Endothelial FAK as a therapeutic target in disease.
Focal adhesions (FA) are important mediators of endothelial cytoskeletal interactions with the extracellular matrix (ECM) via transmembrane receptors, integrins and integrin-associated intracellular proteins. This communication is essential for a variety of cell processes including EC barrier regulation and is mediated by the non-receptor protein tyrosine kinase, focal adhesion kinase (FAK). As FA mediate the basic response of EC to a variety of stimuli and FAK is essential to these responses, the idea of targeting EC FAK as a therapeutic strategy for an assortment of diseases is highly promising. In particular, inhibition of FAK could prove beneficial in a variety of cancers via effects on EC proliferation and angiogenesis, in acute lung injury (ALI) via the attenuation of lung vascular permeability, and in rheumatoid arthritis via reductions in synovial angiogenesis. In addition, there are potential therapeutic benefits of FAK inhibition in cardiovascular disease and diabetic nephropathy as well. Several drugs that target EC FAK are now in existence and include agents currently under investigation in preclinical models as well as drugs that are readily available such as the sphingolipid analog FTY720 and statins. As the role of EC FAK in the pathogenesis of a variety of diseases continues to be explored and new insights are revealed, drug targeting of FAK will continue to be an important area of investigation and may ultimately lead to highly novel and effective strategies to treat these diseases.
Institute for Personalized Respiratory Medicine, Section of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Giovanni A
GA
Infusino
Jeffrey R
JR
Jacobson
D055371:Acute Lung Injury / Q000188:drug therapy / Q000201:enzymology; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000201:enzymology; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000201:enzymology; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000201:enzymology; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019141:Respiratory System Agents / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D018501:Antirheumatic Agents; D002317:Cardiovascular Agents; D047428:Protein Kinase Inhibitors; D019141:Respiratory System Agents; D051416:Focal Adhesion Protein-Tyrosine Kinases