Critical Role for Caspase-8 in Epidermal Growth Factor Signaling

Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Cancer Research (Impact Factor: 9.33). 07/2009; 69(12):5023-9. DOI: 10.1158/0008-5472.CAN-08-3731
Source: PubMed


Caspase-8 has a well-defined canonical role as an apical protease of the extrinsic apoptosis pathway. Evidence is growing, however, that the protein has numerous other nonapoptotic functions. We have previously shown that caspase-8 is required for efficient adhesion-induced activation of the extracellular signal-regulated kinase (Erk)-1/2 pathway. We now show that caspase-8 is also necessary for the efficient activation of downstream events associated with epidermal growth factor (EGF) signaling. This promotion of EGF-induced Erk1/2 activation is independent of the proteolytic activity of caspase-8 and can be recapitulated using only the pro-domains of the protein. In addition, we identify specific residues within the caspase-8 "RXDLL motif" that are essential for Erk pathway activation. Furthermore, these residues are also involved in forming a complex with the tyrosine kinase Src. Caspase-8 null cells and cells reconstituted with caspase-8 harboring point mutations of these critical amino acids also show defective EGF-induced migration as compared with cells reconstituted with the wild-type protein. In sum, we provide the first evidence for caspase-8 as an essential component of growth factor signaling and suggest that this may be due to its association with Src. As the EGF/Src pathway activity has been shown to promote oncogenic events, our findings that caspase-8 is necessary for these activities may help explain why it is rarely deleted or silenced in tumors.

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Available from: Darren "Ben" Finlay, Apr 07, 2014
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    • "This phenotype, however, is not rescued by catalytically inactive caspase-8. How expression of the caspase-8 DEDs alone can be sufficient to induce terminal differentiation in certain cells is as yet unclear, but implies an important non-catalytic role for caspase-8 [37] [38]. 2.2. "
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    Biochimica et Biophysica Acta 06/2011; 1824(1):113-22. DOI:10.1016/j.bbapap.2011.06.005 · 4.66 Impact Factor
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    • "In addition to this role in death receptor-mediated apoptosis, cumulative evidence suggests that caspase-8 performs other non-apoptotic functions in development [1], including proliferation [2], [3], cell migration [4]–[7] and differentiation [3], [8]. We and others previously reported that caspase-8 has the capacity to localize to a number of different cellular locations, including the cytosolic compartment [9], actin-rich ruffles [10], [11], endosomes [12], including those at the front of migrating cells[13], focal adhesions [4] and stable microtubule structures, such as centrosomes [14]. Interestingly, the different domains of caspase-8 appear to favor localization to different cellular compartments. "
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    PLoS ONE 11/2009; 4(11):e7879. DOI:10.1371/journal.pone.0007879 · 3.23 Impact Factor
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    • "Many of the nonapoptotic functions of caspase-8 occur independently of its protease activity (Helfer et al., 2006; Barbero et al., 2008, 2009). Instead, caspase-8 can interact with several Src homology 2 domain-containing proteins, including the p85␣ regulatory subunit of phosphatidylinositol 3-kinase (Senft et al., 2007), Src family kinases (Barbero et al., 2008; Finlay et al., 2009), phosphatase SHP-1 (Jia et al., 2008), and weakly with Grb2 (Barbero et al., 2008). These interactions promote Rac and calpain activity (Helfer et al., 2006; Senft et al., 2007; Barbero et al., 2009), as well as extracellular signal-regulated kinase signaling (Finlay and Vuori, 2007). "
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    Molecular biology of the cell 11/2009; 21(2):369-76. DOI:10.1091/mbc.E09-09-0769 · 4.47 Impact Factor
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