p38 MAPK signalling cascades:
ancient roles and new functions
Enrique Martõ
Â
n-Blanco
Summary
p38 MAPKs are a conserved subfamily of MAPKs
involved in the response to stress found in eukaryotic
cells from yeast to mammals. The recent isolation of
genes coding for members of this signalling cascade in
Drosophila has provided us with the genetic tools to
study their various biological roles and their regulatory
interactions with other signalling pathways. This cas-
cade participates in the immune response, a function
that is remarkably conserved between flies and humans.
Additionally, it appears to exert other fundamental roles
during development, in cell fate specification in imaginal
discs, and in cell polarity during oogenesis. These
functions involve genetic and biochemical interactions
with other signalling cascades, the decapentaplegic/
TGFb, the wingless/Wnt and the torpedo/Ras-ERK path-
ways. In the near future, we can expect a flurry of
information that will allow us to draw a comprehensive
picture of the roles of signalling networks mediated by
p38s during development. BioEssays 22:637±645,
2000. ß 2000 John Wiley & Sons, Inc.
``The role of Science is not just to define a repertoire of
facts, but to determine their extension, their dependence,
their harmony and their roles.'' Claude Bernard, 1876.
(1)
Introduction
Cells in a multicellular organism need to communicate with
each other in order to control their growth, to regulate their
development, and to coordinate their functions. The extra-
cellular signals involved in these processes generate
different types of responses, which depend on specific
intracellular mechanisms, rapid and transient, or slow and
long lasting.
Among the signalling cascades involved in the response
of cells to growth factors, cytokines, or environmental stress,
are those which activate the so-called MAPK family of
kinases. Mitogen-activated protein kinases (MAPKs) were
first identified as insulin-induced protein kinases, and it was
subsequently demonstrated that these proteins were regu-
lated by tyrosine and threonine phosphorylation mediated by
MEKs (MAPK upstream activating kinases). MEKs are
themselves phosphorylated and activated by specific MEK
kinases. These sequences of phosphorylation allow the
amplification of external signals with each phosphorylating
activating step. MAPKs have been shown to play crucial
roles in the development of specific organs and cells in many
species, from Drosophila to mammals.
(2)
Two distinct classes
of MAPKs have been identified so far: p42-p44 (ERK)
MAPKs inducible by growth factors; and SAPKs (Stress-
Activated Protein Kinases), which include p38 MAPKs, and
p46-p54 JNKs inducible by cytokines and cellular stress.
Each MAPK class responds to distinct stimuli and induces
specific biological responses. This specificity is maintained
throughout each cascade and results from selective enzyme-
substrate interactions within each module, i.e. the unique
activity of MAPK kinases (MEKs) which activate the MAPKs
by dual phosphorylation on a TXY motif (see Table 1 for a
compendium of MAPK and MAPK kinases and their
homologues in different species). The activated MAPKs
may then regulate the activity of transcription factor such as
ATF2, Elk-1 and c-Jun, to control gene expression.
(3)
The focus of this review is to analyze the physiological
and developmental roles of this subfamily of MAPKs in light
to the recent identification of p38 homologues in Drosophila.
The p38 MAPKs
p38 was first identified in 1994 as a MAP kinase targeted by
endotoxin and hyperosmolarity in mammalian cells.
(4)
Shortly
thereafter, the cloning of a target for an anti-inflammatory
drug (SB203580) which was identical to p38 was reported
and it was termed CSBP.
(5)
This kinase was found to have
high sequence similarity to the Saccharomyces cerevisiae
HOG1 kinase
(6)
that is involved in host protection from
hyperosmotic stress. Subsequently, various forms of cellular
stress were found to activate the mammalian p38s.
(7)
Further
experiments suggested that p38s participate not only in
inflammatory responses but also in stress-induced signalling,
in cell proliferation and in apoptosis. p38 is 48% identical in
amino acid sequence to ERK2, and 20±25% identical to a
number of other protein kinases. Two domains separated
by a deep channel where potential substrates might bind
characterize protein kinases. The N-terminal domain creates
a binding pocket for the adenine ring of ATP, and the
C-terminal domain contains the presumed catalytic base,
BioEssays 22:637±645, ß 2000 John Wiley & Sons, Inc. BioEssays 22.7 637
Centro de Biologõ
Â
a Molecular Severo Ochoa, CSIC, Facultad de
Ciencias, Universidad Auto
Â
noma de Madrid, Cantoblanco, 28049
Madrid Spain. E-mail: emblanco@cbm.uam.es
Funding agencies: Direccio
Â
n General de Investigacio
Â
n Cientõ
Â
fica y
Te
Â
cnica. Fundacio
Â
n Ramo
Â
n Areces.
Review articles