzymatic
specificity, and selective responsiveness to extracellular stimuli.
The JNK cascade is activated by various stimuli such as growth factors,
cytokines, tumor promoters, protein synthesis inhibitors, ultraviolet
(UV) light irradiation, and oncogenes (1). JNK in turn stimulates the
activity of several transcription factors including c-Jun, ATF-2, Elk,
and Sap-1 (6-8, 31-33). It is not completely understood how the
specificity of the JNK cascade is maintained. One plausible mechanism
is through the existence of multiple JNKKs that have high substrate
specificity and respond to distinct upstream signals. To test this
hypothesis, we have isolated a novel JNK-activating kinase, JNKK2,
which is a close homologue of JNKK1. In contrast to JNKK1, which is
selectively expressed in skeletal muscle and brain, JNKK2 is expressed
in many tissues examined. Unlike JNKK1 which activates both JNK and p38, JNKK2 stimulated only JNK. Furthermore, JNKK2 did not respond to
several extracellular stimuli that activate JNKK1. These data suggest
that JNKK2 is a specific JNK activator and may contribute to the
specificity of the JNK cascade.
EXPERIMENTAL PROCEDURES HeLa cells were grown in Dulbecco's modified
Eagle's medium, supplemented with 10% fetal calf serum, 2 mM glutamine, 100 units/ml penicillin, and 100 mg/ml
streptomycin.
A human JNKK1 cDNA (20) was used as a
probe to isolate JNKK1 homologues by screening a The JNKK2 expression vector was
constructed by inserting a polymerase chain reaction-generated
NcoI-BglII fragment encoding JNKK2 into
NcoI and BglII sites of pSR GST-JNKK2,
GST-JNKK(AA), GST-JNK1, GST-p38, GST-c-Jun, and GST-ATF2 were purified
on glutathione-agarose, as described (20). Histidine-tagged ERK2 was
purified by a nickel-chelate column, according to the manufacturer's
procedure (Pharmacia Biotech Inc.).
HeLa cells were transiently transfected with expression
vectors and harvested as described (20). HA-tagged or M2-Flag-tagged protein kinases were immunoprecipitated with specific antibodies for
3 h at 4 °C. The activity of the immune complex was assayed at
30 °C for 30 min in 30 µl of kinase buffer (20) in the presence of
10 µM [ RESULTS Sequence analysis revealed that
the JNKK2 clone encodes a complete open reading frame which appears to
be a novel MAP kinase kinase (Fig. 1).
The new MAP kinase kinase is closest to hep, a
Drosophila JNK-activating kinase (36) (56.2% identity),
followed by human JNKK1 (20) (42.4% identity), based on the comparison of all known MAP kinase kinases (PILE-UP program, Wisconsin Genetics Computer Group). Northern blot analysis revealed that unlike JNKK1, which is expressed mainly in skeletal muscle and brain, JNKK-2 is
widely expressed in many tissues, with the highest level of expression
in skeletal muscle (data not shown), suggesting that the two JNK
activators may have different roles in different cells.
We and
others have shown that MEKK1 acts as a MAP kinase kinase kinase which
directly phosphorylates and activates JNKK1 (20, 23, 24). In addition,
Rac and Cdc42Hs, members of the Rho small GTP-binding protein family,
are both strong activators of JNKK1 and JNK (34, 37, 38). The effects
of expression of MEKK1 and Rac/Cdc42Hs on JNKK2 activity were examined
in transient transfection assays. Coexpression of the active forms of
MEKK1, Rac1 and -2, and Cdc42Hs strongly activated JNKK2 (Fig.
2A). The active form of RhoA
did not activate JNKK2 (Fig. 2A) but was able to stimulate
ERK activity (data not shown). MEKK1 also directly phosphorylated JNKK2
but not the JNKK2 (S272A/T276A) mutant, in which the putative
activating phosphorylation residues Ser-272 and Thr-276 were replaced
with alanines (Fig. 2B). These results demonstrate that
JNKK2 is a JNK-activating kinase which acts downstream of MEKK1 and
Rac/Cdc42Hs in the JNK signaling pathway.
We also examined the regulation of JNKK2 by UV and the protein
synthesis inhibitor anisomycin, both of which are strong activators of
JNKK1 (Fig. 2C, top panel). UV and anisomycin
only weakly stimulated JNKK2 activity (Fig. 2C, middle
panel), even though JNK activity was stimulated manyfold in the
same transfection assays (Fig. 2C, bottom panel).
It is likely that JNKK2 may respond to upstream signals other than UV
and anisomycin.
MEKK1-activated
HA-JNKK2 was isolated from transfected HeLa cells, and its substrate
specificity was determined by protein kinase assays. JNKK2 efficiently
phosphorylated GST-JNK1, but not GST-p38 or histidine-ERK2 (Fig.
