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EGFRvIII: the promiscuous mutation

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The signaling mechanisms underlying EGFRvIII’s tumorigenicity are not fully understood... Now, in a recent issue of Nature Neuroscience, Jahani-Asl et al. add to our knowledge of how EGFRvIII mediates its profound tumorigenicity... Nonetheless, this low level of sustained signaling through EGFRvIII is insufficient to explain its full tumorigenic activity, which promotes a diverse range of biological activities, including proliferation, survival and angiogenesis... Using the knowledge that EGFRvIII activates the transcription factor STAT3, they simultaneously performed RNA-seq on mouse astrocytes (one of the normal cells of origin for HGG) expressing EGFRvIII in the presence or absence of Stat3... This receptor, OSMR, was highly expressed in all tested HGG stem cell lines and in the EGFRvIII-expressing mouse astrocytes... Furthermore, STAT3 clearly bound to the Osmr gene promoter, and knockdown of Stat3 by lentivirus-mediated RNA interference resulted in a marked reduction in the level of Osmr mRNA, indicating that OSMR is probably a positive feed-forward signal in the EGFRvIII–STAT3 pathway (Figure 1)... Uncovering the role of this cysteine in the EGFRvIII–OSMR complex may provide new mechanistic insight into how this complex is formed and subsequently signals... Importantly, the authors also analyzed two HGG databases and showed that high levels of OSMR were significantly associated with poorer survival... Consistent with this, knockdown of OSMR in the HGG stem cell lines reduced their tumorigenicity in an intracranial model, and knockdown of Osmr in EGFRvIII-expressing mouse astrocytes robustly reduced their in vivo tumor growth by attenuating cell proliferation... Knockdown of Osmr in EGFRvIII-expressing mouse astrocytes also had the surprising effect of significantly reducing EGFRvIII expression, which correlated with loss of phosphorylated STAT3... If replicated, the therapeutic targeting of OSMR could inhibit both EGFRvIII and STAT3 simultaneously... Taken together, these data suggest that targeting OSMR signaling in patients with EGFRvIII-positive HGG tumors would have therapeutic benefit... This is the first study to show how the previously described EGFRvIII–STAT3 signaling pathway contributes to the tumorigenicity of HGG cells and to identify OSMR as a therapeutic target.

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The EGFRvIII–OSMR heterodimer activates STAT3, initiating feed-forward expression of OSMR. EGFRvIII (blue) and OSMR (red) interact at the cell surface, leading to STAT3 (green) phosphorylation and phospho-STAT3 translocation to the nucleus. Nuclear phospho-STAT3 binds to the Osmr promoter and increases Osmr transcription. This results in feed-forward signaling through the EGFRvIII–OSMR heterodimer, which significantly increases HGG growth. Additional aspects of this model that could be explored in future are indicated by dashed lines. These include uncovering the role of JAK family kinases in activating STAT3 and determining whether phospho-STAT3 has a role in maintaining EGFRvIII expression. Yellow circles denote phospho-tyrosine.
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fig1: The EGFRvIII–OSMR heterodimer activates STAT3, initiating feed-forward expression of OSMR. EGFRvIII (blue) and OSMR (red) interact at the cell surface, leading to STAT3 (green) phosphorylation and phospho-STAT3 translocation to the nucleus. Nuclear phospho-STAT3 binds to the Osmr promoter and increases Osmr transcription. This results in feed-forward signaling through the EGFRvIII–OSMR heterodimer, which significantly increases HGG growth. Additional aspects of this model that could be explored in future are indicated by dashed lines. These include uncovering the role of JAK family kinases in activating STAT3 and determining whether phospho-STAT3 has a role in maintaining EGFRvIII expression. Yellow circles denote phospho-tyrosine.

Mentions: The primary ‘hit’ from this analysis was the receptor for the cytokine oncostatin M. This receptor, OSMR, was highly expressed in all tested HGG stem cell lines and in the EGFRvIII-expressing mouse astrocytes. Furthermore, STAT3 clearly bound to the Osmr gene promoter, and knockdown of Stat3 by lentivirus-mediated RNA interference resulted in a marked reduction in the level of Osmr mRNA, indicating that OSMR is probably a positive feed-forward signal in the EGFRvIII–STAT3 pathway (Figure 1).


