description
In glioblastoma, the most prevalent EGFR mutation, present in ~25% of tumors, is the deletion of the ligand binding domain of EGFR, accompanied with amplification of the mutated allele, which results in over-expression of the mutant protein known as EGFRvIII. EGFRvIII mutant is not able to bind a ligand, but dimerizes and autophosphorylates spontaneously and is therefore constitutively active (Fernandes et al. 2001). Point mutations in the extracellular domain of EGFR are also frequently found in glioblastoma, but ligand binding ability and responsiveness are preserved (Lee et al. 2006). Similar to EGFR kinase domain mutants, EGFRvIII mutant needs to maintain association with the chaperone heat shock protein 90 (HSP90) for proper functioning (Shimamura et al. 2005, Lavictoire et al. 2003). CDC37 is a co-chaperone of HSP90 that acts as a scaffold and regulator of interaction between HSP90 and its protein kinase clients. CDC37 is frequently over-expressed in cancers involving mutant kinases and acts as an oncogene (Roe et al. 2004, reviewed by Gray Jr. et al. 2008). Expression of EGFRvIII mutant results in aberrant activation of downstream signaling cascades, namely RAS/RAF/MAP kinase signaling and PI3K/AKT signaling, and possibly signaling by PLCG1, which leads to increased cell proliferation and survival, providing selective advantage to cancer cells that harbor EGFRvIII (Huang et al. 2007). EGFRvIII mutant does not autophosorylate on the tyrosine residue Y1045, a docking site for CBL, and is therefore unable to recruit CBL ubiquitin ligase, which enables it to escape degradation (Han et al. 2006

external resources
NCBI:1268860
REACTOME:R-HSA-5637810

genes
CBL , EGF , EGFR , GAB1 , GRB2 , HRAS , HSP90AA1 , KRAS , NRAS , PIK3CA , PIK3R1 , PLCG1 , SHC1 , SOS1 , CDC37 , MIR1181 ,