3A). However, GST-p38 and histidine-ERK2 can be phosphorylated by their specific upstream kinases, MKK6 and MEK1(EE), respectively (Fig. 3A). The
phosphorylation of JNK by JNKK2 is specific, since JNKK2 did not
phosphorylate mutants JNK1 (APY) or JNK1 (APF), in which the activating
phosphorylation residues Thr-183 and Tyr-185 were replaced by alanine
and phenylalanine (Fig. 3B). Phosphorylation of JNK by JNKK2
in vitro led to JNK activation, as measured in a coupled
kinase assay (Fig. 3C).
The effect of JNKK2 on JNK in vivo was examined in transient
transfection assays. In HeLa cells, cotransfection of JNKK2 stimulated M2 Flag-tagged JNK1 (M2-JNK1) activity (Fig. 3D). The
stimulation by JNKK2 was further potentiated by a suboptimal amount of
cotransfected MEKK1 (Fig. 3D). Under the same conditions,
JNKK2 or JNKK2 plus MEKK1 did not stimulate M2-p38 activity (Fig.
3D). These data demonstrate that JNKK2 is a specific
activator of JNK in vivo.
To determine the effect of JNKK2 on c-Jun
transcriptional activity, HeLa cells were cotransfected with the active
form of MEKK1 and GAL4-c-Jun fusion protein (20). MEKK1 stimulated
GAL4-c-Jun activity 18-fold, as measured by a luciferase reporter gene
driven by a GAL4 responsive promoter (Fig.
4). Coexpression of wild-type JNKK2
potentiated the stimulatory effect of MEKK1 on GAL4-c-Jun, resulting in
28-fold activation (Fig. 4). Neither MEKK1 alone nor MEKK1 plus JNKK2
stimulated the activity of GAL4-c-Jun Ala-63/73, in which both Ser-63
and Ser-73 have been replaced with alanines (Fig. 4). These results
demonstrate that JNKK2 participates in stimulation of c-Jun
transcription activity.
DISCUSSION The specificity of the MAP kinase cascade is determined, in part,
by enzymatic specificity of MAP kinase kinases in the MAP kinase module
(2). JNKK1 was shown to be an efficient MAP kinase kinase of JNK
in vitro (20-22) and is required for JNK activation in vivo (39, 40). However, JNKK1 is also involved in
regulation of p38 (20, 22). In contrast to JNKK1, JNKK2 is a highly
selective kinase that phosphorylates and activates JNK but not p38 or
ERK2 (Fig. 3A). The high substrate specificity of JNKK2
should contribute to the specificity of the JNK cascade.
The specificity of the JNK cascade may also be achieved by limiting the
responsiveness of JNKKs to a certain subset of upstream stimuli. It has
been shown that various extracellular stimuli and proto-oncogenes
stimulate JNK activity, some of which do so through activating JNKK1.
JNKK2 can be significantly activated by MEKK1, Rac, and Cdc42Hs, which
are activators of JNKK1 (Fig. 2A). However, JNKK2 was only
weakly activated by UV and anisomycin (Fig. 2C), both of
which strongly activate JNKK1 (Fig. 2C). Osmotic stress
stimulates JNKK1, but only weakly stimulated JNKK2 activity (data not
shown). The differential response of JNKK1 and JNKK2 to extracellular
stimuli suggests that signaling leading to JNK activation may diverge
upstream of JNK at the level of JNKKs. It is possible that JNKK2 may
mediate the activation of JNK by extracellular stimuli that stimulate
only JNK but not p38. Identification of extracellular stimuli that
specifically activate JNKK2 should provide insights into the
specificity of the JNK signaling pathway.
FOOTNOTES The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF006689. ACKNOWLEDGEMENTS We thank A. Minden and J. Frost for critical
comments and helpful discussions and M. Karin, A. Minden, M. Cobb, G. Johnson, N. Ahn, and J. Han for the different plasmids that made this
work possible. We also thank members of Lin's laboratory, Jeff O'Neal and Nicole Purcell, for reading the manuscript.
REFERENCES
Volume 272, Number 40,
Issue of October 3, 1997
pp. 24751-24754
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
COMMUNICATION:
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
ZAPII HeLa cDNA
library (Stratagene) at low stringency. Thirty positive clones were
obtained after screening 2 × 106 phage. These clones
were grouped and sequenced on both strands by the dideoxy chain
termination method using Sequenase Version II (U. S. Biochemical
Corp.). Nucleotide sequence comparison of clones 4 and 23 with the
GenBankTM data base reveals five sets of nucleotide
sequences (GenBankTM accession numbers AA194047, AA019720,
AA194193, AA258025, and AA252650) that are nearly identical. These
clones were partially sequenced by the Washington University-Merck EST
project. The clones AA194047 and AA019720 were requested and completely sequenced.
3-hemagglutinin
(HA) vector (20). To construct pGEX-KG-JNKK2, the BglII site
of the NcoI-BglII fragment of JNKK2 was blunted,
and the fragment was inserted between the NcoI site and
blunted HindII site of pGEX-KG vector. A ChameleonTM mutagenesis kit (Stratagene) was used to replace Ser-272 and Thr-276 with alanines, to create pGEX-KG-JNKK2 (AA). The expression vectors of
MEKK1, Rac1, Rac2, Cdc42Hs, RhoA, JNK1, p38, MKK6, MEK1, ERK2, c-Jun,
and ATF2 have been described (6, 20, 23, 26, 34, 35).
