Article
- The EMBO Journal (2006) 25, 1895 - 1905
- doi:10.1038/sj.emboj.7601085
Published online: 20 April 2006
Subject Categories:
Src kinase phosphorylates Caspase-8 on Tyr380: a novel mechanism of apoptosis suppression
Silvia Cursi1,2,3,a, Alessandra Rufini2,a, Venturina Stagni1,2,3, Ivano Condò2, Vittoria Matafora4, Angela Bachi4, Antonio Paniccià Bonifazi5, Luigi Coppola5, Giulio Superti-Furga6, Roberto Testi2 and Daniela Barilà1,2,3
- Department of Experimental Medicine and Biochemical Sciences, Dulbecco Telethon Institute, University of Rome 'Tor Vergata', Rome, Italy
- Laboratory of Immunology and Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome 'Tor Vergata', Rome, Italy
- Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy
- Dibit-San Raffaele Scientific Institute, Milan, Italy
- Department of Laboratory Medicine, UOC of Pathology Anatomy, S Filippo Neri Hospital, Rome, Italy
- Center of Molecular Medicine of the Academy of Sciences, Vienna, Austria
Correspondence to:
Daniela Barilà, Department of Experimental Medicine and Biochemical Sciences, Dulbecco Telethon Institute, University of Rome 'Tor Vergata' and Fondazione Santa Lucia, Via del Fosso di Fiozano, 00143 Rome, Italy. Tel.: +39 06 501703168; Fax: +39 06 501703330; E-mail: daniela.barila@uniroma2.it, dbarila@dti.telethon.it
aThese authors equally contributed to this work
Received 19 August 2005; Accepted 17 March 2006
Abstract
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.
Keywords:
- apoptosis,
- cancer,
- Caspase-8,
- Fas-receptor,
- Src non-receptor tyrosine kinase
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