Pathogenic poxviruses reveal viral strategies to exploit the ErbB signaling network

Tzahar, Eldad; Moyer, James D.; Waterman, Hadassa; Barbacci, Elsa G.; Bao, Jing; Levkowitz, Gil; Shelly, Maya; Strano, Sabrina; Pinkas‐Kramarski, Ronit; Pierce, Jacalyn H.; Andrews, Glenn C.; Yarden, Yosef

doi:10.1093/emboj/17.20.5948

Cited by 112 publications

(80 citation statements)

References 63 publications

(98 reference statements)

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“…Thus, EPG partly shares with TFG␣ sensitivity to low pH. The acid-sensitive binding of TFG␣ is attributable to histidine residues embedded in the pocket of a hydrophobic receptor with solvent-accessible surfaces (25), and our homology modeling suggests that histi- Like EPG, ErbB ligands encoded by poxviruses display lower binding affinity relative to their mammalian counterparts, but their biological activities are superior because of ineffective endocytosis of ligand-receptor complexes (26). A master regulator of ErbB-1 endocytosis is c-Cbl, an E3 ubiquitin ligase that sorts active receptors to degradation in lysosomes by tagging them with ubiquitin (reviewed in Ref.…”

Section: The Anomalous Mitogenic Potential Of Epg Is Attributable To mentioning

confidence: 76%

Epigen, the Last Ligand of ErbB Receptors, Reveals Intricate Relationships between Affinity and Mitogenicity

Kochupurakkal

Harari

Di-Segni

et al. 2005

Journal of Biological Chemistry

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Four ErbB receptors and multiple growth factors sharing an epidermal growth factor (EGF) motif underlie transmembrane signaling by the ErbB family in development and cancer. Unlike other ErbB proteins, ErbB-2 binds no known EGF-like ligand. To address the existence of a direct ligand for ErbB-2, we applied algorithms based on genomic and cDNA structures to search sequence data bases. These searches reidentified all known EGF-like growth factors including Epigen (EPG), the least characterized ligand, but failed to identify novel factors. The precursor of EPG is a widely expressed transmembrane glycoprotein that undergoes cleavage at two sites to release a soluble EGF-like domain. A recombinant EPG cannot stimulate cells singly expressing ErbB-2, but it acts as a mitogen for cells expressing ErbB-1 and co-expressing ErbB-2 in combination with the other ErbBs. Interestingly, soluble EPG is more mitogenic than EGF, although its binding affinity is 100-fold lower. Our results attribute the anomalous mitogenic power of EPG to evasion of receptor-mediated depletion of ligand molecules, as well as to inefficient receptor ubiquitylation and down-regulation. In conclusion, EPG might represent the last EGF-like growth factor and define a category of low affinity ligands, whose bioactivity differs from the more extensively studied high affinity ligands.

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Section: The Anomalous Mitogenic Potential Of Epg Is Attributable To mentioning

confidence: 76%

Epigen, the Last Ligand of ErbB Receptors, Reveals Intricate Relationships between Affinity and Mitogenicity

Kochupurakkal

Harari

Di-Segni

et al. 2005

Journal of Biological Chemistry

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“…Some poxviruses encode homologs of the mammalian epidermal growth factor (EGF) (23) that bind ErbB family members (24) and are potent stimulators of cell proliferation (25). The purified variola EGF homolog (D4R) has been shown recently to bind ErbB1 on human epithelial cells (10).…”

Section: Resultsmentioning

confidence: 99%

The host response to smallpox: Analysis of the gene expression program in peripheral blood cells in a nonhuman primate model

Rubins

Hensley

Jahrling

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

112

117

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Smallpox has played an unparalleled role in human history and remains a significant potential threat to public health. Despite the historical significance of this disease, we know little about the underlying pathophysiology or the virulence mechanisms of the causative agent, variola virus. To improve our understanding of variola pathogenesis and variola-host interactions, we examined the molecular and cellular features of hemorrhagic smallpox in cynomolgus macaques. We used cDNA microarrays to analyze host gene expression patterns in sequential blood samples from each of 22 infected animals. Variola infection elicited striking and temporally coordinated patterns of gene expression in peripheral blood. Of particular interest were features that appear to represent an IFN response, cell proliferation, immunoglobulin gene expression, viral dose-dependent gene expression patterns, and viral modulation of the host immune response. The virtual absence of a tumor necrosis factor ␣͞NF-B-activated transcriptional program in the face of an overwhelming systemic infection suggests that variola gene products may ablate this response. These results provide a detailed picture of the host transcriptional response during smallpox infection, and may help guide the development of diagnostic, therapeutic, and prophylactic strategies.

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“…For example, VEGF-C, despite a reduced affinity for VEGFR-2 induces more sustained signaling via this receptor than does VEGF-A (38). Further examples are provided by the epidermal growth factors of several poxviruses, which employ a range of novel receptor activation strategies and thereby are as mitogenic as their cellular counterparts despite lower receptor-binding affinities (42).…”

Section: Discussionmentioning

confidence: 99%

Viral Vascular Endothelial Growth Factors Vary Extensively in Amino Acid Sequence, Receptor-binding Specificities, and the Ability to Induce Vascular Permeability yet Are Uniformly Active Mitogens

Wise

Ueda

Dryden

et al. 2003

Journal of Biological Chemistry

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Infections of humans and ungulates by parapoxviruses result in skin lesions characterized by extensive vascular changes that have been linked to viral-encoded homologues of vascular endothelial growth factor (VEGF). VEGF acts via a family of receptors (VEGFRs) to mediate endothelial cell proliferation, vascular permeability, and angiogenesis. The VEGF genes from independent parapoxvirus isolates show an extraordinary degree of inter-strain sequence variation. We conducted functional comparisons of five representatives of the divergent viral VEGFs. These revealed that despite the sequence divergence, all were equally active mitogens, stimulating proliferation of human endothelial cells in vitro and vascularization of sheep skin in vivo with potencies equivalent to VEGF. This was achieved even though the viral VEGFs bound VEGFR-2 less avidly than did VEGF. Surprisingly the viral VEGFs varied in their ability to cross-link VEGFR-2, induce vascular permeability and bind neuropilin-1. Correlations between these three activities were detected. In addition it was possible to correlate these functional variations with certain sequence and structural motifs specific to the viral VEGFs. In contrast to the conserved ability to bind human VEGFR-2, the viral growth factors did not bind either VEGFR-1 or VEGFR-3. We propose that the extensive sequence divergence seen in the viral VEGFs was generated primarily by selection against VEGFR-1 binding.

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Pathogenic poxviruses reveal viral strategies to exploit the ErbB signaling network

Cited by 112 publications

References 63 publications

Epigen, the Last Ligand of ErbB Receptors, Reveals Intricate Relationships between Affinity and Mitogenicity

Epigen, the Last Ligand of ErbB Receptors, Reveals Intricate Relationships between Affinity and Mitogenicity

The host response to smallpox: Analysis of the gene expression program in peripheral blood cells in a nonhuman primate model

Viral Vascular Endothelial Growth Factors Vary Extensively in Amino Acid Sequence, Receptor-binding Specificities, and the Ability to Induce Vascular Permeability yet Are Uniformly Active Mitogens

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