-32P]ATP (10 Ci/mmol) with
appropriate substrates, as indicated in the figure legends. The
proteins were resolved by 13% SDS-polyacrylamide gel electrophoresis,
followed by autoradiography. The phosphorylated proteins were
quantitated by a phosphorImager.
Fig. 1.
Primary structure of JNKK2. Shown is the
cDNA sequence and deduced amino acid sequence of JNKK2. The protein
sequence is presented in single-letter code. The
GenBankTM accession number of JNKK2 is AF006689.
[View Larger Version of this Image (81K GIF file)]
Fig. 2.
Activation of JNKK2 by activated MEKK1, Rac,
and Cdc42Hs but not UV and anisomycin. A, HeLa cells were
transfected with pSR3-HA-JNKK2 (1 µg) with or without expression
vectors of MEKK1 or the indicated small GTPases (0.5 µg each).
HA-JNKK2 was immunoprecipitated, and its activity was measured by
kinase assays with GST-JNK1 as a substrate. Fold stimulation is
indicated. An aliquot of each sample was analyzed for expression of
HA-JNKK2 by Western blot analysis using an anti-HA antibody (Santa
Cruz). B, HeLa cells were transfected with pSR3-HA-MEKK1
or empty vector (0.5 µg each). HA-MEKK1 was immunoprecipitated, and
its activity was measured by kinase assays with GST-JNKK2 or GST-JNKK2
(S272A/T276A) as a substrate. C, HeLa cells were transfected
with expression vectors of HA-JNKK1 (top panel) or HA-JNKK2
(middle panel) (1 µg each). After 48 h, the cells
were treated with UV (80 J/m2, 20 s) or anisomycin
(Aniso.) (50 ng/ml, 15 min) or left untreated (C,
control). The activity of HA-JNKK1 or HA-JNKK2 was determined as
described in A. Endogenous JNK (bottom panel) was
isolated from JNKK2-transfected HeLa cells by immunoprecipitation with an anti-JNK1 antibody (PharMingen), and its activity was measured by
kinase assays with GST-c-Jun as a substrate.
[View Larger Version of this Image (41K GIF file)]
Fig. 3.
JNKK2 selectively phosphorylates and
activates JNK but not p38 or ERK2. A, HeLa cells were
transfected with pSR3-HA-JNKK2 (1 µg) together with pSR3-MEKK1
(0.2 µg) or with pCMV5-HA-MEK1 (EE) or pcDNA3-HA-MKK6
(1 µg each) expression vectors. After 48 h, the cells
transfected with MKK6 were irradiated with UV (80 J/m2,
20 s). The transfected kinases were immunoprecipitated, and their
activities were determined by kinase assays with GST-JNK1, GST-p38, and
histidine-ERK2 as substrates, as indicated. B,
MEKK1-activated HA-JNKK2 was isolated as described in A, and
its activity was measured by kinase assays with GST-JNK1 wild-type
(WT), GST-JNK1 (APY), and GST-JNK1
(APF) mutants as substrates. C, MEKK1-activated HA-JNKK2 was isolated as described in A, and its activity
was measured in a coupled kinase assay with GST-c-Jun as a substrate. D, HeLa cells were transfected with expression vectors
encoding M2-JNK1 and M2-p38 (1 µg each), HA-JNKK2 (2 and 3 µg), and
MEKK (20 ng), as indicated. M2-JNK1 or M2-p38 were immunoprecipitated with anti-M2-Flag antibody, and their activities were measured by
kinase assays with GST-c-Jun or GST-ATF2 as substrates, respectively. Phosphorylated GST-c-Jun shows a slower migration in the SDS gel, as
indicated.
[View Larger Version of this Image (26K GIF file)]
Fig. 4.
JNKK2 potentiates c-Jun transcriptional
activity. HeLa cells were cotransfected with a 5 × GAL4-Luc
reporter plasmid (1 µg) and expression vectors of
GAL4-c-Jun-(1-223), GAL4-c-Jun-(1-223) (Ala-63/73), MEKK1, JNKK1, and
JNKK2 (10 ng each). Luciferase activity was determined as described
(20). The averages of three experiments are shown. Luciferase activity
expressed by cells transfected with pSR was given an arbitrary value
of 1.
[View Larger Version of this Image (35K GIF file)]
To whom correspondence should be addressed. Tel.: 205-975-9225;
Fax: 205-934-1775; E-mail: lin{at}vh.path.uab.edu.
1
The abbreviations used are: MAP,
mitogen-activated protein; ERK, extracellular signal-related kinase;
JNK, c-Jun NH2-terminal protein kinase; JNKK,
JNK-activating kinase; MEKK, MAP kinase kinase kinase; ATF, activating
transcription factor; HA, hemagglutinin; CBSP, CSAIDTM-binding
protein.
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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