p38 MAPK信号通路：跨物种的古老功能与新发现

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p38 MAPK信号级联，作为一类在真核细胞从酵母到哺乳动物中普遍存在的蛋白激酶家族，其功能历史深远且不断拓展。本文由Enrique Martõn-Blanco撰写，着重探讨了p38 MAPKs在应对压力反应中的核心作用以及其在不同生物学过程中的新发现角色。 p38 MAPK信号传导途径是一种保守的信号转导途径，它在多种生物体的细胞中起着关键的应激反应作用。自最近在果蝇（Drosophila）中成功克隆出该信号传导链路的相关基因后，科学家们得以利用遗传学工具来深入研究这一途径。这使得我们能够更好地理解p38 MAPK在免疫响应中的重要作用，这一功能在昆虫和人类之间具有惊人的相似性。在免疫系统中，p38 MAPK参与调节免疫细胞的活化和炎症反应。此外，p38 MAPK在发育过程中也扮演着关键角色。例如，在幼虫器官形成（如翅膀）的过程中，它与Decapentaplegic（Dpp）、Transforming Growth Factor beta（TGF-β）等其他信号通路相互作用，影响细胞命运决定和分化。在卵子发生（oogenesis）中，p38 MAPK还参与维持细胞极性，确保生殖细胞的正常发育。这些功能的实现涉及到p38 MAPK与其他信号传导途径如wingless/Wnt和torpedo/Ras-ERK的复杂遗传和生化相互作用。随着未来研究的深入，我们有理由期待更多关于p38信号网络在发育过程中如何整合和调控整体生物进程的信息。《生物本质》杂志（BioEssays）2000年的一篇文章中详细介绍了当时的最新进展，强调了这个领域的广阔前景和尚未完全揭示的潜力。 p38 MAPK信号级联不仅保留了古老的应激反应功能，还在发育、免疫和细胞命运选择等生物学过程中展现了新的功能。随着科学研究的深入，我们有望揭示这个信号通路在多细胞生物体中的全面作用，并可能为疾病的治疗和发育生物学提供新的见解。

p38 MAPK signalling cascades:

ancient roles and new functions

Enrique Martõ

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

a Molecular Severo Ochoa, CSIC, Facultad de

Ciencias, Universidad Auto

noma de Madrid, Cantoblanco, 28049

Madrid Spain. E-mail: emblanco@cbm.uam.es

Funding agencies: Direccio

n General de Investigacio

n Cientõ

fica y

cnica. Fundacio

n Ramo

n Areces.

Review articles

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