Abbreviations
AP
Activation protein
ATF
Activating transcription factor
CYP450 Cytochrome P450
EGFR
Epidermal growth factor receptor kinase
JNK
c-Jun N-terminal kinase
MAP
Mitogen-activated protein
SAPK
Stress-activated protein kinases
SAR
Structure-activity relationships
1 Introduction
The c-Jun N-terminal kinases (JNKs) are serine/threonine kinases belonging to the
family of mitogen-activated protein (MAP) kinases. First members of this enzyme
class were discovered in the early 1990s and originally termed as stress-activated
protein kinases (SAPKs). Three different isoforms with molecular weights ranging
from 46 to 55 kDa have been classified within this group, namely, JNK1 (also known
as SAPK-γ/MAPK8), JNK2 (SAPK-α/MAPK9), and JNK3 (SAPK-β/MAPK10),
which are encoded by the three distinct genes jnk1, jnk2, and jnk3, respectively
[1, 2].
The JNKs are activated by different forms of cellular stress via the classical MAP
kinase signaling cascade by tandem phosphorylation by two upstream kinases, in
detail by a MAP kinase kinase kinase and by MAP kinase kinases 4 or 7 (Fig. 1) [4].
Activated JNK can phosphorylate a broad subset of downstream targets including
both transcription factors and nonnuclear substrates [3].
Phosphorylation of c-Jun, which takes part in the formation of the activation
protein (AP)-1, increases the transcriptional activity of this complex. An analogous
effect derives from the phosphorylation of the activating transcription factor
(ATF)-2, which modifies gene expression through the formation of dimers with
members of the Jun family [5]. Besides these two well-characterized pathways,
JNKs can also act on additional nuclear targets, thereby modulating their
effects on gene transcription (Fig. 1). Furthermore, the members of the JNK family
phosphorylate cytosolic and mitochondrial substrates resulting in a modification
of their functionality or in the regulation of their stability [3].
Due to diverse downstream targets, the JNKs are involved in various
physiological functions. These kinases are implicated in the regulation of cell
survival/apoptosis in response to external stimuli. The role of JNKs in cell death
has been described as bivalent, since it depends on the entity of the stimulus and
on the signal integration with additional pathways.
204
P. Koch
AP
Activation protein
ATF
Activating transcription factor
CYP450 Cytochrome P450
EGFR
Epidermal growth factor receptor kinase
JNK
c-Jun N-terminal kinase
MAP
Mitogen-activated protein
SAPK
Stress-activated protein kinases
SAR
Structure-activity relationships
1 Introduction
The c-Jun N-terminal kinases (JNKs) are serine/threonine kinases belonging to the
family of mitogen-activated protein (MAP) kinases. First members of this enzyme
class were discovered in the early 1990s and originally termed as stress-activated
protein kinases (SAPKs). Three different isoforms with molecular weights ranging
from 46 to 55 kDa have been classified within this group, namely, JNK1 (also known
as SAPK-γ/MAPK8), JNK2 (SAPK-α/MAPK9), and JNK3 (SAPK-β/MAPK10),
which are encoded by the three distinct genes jnk1, jnk2, and jnk3, respectively
[1, 2].
The JNKs are activated by different forms of cellular stress via the classical MAP
kinase signaling cascade by tandem phosphorylation by two upstream kinases, in
detail by a MAP kinase kinase kinase and by MAP kinase kinases 4 or 7 (Fig. 1) [4].
Activated JNK can phosphorylate a broad subset of downstream targets including
both transcription factors and nonnuclear substrates [3].
Phosphorylation of c-Jun, which takes part in the formation of the activation
protein (AP)-1, increases the transcriptional activity of this complex. An analogous
effect derives from the phosphorylation of the activating transcription factor
(ATF)-2, which modifies gene expression through the formation of dimers with
members of the Jun family [5]. Besides these two well-characterized pathways,
JNKs can also act on additional nuclear targets, thereby modulating their
effects on gene transcription (Fig. 1). Furthermore, the members of the JNK family
phosphorylate cytosolic and mitochondrial substrates resulting in a modification
of their functionality or in the regulation of their stability [3].
Due to diverse downstream targets, the JNKs are involved in various
physiological functions. These kinases are implicated in the regulation of cell
survival/apoptosis in response to external stimuli. The role of JNKs in cell death
has been described as bivalent, since it depends on the entity of the stimulus and
on the signal integration with additional pathways.
204
P. Koch