Pathway
Constitutive Signaling by EGFRvIII
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. Point mutations in the extracellular domain of EGFR are also frequently found in glioblastoma, but ligand binding ability and responsiveness are preserved.
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Similar to EGFR kinase domain mutants, EGFRvIII mutant needs to maintain association with the chaperone heat shock protein 90 (HSP90) for proper functioning. 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.
EGFRvIII mutant does not autophosorylate on the tyrosine residue Y1069 (i.e. Y1045 in the mature protein), a docking site for CBL, and is therefore unable to recruit CBL ubiquitin ligase, which enables it to escape degradation
What the reference databases state
Statements
13 statements
13 statements · 1 reference database · Subject: Constitutive Signaling by EGFRvIII · Sources: Reactome
- CBL participates in Constitutive Signaling by EGFRvIIIProteinReactome R-HSA-5637810Inferred only
- CDC37 participates in Constitutive Signaling by EGFRvIIIProteinReactome R-HSA-5637810Inferred only
- EGF participates in Constitutive Signaling by EGFRvIIIProteinReactome R-HSA-5637810Inferred only
- EGFR participates in Constitutive Signaling by EGFRvIIIProteinReactome R-HSA-5637810Inferred only
- GAB1 participates in Constitutive Signaling by EGFRvIIIProteinReactome R-HSA-5637810Inferred only
- HRAS participates in Constitutive Signaling by EGFRvIIIProteinReactome R-HSA-5637810Inferred only
- HSP90AA1 participates in Constitutive Signaling by EGFRvIIIProteinReactome R-HSA-5637810Inferred only
- NRAS participates in Constitutive Signaling by EGFRvIIIProteinReactome R-HSA-5637810Inferred only
- PIK3CA participates in Constitutive Signaling by EGFRvIIIProteinReactome R-HSA-5637810Inferred only
- PIK3R1 participates in Constitutive Signaling by EGFRvIIIProteinReactome R-HSA-5637810Inferred only
- PLCG1 participates in Constitutive Signaling by EGFRvIIIProteinReactome R-HSA-5637810Inferred only
- SHC1 participates in Constitutive Signaling by EGFRvIIIProteinReactome R-HSA-5637810Inferred only
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- SOS1 participates in Constitutive Signaling by EGFRvIIIProteinReactome R-HSA-5637810Inferred only