Focal adhesion kinase-regulated signaling events in human cancer

Abstract

Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that is highly expressed or activated in many human cancers. Under specific scenarios, FAK can regulate cell proliferation, cell survival, cell migration and invasion, and has been implicated in the control of tumorigenesis and metastasis. FAK has both catalytic and scaffolding activity, and triggers downstream signals by activation of a number of pathways, including the Ras/mitogen-activated protein kinase pathway, the phosphatidylinositol 3'-kinase/Akt pathway, and Rho family GTPases. Recent evidence also suggests novel signaling interactions between FAK and p53. These signaling events were defined primarily from studies on cells in culture, and elucidating which of these signaling pathways are pathologically relevant downstream of FAK in human cancer remains an important goal in determining the molecular mechanisms of tumorigenesis and metastasis. This review discusses select evidence of these signaling pathways with an emphasis on studies linking these to animal models of cancer and human disease. The role of FAK in the process of epithelial-to-mesenchymal transition and in cancer stem cells and recent therapeutic advances targeting FAK are also discussed.

How to awaken your nanomachines: Site-specific activation of focal adhesion kinases through ligand interactions

“…However, FAK is overexpressed in most cancers, and it endows cancer cells with functions that normal adult tissue cells do not have, such as the capacity to survive following detachment from the supporting structure. In so doing, FAK becomes a key player in cancer cell metastasis and tissue invasion (Fu et al, 2012;Sulzmaier et al, 2014;Zhang and Hochwald, 2014).…”

“…for a detailed description. inhibits p53 following cell detachment (Fu et al, 2012;Golubovskaya et al, 2008a;Lim et al, 2008). If focal adhesion contacts are lost, FAK translocates into the nucleus, where it sequesters and inactivates p53 and other pro-apoptotic effectors in a kinase-independent manner, thereby promoting cell survival.…”

“…It was shown that this association enhances FAK's nuclear localisation and allows it to regulate heterochromatin remodelling and myogenin expression during muscle differentiation (Luo et al, 2009). Thus, the controlled nuclear localisation allows FAK to logically link membrane-proximal stimuli with gene expression and hence to establish a link between adhesion, motility, survival and epigenetic changes (Cance and Golubovskaya, 2008;Fu et al, 2012).…”

Association of the upregulated expression of focal adhesion kinase with poor prognosis and tumor dissemination in hypopharyngeal cancer

“…1 In East Asia, a germline polymorphism of aldehyde dehydrogenase-2, a key enzyme for the elimination of acetaldehyde, is associated with upper aerodigestive tract malignancies, including head and neck SCC (HNSCC). 5,6 FAK functions drive several signaling pathways, which affect tumor phenotypes, includ-ing control of cell survival, motility, invasion, and epithelial-to-mesenchymal transition. 4 Focal adhesion kinase (FAK), encoded by the protein tyrosine kinase 2 gene, is a 125 kDa nonreceptor protein tyrosine kinase located in cellular structures, which are called focal adhesions.…”

Focal Adhesion Kinase-Dependent Role of the Soluble Form of Neurotensin Receptor-3/Sortilin in Colorectal Cancer Cell Dissociation

“…This was demonstrated by the use of the FAK inhibitor II that totally inhibited the effect of sSortilin/NTSR3 on Akt phosphorylation [30]. These findings are crucial since the activation of the FAK pathway is described to be involved in survival mechanisms, and especially in a variety of distinct cancer cell lines’ development and metastasis [41,42]. Indeed, FAK regulates numerous downstream intracellular pathways that mediate either cell migration through actin modification [43] or cell proliferation through transcription factors [44].…”