ArticleMolecular and cellular biology2002
Cytoplasmic death signal triggered by SRC-mediated phosphorylation of the adenovirus E4orf4 protein.
Article in Molecular and cellular biology, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 44 citations in OpenAlex.
- Identification of the Potential Role of the E4orf4 Protein in Adenovirus A, B, C, and D Groups in Cancer Therapy: Computational Approaches.Molecular biotechnology · 2025Article
- The adenoviral protein E4orf4: a probing tool to decipher mechanical stress-induced nuclear envelope remodeling in tumor cells.Cell cycle (Georgetown, Tex.) · 2020Article
- Cancer Treatment Goes Viral: Using Viral Proteins to Induce Tumour-Specific Cell Death.Cancers · 2019Review
- EGFR-mediated apoptosis via STAT3.Experimental cell research · 2017Article
- The Human Adenovirus Type 5 E4orf4 Protein Targets Two Phosphatase Regulators of the Hippo Signaling Pathway.Journal of virology · 2015Article
- Review
- Viral genes as oncolytic agents for cancer therapy.Cellular and molecular life sciences : CMLS · 2015Review
- Regulation of human adenovirus alternative RNA splicing by the adenoviral L4-33K and L4-22K proteins.International journal of molecular sciences · 2015Review
- A functional interplay between the small GTPase Rab11a and mitochondria-shaping proteins regulates mitochondrial positioning and polarization of the actin cytoskeleton downstream of Src family kinases.The Journal of biological chemistry · 2014Article
- Adenovirus E4orf4 protein-induced death of p53-/- H1299 human cancer cells follows a G1 arrest of both tetraploid and diploid cells due to a failure to initiate DNA synthesis.Journal of virology · 2013Article
- Agonistic and antagonistic roles for TNIK and MINK in non-canonical and canonical Wnt signalling.PloS one · 2012Article
- The adenovirus E4orf4 protein targets PP2A to the ACF chromatin-remodeling factor and induces cell death through regulation of SNF2h-containing complexes.Nucleic acids research · 2011Article
- The cytosolic tail of the Golgi apyrase Ynd1 mediates E4orf4-induced toxicity in Saccharomyces cerevisiae.PloS one · 2010Article
- Regulation of cell death by recycling endosomes and golgi membrane dynamics via a pathway involving Src-family kinases, Cdc42 and Rab11a.Molecular biology of the cell · 2009Article
- Localization and importance of the adenovirus E4orf4 protein during lytic infection.Journal of virology · 2009Article
- JNK-mediated phosphorylation of paxillin in adhesion assembly and tension-induced cell death by the adenovirus death factor E4orf4.The Journal of biological chemistry · 2008Article
- Adenovirus E4orf4 hijacks rho GTPase-dependent actin dynamics to kill cells: a role for endosome-associated actin assembly.Molecular biology of the cell · 2006Article
- Review
- Nuclear localization of the adenovirus E4orf4 protein is mediated through an arginine-rich motif and correlates with cell death.Oncogene · 2004Article
- Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein.The Journal of cell biology · 2002Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In transformed cells, the adenovirus E4orf4 death factor works in part by inducing a Src-mediated cytoplasmic apoptotic signal leading to caspase-independent membrane blebbing and cell death. Here we show that Src-family kinases modulate E4orf4 phosphorylation on tyrosine residues. Mutation of tyrosines 26, 42, and 59 to phenylalanines inhibited Src-induced phosphorylation of E4orf4 in vivo and in vitro but had no effect on the molecular association of E4orf4 with Src. However, in contrast to wild-type E4orf4, the nonphosphorylatable E4orf4 mutant was unable to modulate Src-dependent phosphorylation and was deficient in recruiting a subset of tyrosine-phosphorylated proteins. Indeed, the Src substrates cortactin and p62dok were found to associate with wild-type E4orf4 but not with the nonphosphorylatable E4orf4. Importantly, the nonphosphorylatable mutant E4orf4 was preferentially distributed in the cell nucleus, was unable to induce membrane blebbing, and had a highly impaired killing activity. Conversely, an activated form of E4orf4 was obtained by mutation of tyrosine 42 to glutamic acid. This pseudophosphorylated mutant E4orf4 was enriched in the cytoplasm and plasma membrane, showed increased binding to phosphotyrosine-containing proteins, and induced a dramatic blebbing phenotype associated with increased cell death. Altogether, our findings strongly suggest that Src-mediated phosphorylation of adenovirus type 2 E4orf4 is critical to promoting its cytoplasmic and membrane localization and is required for the transduction of E4orf4-Src-dependent induction of membrane blebbing. We propose that E4orf4 acts in part by uncoupling Src-dependent signals to drive the formation of a signaling complex that triggers a cytoplasmic death signal.
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