FAK Family Kinases: A Potential Therapeutic Target for Atherosclerosis

Abstract

Atherosclerosis (AS) is a chronic progressive inflammatory disease of the vascular wall and the primary pathological basis of cardiovascular and cerebrovascular disease. Focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2), two highly homologous members of the FAK family kinases, play critical roles in integrin signaling. They also serve as scaffolding proteins that contribute to the assembly of cellular signaling complexes that regulate cell survival, cell cycle progression, and cell motility. Research indicates that the FAK family kinases is involved in the gene regulation of vascular cells and that aberrant expression of this family is associated with pathological changes in vascular disease. These findings establish the FAK family kinases as a critical signaling mediator in atherosclerotic lesions and inhibition of its activity has the potential to attenuate the pathological progression of AS. This review highlights the indispensable role of the FAK family kinases in abnormal vascular smooth muscle cell proliferation, endothelial cell dysfunction, inflammation, and lipid metabolism associated with AS. We also summarize therapeutic targets against the FAK family kinases, providing valuable insights into therapeutic strategies for AS.

Keywords: FAK family kinases; atherosclerosis; cellular signaling; inhibitors.

Figure 1

The structure of the FAK Kinase Family. TFAK and Pyk2 consist of three structural domains: the central kinase structural domain, the N-terminal FERM structural domain, and a C-terminal structural domain containing an adhesion targeting sequence. The central kinase structural domain is flanked by three proline-rich regions. The nuclear localization sequence (NLS) of the FERM structural domain and the nuclear export sequence (NES) of the kinase structural domain facilitate the shuttling of FAK and Pyk2 between the nucleus and the cytoplasm. Key sites for tyrosine phosphorylation (P) are marked in yellow.

Figure 2

Potential role of FAK family kinases in atherosclerosis. FAK family kinases are involved in the pathogenesis of atherosclerosis by regulating VSMC phenotypic switching, EC dysfunction, foam cell formation, and inflammatory response mechanisms.