Ephrin-Eph receptor tyrosine kinases for potential therapeutics against hepatic pathologies

Abstract

Hepatic fibrosis is the common pathological change that occurs due to increased synthesis and accumulation of extracellular matrix components. Chronic insult from hepatotoxicants leads to liver cirrhosis, which if not reversed timely using appropriate therapeutics, liver transplantation remains the only effective therapy. Often the disease further progresses into hepatic carcinoma. Although there is an increased advancement in understanding the pathological phenotypes of the disease, additional knowledge of the novel molecular signaling mechanisms involved in the disease progression would enable the development of efficacious therapeutics. Ephrin-Eph molecules belong to the largest family of receptor tyrosine kinases (RTKs) which are identified to play a crucial role in cellular migratory functions, during morphological and developmental stages. Additionally, they contribute to the growth of a multicellular organism as well as in pathological conditions like cancer, and diabetes. A wide spectrum of mechanistic studies has been performed on ephrin-Eph RTKs in various hepatic tissues under both normal and diseased conditions revealing their diverse roles in hepatic pathology. This systematic review summarizes the liver-specific ephrin-Eph RTK signaling mechanisms and recognizes them as druggable targets for mitigating hepatic pathology.

Keywords: Cholangiocarcinoma; Eph RTKs; Ephrins; Hepatic fibrosis; Hepatocellular carcinoma; NAFLD.

Fig. 1

Schematic representation of the structural domains of Ephrin A and B ligands and Eph receptor Formation of the heterocomplex facilitates bi-directional signaling in which numerous signaling pathways play a role in cell function and disease pathology and can be activated through both ephrins—“reverse” and Eph—“forward” signaling. SAM domain plays a regulatory role for target-specific binding and the Src family plays a role in reverse signaling of the Eph and ephrins. These signaling events include activation of PI₃K, Src family kinases, JAK-STAT, and RAF GTPases that are downstream of Ephrins and the Eph receptor. (Abbreviation: SAM, Sterile Alpha Motif; PDZ, Postsynaptic 95 Density Zona occludens; GPI, Glycosyl Phosphatidyl Inositol. P; representative of tyrosine phosphorylation sites—JAK, Janus kinase; STAT, signal transducer and activator of transcription)