In vivo functions of mitogen-activated protein kinases: conclusions from knock-in and knock-out mice

Abstract

Multicellular organisms achieve intercellular communication by means of signalling molecules whose effect on the target cell is mediated by signal transduction pathways. Such pathways relay, amplify and integrate signals to elicit appropriate biological responses. Protein kinases form crucial intermediate components of numerous signalling pathways. One group of protein kinases, the mitogen-activated protein kinases (MAP kinases) are kinases involved in signalling pathways that respond primarily to mitogens and stress stimuli. In vitro studies revealed that the MAP kinases are implicated in several cellular processes, including cell division, differentiation, cell survival/apoptosis, gene expression, motility and metabolism. As such, dysfunction of specific MAP kinases is associated with diseases such as cancer and immunological disorders. However, the genuine in vivo functions of many MAP kinases remain elusive. Genetically modified mouse models deficient in a specific MAP kinase or expressing a constitutive active or a dominant negative variant of a particular MAP kinase offer valuable tools for elucidating the biological role of these protein kinases. In this review, we focus on the current status of MAP kinase knock-in and knock-out mouse models and their phenotypes. Moreover, examples of the application of MAP kinase transgenic mice for validating therapeutic properties of specific MAP kinase inhibitors, and for investigating the role of MAP kinase in pathogen-host interactions will be discussed.

Effect of pressure overload-induced hypertrophy on the expression and localization of p38 MAP kinase isoforms in the mouse heart

“…Interactions with TAB1 or ZAP-70 [6,7] induce autophosphorylation of p38 within the activation loop whereas interactions with Hsp90-Cdc37 supressed this autophosphorylation [8]. Although the exact role of each p38 isoform remains to be determined, each p38 isoform has been independently knocked out in mice: p38α-deficient mice show embryonic lethality due to placental defects, whereas p38β-, p38γ-, and p38δ-null mice appear to have normal phenotypes [9]. Transgenic mice expressing dominant negative forms of p38α and p38β are resistance to cardiac fibrosis during pressure overload [10].…”

The role of stress-activated protein kinase signaling in renal pathophysiology

“…Genetic deletion of p38α induces embryonic death of mice due to placental defects. In contrast, mice with p38β, γ, or δ knockout show a normal phenotype (5). Most of our understanding of p38 kinase function comes from the use of pharmacological inhibitors of the p38α and p38β isoforms.…”

GADD45β Enhances Col10a1 Transcription via the MTK1/MKK3/6/p38 Axis and Activation of C/EBPβ-TAD4 in Terminally Differentiating Chondrocytes

“…The MAPK signaling pathways are involved in many cellular processes, such as gene regulation, intracellular metabolism, differentiation, proliferation, mobility, and survival or death (18,19). MAPKs are activated by MAPK kinases (MAP2K) via phosphorylation of conserved threonine and tyrosine residues in their activation loops, followed by phosphorylation of downstream kinases and targets, including transcription factors that regulate a variety of target genes (20).…”