New insights into the role and mechanism of c-Jun-N-terminal kinase signaling in the pathobiology of liver diseases

Abstract

Mitogen-activated protein kinase (MAPK) signaling in the liver occurs in response to physical and chemical stress, including alterations in nutrients, growth factors, cytokines, extracellular matrix, DNA damage, drugs and toxins. This signaling pathway plays a role in liver injury and diseases such as drug induced hepatotoxicity, viral hepatitis, infection and inflammation, NAFLD, NASH, ALD, ischemia/reperfusion, fibrosis, regeneration, and carcinogenesis (1-4). In mammals, three major groups of MAPK have been identified. Each of these groups of MAPK is activated by a protein kinase cascade. MAPK signaling cascades consist of at least three components, or tiers: MAPK kinase kinase (MAP3K), MAPK kinase (MAP2K), and MAPK. The groups are named according to their executing downstream MAPK, such as the extracellular signal-regulated kinase (ERK), the p38 kinase, and the c-Jun N-terminal kinase (JNK) families. In the liver, JNK is a dominant effector MAPK which catalyzes the phosphorylation of numerous substrate proteins including nuclear AP1 transcription factors (c-Jun, etc) as well as protein kinases and phosphatases, scaffold proteins, and other functional proteins (4, 5). JNK activation and substrate phosphorylation has two major direct consequences: regulation of gene expression through AP1 transcription factors and direct activation or inhibition of protein targets (Fig.1). The liver expresses both JNK1 and JNK2. In this review we will focus on recent studies from many different laboratories in the past 5 years which have improved our understanding of the role of JNK signaling pathway in the pathogenesis of liver diseases and promise to lead to exciting therapeutic applications. Because of the broad nature of this subject, we have selected specific areas which illustrate the important recent conceptual advances. This article is protected by copyright. All rights reserved.

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