Disruption of FAK signaling: a side mechanism in cytotoxicity.
Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase (PTK) which acts as an early modulator in the integrin signaling cascade. FAK phosphorylation and its consequent activation regulate several basic biological cellular functions. On the contrary, dysregulation of FAK signaling is implicated in the malignant transformation of cells, as well as in nonmalignant pathological conditions. With respect to cytotoxicity, accumulating data indicate that FAK participates in the mechanism of action of the known cytotoxic reactive oxygen species (ROS). Additionally, evidence was presented that different cytotoxic substances, such as arsenic (As), lead (Pb), acrylamide, methylisothiazolinone (MIT), dichlorovinylcysteine (DCVC) and halothane, acted, at least in part, by downregulating FAK tyrosine phosphorylation, while the bacterial toxins Pasteurella multocida toxin and Escherichia coli cytotoxic necrotizing factor, have been shown to exert cytotoxic effects by inducing FAK tyrosine phosphorylation. The observation that upregulation as well as downregulation of FAK activity both result in cytotoxic effects seems contradictory. Even though a common mode of action, with respect to the dysregulation of FAK signaling, for these cytotoxic substances has not yet been discovered, a cumulative approach could be established by focusing on FAK activation and signaling cascade. According to these data, interfering with FAK signaling might be of a potential use in blocking these cytotoxic effects. Further studies are needed on the possible implication of FAK in substance-induced cytotoxicity, as well as the possibility that such effects might be hindered or even blocked by restoring FAK signaling.
Chatzizacharias
Nikolaos A
NA
Department of Forensic Medicine and Toxicology, University of Athens, Medical School, 75, Mikras Asias Street, Goudi, Athens GR11527, Greece.
Kouraklis
Gregory P
GP
Theocharis
Stamatios E
SE
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000633:toxicity*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects*
D003603:Cytotoxins; D051416:Focal Adhesion Protein-Tyrosine Kinases