Heterodimerization of Epidermal Growth Factor Receptor and Wild-Type or Kinase-Deficient Neu: A Mechanism of Interreceptor Kinase Activation and Transphosphorylation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 4; pp. 1500 - 1504
• Main Authors: Qian, Xiaolan, LeVea, Charles M., Freeman, Jon K., Dougall, William C., Greene, Mark I.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 15-02-1994; National Acad Sciences; National Academy of Sciences
• Subjects: Animals; Antibodies; Biochemistry; Biological and medical sciences; Blotting, Western; Cell lines; Cell receptors; Cell structures and functions; Cells, Cultured; Cellular immunity; Complementary DNA; Cross-Linking Reagents; DNA Mutational Analysis; Enzyme Activation; ErbB Receptors - deficiency; ErbB Receptors - genetics; ErbB Receptors - metabolism; Fibroblasts; Fundamental and applied biological sciences. Psychology; Gels; Hormone receptors. Growth factor receptors. Cytokine receptors. Prostaglandin receptors; Immunoprecipitation; Macromolecular Substances; Mice; Molecular and cellular biology; Phosphorylation; Phosphotyrosine; Point mutation; Precipitin Tests; Protein Binding; Protein Conformation; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptor, ErbB-2; Receptors; Recombinant Proteins - metabolism; Sequence Deletion; Transfection; Tyrosine - analogs & derivatives; Tyrosine - biosynthesis; Enzyme; Gene product; Transferases; Rodentia; Molecular interaction; In vitro; Vertebrata; Membrane receptor; Mammalia; Epidermal growth factor; Enzymatic activity; Mouse; Polypeptide; Fibroblast; Protein-tyrosine kinase; Protooncogene; Growth factor
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.4.1500

We have shown that members of the erbB family undergo homodimer and heterodimer formation. The rat p185c-neuand the epidermal growth factor receptor (EGFR) can associate into an active heterodimeric tyrosine kinase. Overexpression of these two receptors also results in a transformed phenotype. We now show that mutant Neu proteins resulting from a point mutation at the ATP-binding site (N757) or cytoplasmic domain deletions (N691stop) are still able to undergo EGF-induced heterodimerization with EGFR. Analysis of heterodimer formation between EGFR and truncated Neu proteins revealed that heterodimerization is preferred over homodimerization of EGFR. N757 can be transphosphorylated by associated EGFR upon EGF stimulation. However, the heterodimer composed of EGFR and N691stop is kinase inactive. These results provided evidence that the Neu ectodomain is sufficient to associate with EGFR physically, and the cytoplasmic domain interaction is required for heterodimeric kinase activation, indicating that Neu/c-erbB2 is not just a simple substrate for EGFR but a transactivator as well.