Signal transduction pathways in liver and the influence of hepatitis C virus infection on their activities

Abstract

In liver, the most intensively studied transmembrane and intracellular signal transduction pathways are the Janus kinase signal transduction pathway, the mitogen-activated protein kinases signal transduction pathway, the transforming growth factor beta signal transduction pathway, the tumor necrosis factor alpha signal transduction pathway and the recently discovered sphingolipid signal transduction pathway. All of them are activated by many different cytokines and growth factors. They regulate specific cell mechanisms such as hepatocytes proliferation, growth, differentiation, adhesion, apoptosis, and synthesis and degradation of the extracellular matrix. The replication cycle of hepatitis C virus (HCV) is intracellular and requires signal transduction to the nucleus to regulate transcription of its genes. Moreover, HCV itself, by its structural and non-structural proteins, could influence the activity of the second signal messengers. Thus, the inhibition of the transmembrane and intracellular signal transduction pathways could be a new therapeutic target in chronic hepatitis C treatment.

Figure 1

Signal transduction pathway. A: Janus kinase (JAK); B: Mitogen-activated protein kinase (MAPK); C: Transforming growth factor-β (TGF-β); D: Tumor necrosis factor α (TNF-α); E: Sphingolipid. +: Activation; P: Phosphorylation; STAT: Signal transducers and activators of transcription; STATs: Activated STAT; PIAS: Proteins inhibitor of activated STAT; SOCS: Suppressor of cytokine signaling; RAS: Small GTP-binding protein; PKC: Protein kinase C; PAK: P21-activated kinase; RAF: Serine/threonine kinase; MKK: Mitogen-activated protein kinase kinase; ERK: Extracellular signal-regulated protein kinase; SAPK: Stress activated protein kinase; JNK: C-Jun-NH2-terminal kinase; TGFR I and II: Membrane receptors of TGF-β; SMAD: Class of proteins that modulate the activity of transforming growth factor β ligands; TNF-R1: Membrane receptor of TNF-α; DD: Death domain; TRADD: TNFR associated protein with death domain; FADD: Fas associated death domain; TRAF 1/2: TNF-associated factor-2; RID:Receptor-interacting protein; NFκB: Transcription factor; NSD: TNF-R1 domain activating neutral sphingomyelinase; FAN: TNF-R1 adaptor protein; A-SMase: Acid sphingomyelinase; N-SMase: Neutral sphingomyelinase; SM: Sphingomyelin; CER: Ceramide; C1P: Ceramide-1-phosphate; CDases: Ceramidases; SFO: Sphingosine; S1P: Sphingosine-1-phosphate; ROS: Reactive oxygen species; CAPK: Ceramide-activated kinase.