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Constitutive Signaling by EGFRvIII
Stable Identifier
R-HSA-5637810
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
Locations in the PathwayBrowser
Expand all
Disease (Homo sapiens)
Diseases of signal transduction by growth factor receptors and second messengers (Homo sapiens)
Signaling by EGFR in Cancer (Homo sapiens)
Signaling by EGFRvIII in Cancer (Homo sapiens)
Constitutive Signaling by EGFRvIII (Homo sapiens)
General
SBML
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Level 3
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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 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 (Han et al. 2006)
Participants
Events
EGFRvIII mutant binds chaperone proteins HSP90 and CDC37.
(Homo sapiens)
EGFRvIII cancer variant does not bind EGF ligand
(Homo sapiens)
Ligand-independent dimerization of EGFRvIII mutant
(Homo sapiens)
Trans-autophosphorylation of EGFRvIII mutant dimers
(Homo sapiens)
Binding of GRB2:SOS1 complex to phosphorylated EGFRvIII
(Homo sapiens)
SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in complex with p-EGFRvIII)
(Homo sapiens)
Binding of SHC1 to p-5Y-EGFRvIII
(Homo sapiens)
Phosphorylation of SHC1 by p-5Y-EGFRvIII
(Homo sapiens)
Phosphorylated SHC1 in complex with p-5Y-EGFRvIII recruits GRB2:SOS1 complex
(Homo sapiens)
SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in complex with phosphorylated SHC1 and p-EGFRvIII)
(Homo sapiens)
Binding of GRB2:GAB1 complex to p-EGFRvIII mutant
(Homo sapiens)
Binding of PI3K to complex of GRB2:GAB1 and p-EGFRvIII
(Homo sapiens)
Conversion of PIP2 to PIP3 by PI3K bound to phosphorylated EGFRvIII
(Homo sapiens)
PLC-gamma 1 binds to p-EGFRvIII mutant
(Homo sapiens)
Phosphorylation of PLC-gamma 1 by p-EGFRvIII mutant
(Homo sapiens)
Dissociation of phosphorylated PLC-gamma 1 from p-EGFRvIII mutant
(Homo sapiens)
EGFRvIII does not bind CBL
(Homo sapiens)
HSP90 is inactivated by binding to benzaquinoid ansamycins
(Homo sapiens)
Participates
as an event of
Signaling by EGFRvIII in Cancer (Homo sapiens)
Disease
Name
Identifier
Synonyms
cancer
DOID:162
malignant tumor, malignant neoplasm, primary cancer
Cross References
BioModels Database
BIOMD0000000399
,
BIOMD0000000883
,
BIOMD0000000656
,
BIOMD0000000655
,
BIOMD0000000648
,
BIOMD0000000652
,
BIOMD0000000019
,
BIOMD0000000654
,
BIOMD0000000594
,
BIOMD0000000175
,
BIOMD0000000255
,
BIOMD0000000477
,
BIOMD0000000595
,
BIOMD0000000223
,
BIOMD0000000653
Authored
Orlic-Milacic, M (2011-11-04)
Reviewed
Greulich, H (2011-11-15)
Savas, S (2011-11-15)
Created
Orlic-Milacic, M (2014-11-13)
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