We identified Caspase-8 as a new substrate for Src kinase. Phosphorylation occurs on Tyr380, situated in the linker region between the large and the small subunits of human Procaspase-8, and results in downregulation of Caspase-8 proapoptotic function. Src activation triggers Caspase-8 phosphorylation on Tyr380 and impairs Fas-induced apoptosis. Accordingly, Src failed to protect Caspase-8-defective human cells in which a Caspase-8-Y380F mutant is expressed from Fas-induced cell death. Remarkably, Src activation upon EGF-receptor stimulation triggers endogenous Caspase-8 phosphorylation and prevents Fas-induced apoptosis. Tyr380 is phosphorylated also in human colon cancers where Src is aberrantly activated. These data provide the first evidence for a direct role of tyrosine phosphorylation in the control of caspases and reveal a new mechanism through which tyrosine kinases inhibit apoptosis and participate in tumor progression.
Ataxia telangiectasia (A-T) is a rare cancer-predisposing genetic disease, caused by the lack of functional ATM kinase, a major actor of the double strand brakes (DSB) DNA-damage response. A-T patients show a broad and diverse phenotype, which includes an increased rate of lymphoma and leukemia development. Fas-induced apoptosis plays a fundamental role in the homeostasis of the immune system and its defects have been associated with autoimmunity and lymphoma development. IntroductionAtaxia telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar progressive neurodegeneration leading to ataxia, dilatation of blood vessels in the eye and facial area (telangiectasia), sensitivity to ␥-irradiation, high incidence of tumorigenesis in the lymphoid system, and deficiency in immunoresponses. A-T pathology is characterized by the loss of functional ATM protein kinase. Following DNA damage, ATM is rapidly activated and (auto)phosphorylated, 1 and, in turn, it phosphorylates a number of substrates that all contribute to cell growth arrest or, alternatively, apoptosis (reviewed in Shiloh 2 ). The higher cancer predisposition of A-T patients has been associated with the lack of DNA-damage response, which results in genomic instability. 3 The immune system is the major target of tumor development in these patients, and lymphoma and leukemia are very frequent. 4,5 This clinical feature is consistent with the central role of ATM in the management of the DNA DSBs generated during the immune system development and function in physiological conditions. 6 Indeed most of the lymphomas developed in A-T patients are characterized by aberrant VDJ recombination. 6 More interestingly, ATM expression is aberrantly low in several B-and T-cell lymphomas irrespective of A-T genotype. [7][8][9][10] Fas (CD95/APO-1) is a transmembrane protein belonging to the tumor necrosis factor superfamily. Upon binding of Fas ligand or agonistic antibodies, the Fas receptor recruits several cytosolic proteins to form the death-inducing signaling complex (DISC). This is necessary to catalyze dimerization and processing of procaspase-8 to generate the active caspase-8 tetramer, composed of 2 p18 and 2 p10 subunits, which initiates the caspase cascade. 11 activation is absolutely required to trigger receptoractivated apoptotic response, 12 and its catalytic activity has to be tightly regulated to avoid inappropriate activation and undesired cell death. 13 FLIP protein is structurally similar to procaspase-8 and can therefore compete with procaspase-8 for binding to DISC, thus preventing caspase-8 activation and the following apoptotic cascade. Two isoforms of FLIP, arising from alternative splicing, are normally present in most of the cells. FLIP-long (FLIP-L), similarly to procaspase-8, has 2 DED domains that mediate the recruitment to the DISC, as well as a p18 and a p10 subunit, but it lacks the Cys residue in the active site and is therefore catalytically impaired. However, in some contexts FLIP-L can also dimerize and theref...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.