Role of MAPKs in development and differentiation: lessons from knockout mice

Abstract

The ERK, p38MAPK, JNK mitogen-activated protein kinases (MAPKs) are intracellular signaling pathways that play a pivotal role in many essential cellular processes such as proliferation and differentiation. These cascades are activated by a large variety of stimuli and display a high degree of homology. So far, seven MAPK isoforms have been invalidated in mice leading to the discovery of their important functions in development and differentiation. As we could expect because of their multiple and specific properties in vitro, knockout (KO) of MAPK pathways leads to distinct phenotypes in mice. Surprisingly, into a given cascade, KOs of the various isoforms assign specific non-redundant biological functions to each isoform, without compensation by the others. These results emphasize the notion that, although initiated by the same external stimuli, these intracellular cascades activate kinase isoforms each with its own specific role.

Introduction

Cells encounter an enormous variety of signals in their environment and must respond to each stimulus appropriately with changes in their genetic programs. Many of these external signals are transduced by a highly conserved eukaryotic signaling mechanism, the mitogen-activated protein kinase (MAPK) cascades. MAPKs participate in signal transduction pathways that control intracellular events including acute responses to hormones and major developmental changes in organisms.

In mammals, at least four distinct groups of MAPKs have been recognized: extracellular signal-regulated kinases (ERKs) 1 and 2 (ERK 1/2 or p44/p42), c-Jun amino-terminal kinases or stress-activated protein kinases (JNK/SAPK) 1–3, p38MAPK α, β, γ and δ, and ERK5 (for review see [1], [2]). Most of our present knowledge comes from the study of three groups of MAPKs: ERK1/2; JNK1/2 and p38MAPK. These serine/threonine kinases are regulated by phosphorylation cascades organized in specific modules. All modules comprise two additional protein kinases activated in series and leading to activation of a specific MAP kinase: a MAP kinase kinase (MAPKK or MAP2K), represented by MEK or MKK proteins, which phosphorylates a specific MAPK, and a MAP kinase kinase kinase (MAPKKK or MAP3K), represented by Raf and MEKK proteins, which phosphorylates a specific MAPKK (Fig. 1).

Numerous in vitro studies, using specific chemical inhibitors, have shed light on physiological roles of MAPKs and their signaling pathways. However, inhibitors are rarely specific for one isoform but rather exert their activity on the upstream kinases. The gene-targeting technology has contributed to our knowledge of MAPK signaling cascades in vivo. In particular, analysis of knockouts (KOs) of MAPKs, activators of MAPKs, and substrates of MAPKs have revealed surprising and intriguing results regarding cell and development-specific functions of MAPK signaling cascades. Interestingly, it points out important differences between highly homolog isoforms. In this review, we focus on the role of ERK1/2, JNK1/2, p38MAPK and ERK5 in development and metabolism based on MAPK KO mice phenotypes.

MAPK pathways are activated by a variety of stimuli, but it is generally assumed that ERK1/2 are activated by mitogens such as growth factors, serum, and phorbol esters, while JNK and p38 MAPK respond to stress such as osmotic stress, UV and cytokines (for review see [3]). Although each MAPK presents unique characteristics, a number of features are shared by the MAPK pathways studied to date.

The specificity of activation and function of MAPK signaling modules is determined, in part, by scaffold proteins that create multi-enzyme complexes. These scaffold proteins appear to facilitate MAPK activation, in response to specific physiological stimuli, and to protect the bound MAPK module against activation by irrelevant stimuli. This pivotal regulation is mainly carried out by scaffolding inhibitor and adaptor proteins that enhance, decrease or redirect the signal flux (for review see [4], [5]).

Once activated MAPKs phosphorylate a large panel of substrates on serine and threonine most often followed by proline residues. One subset of MAPKs targets is composed of protein kinases called MAPK-activated protein kinases (MKs). MKs play a crucial role in a variety of biological functions in response to mitogens or stress. In addition to enhancing gene expression via intermediary kinases that increase the accessibility of DNA, MAPKs also directly phosphorylate a second subset of proteins, transcription factors and regulate their activities.