Aberrant activation of receptor tyrosine kinases (RTK) is causally linked to the 
pathobiological traits of glioblastoma and genesis of glioma stem-like cells 
(GSC), but the underlying mechanism is still unknown. Here, we show that 
epidermal growth factor receptor (EGFR) signaling regulates the proliferation, 
angiogenesis, and acquisition of GSC characteristics by inducing inhibitor of 
differentiation 3 (ID3) and ID3-regulated cytokines [GRO1 and interleukins 
(IL)-6 and 8] induction. We found that EGFR-mediated ID3 expression was 
regulated by Smad5, which was directly phosphorylated by AKT. Furthermore, ID3 
alone imparted GSC features to primary astrocytes derived from 
Ink4a/Arf-deficient mouse, and EGFR-ID3-IL-6 signaling axis gave rise to tumor 
cell heterogeneity. Conversely, EGFR inhibitors suppressed EGFR-AKT-Smad5-driven 
induction of ID3, which led to a decrease in the tumorsphere forming ability of 
GSCs and U87MG cells that possess an active mutant EGFR, EGFRvIII, without 
obvious cytotoxic effects. However, these cells seemed to regain colonogenic 
ability after removal of the EGFR inhibitors. Together, the results delineate a 
novel integrative molecular mechanism in which the RTK-ID signaling pathway 
governs genesis and maintenance of GBM histopathologic features, such as 
GSCs-based tumor initiation, progression, and angiogenesis.