title: A basic peptide within the juxtamembrane region is required for EGF receptor dimerization.
abstract: The epidermal growth factor receptor (EGFR) is fundamental for normal cell growth and organ development, but has also been implicated in various pathologies, notably tumors of epithelial origin. We have previously shown that the initial 13 amino acids (P13) within the intracellular juxtamembrane region (R645-R657) are involved in the interaction with calmodulin, thus indicating an important role for this region in EGFR function. Here we show that P13 is required for proper dimerization of the receptor. We expressed either the intracellular domain of EGFR (TKJM) or the intracellular domain lacking P13 (DeltaTKJM) in COS-7 cells that express endogenous EGFR. Only TKJM was immunoprecipitated with an antibody directed against the extracellular part of EGFR, and only TKJM was tyrosine phosphorylated by endogenous EGFR. Using SK-N-MC cells, which do not express endogenous EGFR, that were stably transfected with either wild-type EGFR or recombinant full-length EGFR lacking P13 demonstrated that P13 is required for appropriate receptor dimerization. Furthermore, mutant EGFR lacking P13 failed to be autophosphorylated. P13 is rich in basic amino acids and in silico modeling of the EGFR in conjunction with our results suggests a novel role for the juxtamembrane domain (JM) of EGFR in mediating intracellular dimerization and thus receptor kinase activation and function.
authors.affiliation: Department of Pharmacology, Linköping University, SE-58185 Linköping, Sweden.
authors.forename: Sami
authors.initials: S
authors.lastname: Aifa
authors.forename: Jan
authors.initials: J
authors.lastname: Aydin
authors.forename: Gunnar
authors.initials: G
authors.lastname: Nordvall
authors.forename: Ingemar
authors.initials: I
authors.lastname: Lundström
authors.forename: Samuel P S
authors.initials: SP
authors.lastname: Svensson
authors.forename: Ola
authors.initials: O
authors.lastname: Hermanson
mesh_terms: D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism*; D019281:Dimerization; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D017434:Protein Structure, Tertiary / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction / Q000502:physiology
chemical_list: D008565:Membrane Proteins; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases