The epidermal growth factor receptor variant <scp>III</scp> (<scp>EGFR</scp>v<scp>III</scp>): where wild things are altered

<jats:p>The epidermal growth factor receptor (<jats:styled-content style="fixed-case">EGFR</jats:styled-content>) is overexpressed in a variety of human epithelial tumors, often as a consequence of gene amplification. Tumors with <jats:italic><jats:styled-content style="fixed-case">EGFR</jats:styled-content></jats:italic> gene amplification frequently contain <jats:italic><jats:styled-content style="fixed-case">EGFR</jats:styled-content></jats:italic> gene rearrangements, with the most common extracellular domain mutation being <jats:styled-content style="fixed-case">EGFR</jats:styled-content>v<jats:styled-content style="fixed-case">III</jats:styled-content>. This mutation leads to a deletion of exons 2–7 of the <jats:italic><jats:styled-content style="fixed-case">EGFR</jats:styled-content></jats:italic> gene and renders the mutant receptor incapable of binding any known ligand. Despite this, <jats:styled-content style="fixed-case">EGFR</jats:styled-content>v<jats:styled-content style="fixed-case">III</jats:styled-content> displays low‐level constitutive signaling that is augmented by reduced internalization and downregulation. Aberrant <jats:styled-content style="fixed-case">EGFR</jats:styled-content>v<jats:styled-content style="fixed-case">III</jats:styled-content> signaling has been shown to be important in driving tumor progression and often correlates with poor prognosis. It is clear that <jats:styled-content style="fixed-case">EGFR</jats:styled-content>v<jats:styled-content style="fixed-case">III</jats:styled-content> is expressed in a considerable proportion of patients with glioblastoma multiforme (<jats:styled-content style="fixed-case">GBM</jats:styled-content>). The presence of <jats:styled-content style="fixed-case">EGFR</jats:styled-content>v<jats:styled-content style="fixed-case">III</jats:styled-content> in other tumor types, however, remains controversial. In this review, we critically analyze the evidence for the expression of <jats:styled-content style="fixed-case">EGFR</jats:styled-content>v<jats:styled-content style="fixed-case">III</jats:styled-content> in a range of tumor types and discuss recent findings pertinent to its function and biology in <jats:styled-content style="fixed-case">GBM</jats:styled-content>.</jats:p>