EGFR Phosphorylates Tumor-Derived EGFRvIll Driving STAT3/5 and Progression in Glioblastoma

EGFRvIll, a frequently occurring mutation in primary glioblastoma, results in a protein product that cannot bind ligand, but signals constitutively. Deducing how EGFRvIll causes transformation has been difficult because of autocrine and paracrine loops triggered by EGFRvIll alone or in heterodimers with wild-type EGFR. Here, we document coexpression of EGFR and EGFRvIll in primary human glioblastoma that drives transformation and tumorigenesis in a cell-intrinsic manner. We demonstrate enhancement of downstream STAT signaling triggered by EGFR-catalyzed phosphorylation of EGFRvIll, implicating EGFRvIll as a substrate for EGFR. Subsequent phosphorylation of STAT3 requires nuclear entry of EGFRvIll and formation of an EGFRvIll-STAT3 nuclear complex. Our findings clarify specific oncogenic signaling relationships between EGFR and EGFRvIll in glioblastonna..