Pathway
Signaling by ERBB2 ECD mutants
ERBB2 extracellular domain (ECD) mutants harbor missense mutations that lead to substitutions of amino acid residues in the heterodimerization arm contact surface, involved in formation of ERBB2 heterodimers. The functionally studied ERBB2 ECD mutants, ERBB2 G309A, ERBB2 G309E and ERBB2 S310F seem to preferntially heterodimerize with EGFR. Heterodimerization of ERBB2 G309E involves formation of disulfide bonds. ERBB2 S310F shows stronger activation of downstream signaling than ERBB2 G309A and ERBB2 G309E, and is hyperphosphorylated on tyrosine residues in the C-tail, while the C-tail phosphorylation of ERBB2 G309A and ERBB2 G309E is comparable to the wild type ERBB2.
Continue reading
RAS signaling and PLCgamma1 signaling are activated dowsntream of all three ERBB2 ECD mutants, ERBB2 G309A, ERBB2 G309E and ERBB2 S310F, as evidenced by activating phosphorylation on ERKs (MAPK1 and MAPK3) and PLCG1, respectively. ERBB2 G309E and ERBB2 S310F also activate PI3K/AKT signaling, demonstrated by activating phosphorylation of AKT1. Activation of PI3K/AKT signaling downstream of ERBB2 G309A has not been tested. Signaling downstream of ERBB2 S310Y has been poorly characterized and it is annotated as a candidate. Many regulators of cell migration show increased phosphorylation in cells expressing ERBB2 G309E and ERBB2 S310F.
Comapred with the wild type ERBB2, ERBB2 G309E, ERBB2 S310F and ERBB2 S310Y are more sensitive to the ERBB2-directed therapeutic antibody trastuzumab (herceptin) and to tyrosine kinase inhibitors lapatinib, neratinib and afatinib. ERBB2 G309A was also responsive to trastuzumab, lapatinib and neratinib.
What the reference databases state
Statements
14 statements
14 statements · 1 reference database · Subject: Signaling by ERBB2 ECD mutants · Sources: Reactome
- CDC37 participates in Signaling by ERBB2 ECD mutantsProteinReactome R-HSA-9665348Inferred only
- EGF participates in Signaling by ERBB2 ECD mutantsProteinReactome R-HSA-9665348Inferred only
- EGFR participates in Signaling by ERBB2 ECD mutantsProteinReactome R-HSA-9665348Inferred only
- ERBB2 participates in Signaling by ERBB2 ECD mutantsProteinReactome R-HSA-9665348Inferred only
- ERBIN participates in Signaling by ERBB2 ECD mutantsProteinReactome R-HSA-9665348Inferred only
- GAB1 participates in Signaling by ERBB2 ECD mutantsProteinReactome R-HSA-9665348Inferred only
- HRAS participates in Signaling by ERBB2 ECD mutantsProteinReactome R-HSA-9665348Inferred only
- HSP90AA1 participates in Signaling by ERBB2 ECD mutantsProteinReactome R-HSA-9665348Inferred only
- NRAS participates in Signaling by ERBB2 ECD mutantsProteinReactome R-HSA-9665348Inferred only
- PIK3CA participates in Signaling by ERBB2 ECD mutantsProteinReactome R-HSA-9665348Inferred only
- PIK3R1 participates in Signaling by ERBB2 ECD mutantsProteinReactome R-HSA-9665348Inferred only
- PLCG1 participates in Signaling by ERBB2 ECD mutantsProteinReactome R-HSA-9665348Inferred only
Show the remaining 2
- SHC1 participates in Signaling by ERBB2 ECD mutantsProteinReactome R-HSA-9665348Inferred only
- SOS1 participates in Signaling by ERBB2 ECD mutantsProteinReactome R-HSA-9665348Inferred only