Identification of a region within the ErbB2/HER2 intracellular domain that is necessary for ligand-independent association.
Ligand-independent ErbB2 activation occurs principally by two distinct mechanisms: overexpression and mutation. Overexpression of ErbB2 at the plasma membrane drives receptor self-association in a concentration-dependent manner, which in turn leads to constitutive receptor activation. Subsets of human breast cancers contain a molecular alteration that leads to erbB2 gene amplification and subsequent protein overexpression. Although not recognized to occur in human cancers, mutation can also lead to increased ErbB2 association. A well characterized mutant of the rodent ortholog neu involves substitution of glutamate for valine within the transmembrane domain. In each case, a number of explanations have been proposed to explain the resulting ErbB2 activation. These include stabilization of receptor oligomers, release of negative constraints, and altered receptor conformations. Here we define a short amino acid segment comprising amino acids 966-968 in the intracellular domain that seemingly disrupts receptor-receptor association that is driven either by overexpression or mutation in the transmembrane region. Because of the hydrophobic nature of these amino acids (VVI), we propose that alteration of this segment likely results in a global conformational change in an area that has been proposed previously to be a dimerization motif for ErbB homomeric association.
Penuel
Elicia
E
Molecular Oncology Department, Genentech, Inc., South San Francisco, California 94080, USA.
Akita
Robert W
RW
Sliwkowski
Mark X
MX
D020816:Amino Acid Motifs; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D019556:COS Cells; D019281:Dimerization; D018698:Glutamic Acid / Q000737:chemistry; D006801:Humans; D020014:K562 Cells; D008024:Ligands; D009154:Mutation; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D014633:Valine / Q000737:chemistry
D000596:Amino Acids; D018698:Glutamic Acid; D008024:Ligands; D018719:Erb-b2 Receptor Tyrosine Kinases; D014443:Tyrosine; D014633:Valine