EGFRvIII: the promiscuous mutation
The EGFRvIII–OSMR heterodimer activates STAT3, initiating feed-forward expression of OSMR. EGFRvIII (blue) and OSMR (red) interact at the cell surface, leading to STAT3 (green) phosphorylation and phospho-STAT3 translocation to the nucleus. Nuclear phospho-STAT3 binds to the Osmr promoter and increases Osmr transcription. This results in feed-forward signaling through the EGFRvIII–OSMR heterodimer, which significantly increases HGG growth. Additional aspects of this model that could be explored in future are indicated by dashed lines. These include uncovering the role of JAK family kinases in activating STAT3 and determining whether phospho-STAT3 has a role in maintaining EGFRvIII expression. Yellow circles denote phospho-tyrosine.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979472&req=5

fig1: The EGFRvIII–OSMR heterodimer activates STAT3, initiating feed-forward expression of OSMR. EGFRvIII (blue) and OSMR (red) interact at the cell surface, leading to STAT3 (green) phosphorylation and phospho-STAT3 translocation to the nucleus. Nuclear phospho-STAT3 binds to the Osmr promoter and increases Osmr transcription. This results in feed-forward signaling through the EGFRvIII–OSMR heterodimer, which significantly increases HGG growth. Additional aspects of this model that could be explored in future are indicated by dashed lines. These include uncovering the role of JAK family kinases in activating STAT3 and determining whether phospho-STAT3 has a role in maintaining EGFRvIII expression. Yellow circles denote phospho-tyrosine.
Mentions: The primary ‘hit’ from this analysis was the receptor for the cytokine oncostatin M. This receptor, OSMR, was highly expressed in all tested HGG stem cell lines and in the EGFRvIII-expressing mouse astrocytes. Furthermore, STAT3 clearly bound to the Osmr gene promoter, and knockdown of Stat3 by lentivirus-mediated RNA interference resulted in a marked reduction in the level of Osmr mRNA, indicating that OSMR is probably a positive feed-forward signal in the EGFRvIII–STAT3 pathway (Figure 1).

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

The signaling mechanisms underlying EGFRvIII’s tumorigenicity are not fully understood... Now, in a recent issue of Nature Neuroscience, Jahani-Asl et al. add to our knowledge of how EGFRvIII mediates its profound tumorigenicity... Nonetheless, this low level of sustained signaling through EGFRvIII is insufficient to explain its full tumorigenic activity, which promotes a diverse range of biological activities, including proliferation, survival and angiogenesis... Using the knowledge that EGFRvIII activates the transcription factor STAT3, they simultaneously performed RNA-seq on mouse astrocytes (one of the normal cells of origin for HGG) expressing EGFRvIII in the presence or absence of Stat3... This receptor, OSMR, was highly expressed in all tested HGG stem cell lines and in the EGFRvIII-expressing mouse astrocytes... Furthermore, STAT3 clearly bound to the Osmr gene promoter, and knockdown of Stat3 by lentivirus-mediated RNA interference resulted in a marked reduction in the level of Osmr mRNA, indicating that OSMR is probably a positive feed-forward signal in the EGFRvIII–STAT3 pathway (Figure 1)... Uncovering the role of this cysteine in the EGFRvIII–OSMR complex may provide new mechanistic insight into how this complex is formed and subsequently signals... Importantly, the authors also analyzed two HGG databases and showed that high levels of OSMR were significantly associated with poorer survival... Consistent with this, knockdown of OSMR in the HGG stem cell lines reduced their tumorigenicity in an intracranial model, and knockdown of Osmr in EGFRvIII-expressing mouse astrocytes robustly reduced their in vivo tumor growth by attenuating cell proliferation... Knockdown of Osmr in EGFRvIII-expressing mouse astrocytes also had the surprising effect of significantly reducing EGFRvIII expression, which correlated with loss of phosphorylated STAT3... If replicated, the therapeutic targeting of OSMR could inhibit both EGFRvIII and STAT3 simultaneously... Taken together, these data suggest that targeting OSMR signaling in patients with EGFRvIII-positive HGG tumors would have therapeutic benefit... This is the first study to show how the previously described EGFRvIII–STAT3 signaling pathway contributes to the tumorigenicity of HGG cells and to identify OSMR as a therapeutic target.

No MeSH data available.