Role of the Extracellular Signal-Regulated Kinase 1/2 Signaling Pathway in Ischemia-Reperfusion Injury

Abstract

Extracellular signal-regulated kinase 1/2 (ERK_1/2), an important member of the mitogen-activated protein kinase family, is found in many organisms, and it participates in intracellular signal transduction. Various stimuli induce phosphorylation of ERK_1/2 in vivo and in vitro. Phosphorylated ERK_1/2 moves to the nucleus, activates many transcription factors, regulates gene expression, and controls various physiological processes, finally inducing repair processes or cell death. With the aging of the population around the world, the occurrence of ischemia-reperfusion injury (IRI), especially in the brain, heart, kidney, and other important organs, is becoming increasingly serious. Abnormal activation of the ERK_1/2 signaling pathway is closely related to the development and the metabolic mechanisms of IRI. However, the effects of this signaling pathway and the underlying mechanism differ between various models of IRI. This review summarizes the ERK_1/2 signaling pathway and the molecular mechanism underlying its role in models of IRI in the brain, heart, liver, kidneys, and other organs. This information will help to deepen the understanding of ERK_1/2 signals and deepen the exploration of IRI treatment based on the ERK_1/2 study.

Keywords: ERK1/2 signaling pathway; damage effect; ischemia-reperfusion injury; molecular mechanism; protective effect; therapeutic target.

Figure 1

Summary of the classical Ras-Raf-MEK-ERK_1/2 signaling pathway. Extracellular signals stimulate G-protein-coupled receptors (GCPRs), receptor tyrosine kinases (RTKs), and integrins on the membrane, and activate ERK_1/2, a key signaling molecule, via a series of cascade reactions. ERK_1/2 is usually located in the cytoplasm. Once activated, ERK_1/2 rapidly crosses the nuclear membrane, reactivates transcription factors, regulates transcription of target genes, induces expression or activation of specific proteins, and finally regulates cellular metabolism and function.

Figure 2

Summary of the functions of the ERK_1/2 signaling pathway. Cytokines regulate cellular processes via the ERK_1/2 signaling pathway. Extracellular stimulation leads to phosphorylation of ERK_1/2, which affects various cellular activities by mediating activation of transcription factors.

Figure 3

Summary of the role of the ERK_1/2 signaling pathway in CIRI. (A) Neuroprotection against CIRI via activation of the ERK_1/2 signaling pathway. A few studies reported that activation of the ERK_1/2 signaling pathway elicits neuroprotective effects against CIRI. (B) Neuroprotection against CIRI via blockade of the ERK_1/2 signaling pathway. Most studies reported that inhibition of the ERK_1/2 signaling pathway blocks downstream damage, including inflammation and apoptosis, and thereby protects against CIRI.