Conserved signaling
pathways that
activate the
mitogen-activated
protein kinases
(MAPKs) are involved
in relaying
extracellular
stimulations to
intracellular
responses. The MAPKs
coordinately
regulate cell
proliferation,
differentiation,
motility, and
survival, which are
functions also known
to be mediated by
members of a growing
family of
MAPK-activated
protein kinases
(MKs; formerly known
as MAPKAP kinases).
The MKs are related
serine/threonine
kinases that respond
to mitogenic and
stress stimuli
through
proline-directed
phosphorylation and
activation of the
kinase domain by
extracellular
signal-regulated
kinases 1 and 2 and
p38 MAPKs. There are
currently 11
vertebrate MKs in
five subfamilies
based on primary
sequence homology:
the ribosomal S6
kinases, the
mitogen- and
stress-activated
kinases, the
MAPK-interacting
kinases,
MAPK-activated
protein kinases 2
and 3, and MK5. In
the last 5 years,
several MK
substrates have been
identified, which
has helped
tremendously to
identify the
biological role of
the members of this
family. Together
with data from the
study of MK-knockout
mice, the identities
of the MK substrates
indicate that they
play important roles
in diverse
biological
processes, including
mRNA translation,
cell proliferation
and survival, and
the nuclear genomic
response to mitogens
and cellular
stresses. In this
article, we review
the existing data on
the MKs and discuss
their physiological
functions based on
recent discoveries.
Cells recognize
and respond to
extracellular
stimuli by engaging
specific
intracellular
programs, such as
the signaling
cascade that leads
to activation of the
mitogen-activated
protein kinases
(MAPKs). All
eukaryotic cells
possess multiple
MAPK pathways, which
coordinately
regulate diverse
cellular activities
running the gamut
from gene
expression, mitosis,
and metabolism to
motility, survival
and apoptosis, and
differentiation. To
date, five distinct
groups of MAPKs have
been characterized
in mammals:
extracellular
signal-regulated
kinases (ERKs) 1 and
2 (ERK1/2), c-Jun
amino-terminal
kinases (JNKs) 1, 2,
and 3, p38 isoforms
α, β, γ, andδ ,
ERKs 3 and 4, and
ERK5 (reviewed in
references 25 and
103). Since
Saccharomyces
cerevisiae possesses
six different MAPKs,
the relative
complexity of the
human genome
suggests that there
are probably several
additional
vertebrate MAPK
subfamilies (118).
The most extensively
studied groups of
vertebrate MAPKs to
date are the ERK1/2,
JNKs, and p38
kinases.
MAPKs
can be activated by
a wide variety of
different stimuli,
but in general, ERK1
and ERK2 are
preferentially
activated in
response to growth
factors and phorbol
esters, while the
JNK and p38 kinases
are more responsive
to stress stimuli
ranging from osmotic
shock and ionizing
radiation to
cytokine stimulation
(reviewed in
reference 147) (Fig.
1). Although each
MAPK has unique
characteristics, a
number of features
are shared by the
MAPK pathways
studied to date.
Each family of MAPKs
is composed of a set
of three
evolutionarily
conserved,
sequentially acting
kinases: a MAPK, a
MAPK kinase (MAPKK),
and a MAPKK kinase
(MAPKKK). The
MAPKKKs, which are
serine/threonine
kinases, are often
activated through
phosphorylation
and/or as a result
of their interaction
with a small
GTP-binding protein
of the Ras/Rho
family in response
to extracellular
stimuli (36, 98).
MAPKKK activation
leads to the
phosphorylation and
activation of a
MAPKK, which then
stimulates MAPK
activity through
dual phosphorylation
on threonine and
tyrosine residues
located in the
activation loop of
kinase subdomain
VIII. Once
activated, MAPKs
phosphorylate target
substrates on serine
or threonine
residues followed by
a proline; however,
substrate
selectivity is often
conferred by
specific interaction
motifs located on
physiological
substrates.
Furthermore, MAPK
cascade specificity
is also mediated
through interaction
with scaffolding
proteins which
organize pathways in
specific modules
through simultaneous
binding of several
components.