Three dimensional structure of the transmembrane region of the proto-oncogenic and oncogenic forms of the neu protein.

Abstract

The neu proto-oncogene may be converted into a dominantly transforming oncogene by a single point mutation. Substitution of a valine residue at position 664 in the transmembrane region with glutamic acid activates the tyrosine kinase of the molecule and is associated with increased receptor dimerization. Previously we have proposed a model in which the glutamic acid side chain stabilizes receptor dimerization by hydrogen bonding. Other models have been proposed in which the mutation leads to a conformational change in the transmembrane region mimicking that assumed to occur following binding of a natural ligand. Synthetic peptides representing part of the transmembrane region were prepared. Some residues were replaced with serine in order to improve peptide solubility to allow purification and analysis. Both the peptides containing valine and glutamic acid dissolved in water and in an artificial lipid monolayer. The structures of the peptides were determined by NMR spectroscopy to be a-helical. No significant difference in conformation was observed between the two peptides. This result does not support the model proposing a conformational change. The receptor structures determined experimentally do allow alternative models involving receptor transmembrane region packing.

Critical Role of the Platelet-derived Growth Factor Receptor (PDGFR) β Transmembrane Domain in the TEL-PDGFRβ Cytosolic Oncoprotein

“…The TM sequence of PDGFR␤ is predicted to adopt an ␣-helical conformation and to determine the relative orientation of the catalytic subunits in the dimeric receptor (34,45,46). The way in which two adjacent kinase domains face each other was shown to be critical for receptor activation in experiments where a dimerization motif was shifted in the PDGFR␤ TM domain and caused periodic activation of the receptor (47).…”

Attenuation of PI3K/Akt-Mediated Tumorigenic Signals through PTEN Activation by DNA Vaccine-Induced Anti-ErbB2 Antibodies

“…Activated rat ErbB2 exhibits a single-point mutation in the TM domain, leading to ligand-independent receptor homo-and heterodimerization (31,41). Thus, it is likely that on TUBO cells, physical and functional interactions between autochthonous mouse ErbB3 and transgenic rat ErbB2 could occur, despite their cross-species molecular structure.…”

Novel Engineered Trastuzumab Conformational Epitopes Demonstrate In Vitro and In Vivo Antitumor Properties against HER-2/neu

“…BALB/c inbred mice transgenic for the transforming activated rat HER-2/neu oncogene under the control of a mammary-specific promoter is likely the most aggressive model of HER-2/neu carcinogenesis (27). A point mutation that replaces the valine residue at position 664 in the transmembrane domain with glutamic acid favors HER-2/neu homo-and heterodimerization and renders the neu gene product constitutively active (37). Animals rapidly develop tumors; in preliminary studies using untreated mice, all animals developed tumors by 25 wk of age.…”