J Liver Cancer.  2021 Mar;21(1):1-11. 10.17998/jlc.21.1.1.

Ras Mitogen-activated Protein Kinase Signaling and Kinase Suppressor of Ras as Therapeutic Targets for Hepatocellular Carcinoma

• Moon H
• Ro SW

• KMID: 2514230
• DOI: http://doi.org/10.17998/jlc.21.1.1

Abstract

Hepatocellular carcinoma (HCC) is a high incidence cancer and a major health concern worldwide. Among the many molecular signaling pathways that are dysregulated in HCC, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK) signaling pathway has gained renewed attention from basic and clinical researchers. Mutations in Ras and Raf genes which are known to activate the Ras/Raf/MAPK signaling pathway have been infrequently detected in human HCC; however, the Ras/Raf/MAPK signaling pathway is activated in more than 50% of HCC cases, suggesting an alternative mechanism for the activation of the signaling pathway. Kinase suppressor of Ras acts as a molecular scaffold for facilitating the assembly of Ras/Raf/MAPK signaling pathway components and has been implicated in the regulation of this signaling pathway. In this review, we provide important insights into the cellular and molecular mechanisms involved in the activation of the Ras/Raf/MAPK signaling pathway and discuss potential therapeutic strategies for HCC.

Keyword

Hepatocellular carcinoma; Ras mitogen-activated protein kinase signaling; Kinase suppressor of Ras; Carcinogenesis

Figure

• 

  Figure 1 Function of the scaffold protein kinase suppressor of Ras (KSR). KSR contributes to activation of the Ras mitogen-activated protein kinase (Ras/Raf/MAPK) signaling pathway leading to a pivotal oncogenic response. RTK, receptor tyrosine kinase; GPCR, G-protein-coupled receptor; GTP, guanosine triphosphate; MEK, mitogen/extracellular protein kinase; PP2A, protein phosphatase-2A; C-TAK1, Cdc25C-associated kinase 1; MAPK, mitogen-activated protein kinase.

• 

  Figure 2 Structural similarity in rapidly accelerated fibrosarcoma (RAF) and kinase suppressor of Ras (KSR) protein. RAF and KSR protein include the cysteine-rich sequences (CR1 and CA3), the serine/threonine rich sequences (CR2 and CA4) and the kinase domain (CR3 and CA5). Importantly, the mitogen-activated protein kinase (MAPK) binds to CA4, and mitogen/extracellular protein kinase (MEK) bind to the C-terminal region containing the CA5 domain. RBD, RAS-binding domain; CC-SAM, coiled-coil and sterile-α-motif.

• 

  Figure 3 Schematic representation of inducers that activate the Ras mitogen-activated protein kinase (Ras/Raf/MAPK) signaling pathway in hepatocellular carcinoma (HCC). HBx of hepatitis B virus (HBV) directly activates Ras via Src, and the hepatitis C virus (HCV) NS3/4A complex stimulates protein kinase C (PKC) to promote production of MAPK. Activation of receptor tyrosine kinases (RTKs) by dysregulated upstream signals stimulates the exchange of guanosine triphosphate for guanosine diphosphate in Ras, and this activated Ras interacts directly with the target effectors. Inactivation of Raf kinase inhibitor protein, which inhibits G-protein-coupled receptors kinases by PKC and interferes with regulation of the Ras/Raf/MAPK signaling pathway by interaction with the Raf-1 kinase, leads to activation of MAPK. Scaffold proteins that contribute to the spatiotemporal activation of the Ras/Raf/MAPK signaling are KSR, MEK-partner 1, Sef and Paxillin.

• 

  Figure 4 Mechanism of action of molecular targeted drugs. The drugs are kinase inhibitors with activity against kinases and their receptors associated with Ras mitogen-activated protein kinase (Ras/Raf/MAPK) signaling. Type I kinase inhibitors are erlotinib, sunitinib, cabozantinib and lenvatinib, and type II kinase inhibitors are sorafenib and regorafenib. VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; SCFR, stem cell growth factor receptor; FGFR, fibroblast growth factor receptor; HGFR, hepatocyte growth factor receptor; EGFR, endothelial growth factor receptor. MEK, mitogen/extracellular protein kinase.

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