title: Structural analysis of p185c-neu and epidermal growth factor receptor tyrosine kinases: oligomerization of kinase domains.
abstract: The epidermal growth factor receptor (EGFR) and p185c-neu proteins associate as dimers to create an efficient signaling assembly. Overexpression of these receptors together enhances their intrinsic kinase activity and concomitantly results in oncogenic cellular transformation. The ectodomain is able to stabilize the dimer, whereas the kinase domain mediates biological activity. Here we analyze potential interactions of the cytoplasmic kinase domains of the EGFR and p185c-neu tyrosine kinases by homology molecular modeling. This analysis indicates that kinase domains can associate as dimers and, based on intermolecular interaction calculations, that heterodimer formation is favored over homodimers. The study also predicts that the self-autophosphorylation sites located within the kinase domains are not likely to interfere with tyrosine kinase activity, but may regulate the selection of substrates, thereby modulating signal transduction. In addition, the models suggest that the kinase domains of EGFR and p185c-neu can undergo higher order aggregation such as the formation of tetramers. Formation of tetrameric complexes may explain some of the experimentally observed features of their ligand affinity and hetero-receptor internalization.
authors.affiliation: Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: R
authors.initials: R
authors.lastname: Murali
authors.forename: P J
authors.initials: PJ
authors.lastname: Brennan
authors.forename: T
authors.initials: T
authors.lastname: Kieber-Emmons
authors.forename: M I
authors.initials: MI
authors.lastname: Greene
mesh_terms: D000595:Amino Acid Sequence; D001704:Biopolymers; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D001704:Biopolymers; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases