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HER2 Stabilizes EGFR and Itself by Altering Autophosphorylation Patterns in a Manner That Overcomes Regulatory Mechanisms and Promotes Proliferative and Transformation Signaling
- Source :
- Oncogene
- Publication Year :
- 2012
-
Abstract
- One of the causes of breast cancer is overexpression of the human epidermal growth factor receptor 2 (HER2). Enhanced receptor autophosphorylation and resistance to activation-induced downregulation have been suggested as mechanisms for HER2-induced sustained signaling and cell transformation. However, the molecular mechanisms underlying these possibilities remain incompletely understood. In the current report, we present evidence that show that HER2 overexpression does not lead to receptor hyper-autophosphorylation, but alters patterns in a manner that favors receptor stability and sustained signaling. Specifically, HER2 overexpression blocks epidermal growth factor receptor (EGFR) tyrosine phosphorylation on Y1045 and Y1068, the known docking sites of c-Cbl and Grb2, respectively, whereas promoting phosphorylation on Y1173, the known docking site of the Gab adaptor proteins and phospholipase C gamma. Under these conditions, HER2 itself is phosphorylated on Y1221/1222, with no known role, and on Y1248 that corresponds to Y1173 of EGFR. Interestingly, suppressed EGFR autophosphorylation on the Grb2 and c-Cbl-binding sites correlated with receptor stability and sustained signaling, suggesting that HER2 accomplishes these tasks by altering autophosphorylation patterns. In conformity with these findings, mutation of the Grb2-binding site on EGFR (Y1068F-EGFR) conferred resistance to ligand-induced degradation, which in turn induced sustained signaling, and increased cell proliferation and transformation. These findings suggest that the Grb2-binding site on EGFR is redundant for signaling, but critical for receptor regulation. On the other hand, mutation of the putative Grb2-binding site in HER2 (Y1139) did not affect stability, signaling or transformation, suggesting that Y1139 in HER2 may not serve as a Grb2-binding site. In agreement with the role of EGFR in HER2 signaling, inhibition of EGFR expression reduced HER2-induced anchorage-independent growth and tumorigenesis. These results imply that complementing HER2-targeted therapies with anti-EGFR drugs may be beneficial in HER2-positive breast cancer.
- Subjects :
- Cancer Research
Receptor, ErbB-2
EGFR
Breast Neoplasms
Article
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Growth factor receptor
HER2
Cell Line, Tumor
Genetics
Humans
Epidermal growth factor receptor
Proto-Oncogene Proteins c-cbl
Phosphorylation
skin and connective tissue diseases
Molecular Biology
030304 developmental biology
Cell Proliferation
GRB2 Adaptor Protein
0303 health sciences
biology
Autophosphorylation
Ubiquitination
Signal transducing adaptor protein
Tyrosine phosphorylation
3. Good health
Cell biology
ErbB Receptors
tumorigenesis
Cell Transformation, Neoplastic
chemistry
030220 oncology & carcinogenesis
Cancer research
biology.protein
Female
GRB2
autophosphorylation
Signal transduction
Protein Multimerization
signaling
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 14765594 and 09509232
- Volume :
- 32
- Issue :
- 35
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....592948e3f566cb5db06ab9d22a625852