title: EphA2 Receptor Unliganded Dimers Suppress EphA2 Pro-tumorigenic Signaling.
abstract: The EphA2 receptor tyrosine kinase promotes cell migration and cancer malignancy through a ligand- and kinase-independent distinctive mechanism that has been linked to high Ser-897 phosphorylation and low tyrosine phosphorylation. Here, we demonstrate that EphA2 forms dimers in the plasma membrane of HEK293T cells in the absence of ephrin ligand binding, suggesting that the current seeding mechanism model of EphA2 activation is incomplete. We also characterize a dimerization-deficient EphA2 mutant that shows enhanced ability to promote cell migration, concomitant with increased Ser-897 phosphorylation and decreased tyrosine phosphorylation compared with EphA2 wild type. Our data reveal a correlation between unliganded dimerization and tumorigenic signaling and suggest that EphA2 pro-tumorigenic activity is mediated by the EphA2 monomer. Thus, a therapeutic strategy that aims at the stabilization of EphA2 dimers may be beneficial for the treatment of cancers linked to EphA2 overexpression.
authors.affiliation: Department of Materials Science and Engineering, The Johns Hopkins University, Baltimore, Maryland 21218.
authors.forename: Deo R
authors.initials: DR
authors.lastname: Singh
authors.affiliation: Department of Materials Science and Engineering, The Johns Hopkins University, Baltimore, Maryland 21218.
authors.forename: Fozia
authors.initials: F
authors.lastname: Ahmed
authors.affiliation: Department of Program in Molecular Biophysics, The Johns Hopkins University, Baltimore, Maryland 21218 and.
authors.forename: Christopher
authors.initials: C
authors.lastname: King
authors.affiliation: Department of Materials Science and Engineering, The Johns Hopkins University, Baltimore, Maryland 21218.
authors.forename: Nisha
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Materials Science and Engineering, The Johns Hopkins University, Baltimore, Maryland 21218.
authors.forename: Matt
authors.initials: M
authors.lastname: Salotto
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, San Diego, California 92037.
authors.forename: Elena B
authors.initials: EB
authors.lastname: Pasquale
authors.affiliation: Department of Materials Science and Engineering, The Johns Hopkins University, Baltimore, Maryland 21218; Department of Program in Molecular Biophysics, The Johns Hopkins University, Baltimore, Maryland 21218 and. Electronic address: kh@jhu.edu.
authors.forename: Kalina
authors.initials: K
authors.lastname: Hristova
mesh_terms: D019943:Amino Acid Substitution; D002465:Cell Movement; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D016297:Mutagenesis, Site-Directed; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009997:Osmotic Pressure; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D036104:Receptor, EphA2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008024:Ligands; D015513:Oncogene Proteins; D036104:Receptor, EphA2
keywords: dimerization; membrane protein; receptor tyrosine kinase; signal transduction; thermodynamics