Focal Adhesion Kinase: Insight into Molecular Roles and Functions in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Due to the high incidence of post-operative recurrence after current treatments, the identification of new and more effective drugs is required. In previous years, new targetable genes/pathways involved in HCC pathogenesis have been discovered through the help of high-throughput sequencing technologies. Mutations in TP53 and β-catenin genes are the most frequent aberrations in HCC. However, approaches able to reverse the effect of these mutations might be unpredictable. In fact, if the reactivation of proteins, such as p53 in tumours, holds great promise as anticancer therapy, there are studies arguing that chronic activation of these types of molecules may be deleterious. Thus, recently the efforts on potential targets have focused on actionable mutations, such as those occurring in the gene encoding for focal adhesion kinase (FAK). This tyrosine kinase, localized to cellular focal contacts, is over-expressed in a variety of human tumours, including HCC. Moreover, several lines of evidence demonstrated that FAK depletion or inhibition impair in vitro and in vivo HCC growth and metastasis. Here, we provide an overview of FAK expression and activity in the context of tumour biology, discussing the current evidence of its connection with HCC development and progression.

Keywords: cancer stem cells; focal adhesion kinase; hepatocellular carcinoma; metastasis; proliferation.

Figure 1

FAK protein structure and activation. (A) Schematic representation of the FAK protein structure. The N-terminal domain comprises a FERM domain, a nuclear export sequence 1 (NES1), a nuclear localization sequence (NLS) a proline-rich region (PRR1) and a 397-tyrosine auto-phosphorylation site (Y397). The central kinase domain contains Y576/Y577 phosphorylation sites, crucial for the kinase activity of FAK. The C-terminal domain includes a focal adhesion targeting (FAT) sequence and two proline regions (PRR2 and PRR3), which are important for binding with several molecular regulators and effectors. In C-terminal domain Y861 and Y925 phosphorylation sites are also included; (B) model of FAK activation. FERM domain binds to the central kinase domain maintaining FAK into an inactive form. Auto-phosphorylation at Y397 site removes FAK inhibition. Src kinase binds FAK at phosphorylation Y397 site generating a FAK-Src signalling complex, which contributes, after phosphorylation of Y576 and Y577 residues, to full activation of FAK activity.

Figure 2

A model of regulation of CSCs based on p53/Nanog/FAK cross-linked-signalling. FAK may translocate into the nucleus where interacts with p53 and Mdm-2. This interaction causes p53 ubiquitination and consequent degradation via proteasome; and reduces p53 binding and repressive activity on Nanog and FAK promoters. In this way, Nanog and FAK over-expression, as well as their function and physical interaction, are self-perpetuated promoting CSC survival and self-renewal.