New Insights on the Nuclear Functions and Targeting of FAK in Cancer

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed and activated in both adult and pediatric cancers, where it plays important roles in the regulation of pathogenesis and progression of the malignant phenotype. FAK exerts its functions in cancer by two different ways: a kinase activity in the cytoplasm, mainly dependent on the integrin signaling, and a scaffolding activity into the nucleus by networking with different gene expression regulators. For this reason, FAK has to be considered a target with high therapeutic values. Indeed, evidence suggests that FAK targeting could be effective, either alone or in combination, with other already available treatments. Here, we propose an overview of the novel insights about FAK's structure and nuclear functions, with a special focus on the recent findings concerning the roles of this protein in cancer. Additionally, we provide a recent update on FAK inhibitors that are currently in clinical trials for patients with cancer, and discuss the challenge and future directions of drug-based anti-FAK targeted therapies.

Keywords: ATP-competitive inhibitors; FAK; PROTACs; adult cancers; allosteric inhibitors; combination therapy; pediatric cancers; targeted therapy.

Figure 1

Schematic representation of the molecular structure of FAK and some of its interactors. FAK structure consists of three main domains: the N-terminal FERM, the central kinase and the C-terminal FAT domain. The FERM domain includes three lobes, i.e., F1, F2 and F3, which are bound from transcription factors (among which are GATA4 and p53) and E3 ubiquitin ligases (among which are CHIP and MDM2). While it is known that p53 and MDM2, respectively, bind the F1 and F3 lobes of the FERM of FAK, for GATA4 and CHIP it is, only known that they bind the FERM domain, but unknown is to which of its three lobes. In the FERM domain a nuclear export signal (NES) in the lobe F1 and a nuclear localization signal (NLS) in the lobe F2, responsible for the nuclear export and localization of the protein, are reported. A NES is also found in the kinase domain. FAK structure further comprises three proline-rich (PR) regions that serve as binding sites for the Src homology (SH) 3 domains of several proteins. The main phosphorylation sites are shown with brown circles. In particular, the Tyr397 activation site, the Tyr576 and Tyr577 in the activation loop and the Tyr925 binding site for the SH2 domains are reported. The arrows indicate the FAK domain to which some of its interactors bind, while the grey rectangle shows the FAK interactors with still unknown binding sites.

Figure 2

FAK functions in the nucleus. Graphical representation of the nuclear functions of FAK and its interactors. (A) FAK acts as a scaffold to stabilize complexes between p53 or GATA4 and the ubiquitin E3 ligases Mdm2 or CHIP, respectively. This leads to p53 and GATA4 polyubiquitination and subsequent degradation by the proteasome; (B) FAK acts as a regulator of gene expression by controlling chromatin accessibility, acting on a variety of epigenetic modulators (MBD2, Ezh2, NuRD complex); transcriptionally regulating the expression of transcription factors, such as IL33 and ST2; or forming molecular complexes with transcription factors such as TAF9 and Runx1. By regulating gene expression, nuclear FAK can be involved in apoptosis, inflammation, cell cycle, angiogenesis and cytokine expression. Figure realized with BioRender software (https://biorender.com/, accessed on 27 December 2021).