title: Unliganded EphA3 dimerization promoted by the SAM domain.
abstract: The erythropoietin-producing hepatocellular carcinoma A3 (EphA3) receptor tyrosine kinase (RTK) regulates morphogenesis during development and is overexpressed and mutated in a variety of cancers. EphA3 activation is believed to follow a 'seeding mechanism' model, in which ligand binding to the monomeric receptor acts as a trigger for signal-productive receptor clustering. We study EphA3 lateral interactions on the surface of live cells and we demonstrate that EphA3 forms dimers in the absence of ligand binding. We further show that these dimers are stabilized by interactions involving the EphA3 sterile α-motif (SAM) domain. The discovery of unliganded EphA3 dimers challenges the current understanding of the chain of EphA3 activation events and suggests that EphA3 may follow the 'pre-formed dimer' model of activation known to be relevant for other receptor tyrosine kinases. The present work also establishes a new role for the SAM domain in promoting Eph receptor lateral interactions and signalling on the cell surface.
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21212, U.S.A.
authors.forename: Deo R
authors.initials: DR
authors.lastname: Singh
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21212, U.S.A.
authors.forename: QingQing
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD 21212, U.S.A.
authors.forename: Christopher
authors.initials: C
authors.lastname: King
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21212, U.S.A.
authors.forename: Matt
authors.initials: M
authors.lastname: Salotto
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21212, U.S.A.
authors.forename: Fozia
authors.initials: F
authors.lastname: Ahmed
authors.affiliation: Vaccine Center, The Wistar Institute, Philadelphia, PA 19104, U.S.A.
authors.forename: Xiang Yang
authors.initials: XY
authors.lastname: Zhou
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, U.S.A.
authors.forename: Elena B
authors.initials: EB
authors.lastname: Pasquale
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21212, U.S.A. Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD 21212, U.S.A. kh@jhu.edu.
authors.forename: Kalina
authors.initials: K
authors.lastname: Hristova
mesh_terms: D020816:Amino Acid Motifs; D057809:HEK293 Cells; D006801:Humans; D055503:Protein Multimerization / Q000502:physiology*; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D036121:Receptor, EphA3; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C491718:EPHA3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D036121:Receptor, EphA3
keywords: EphA3; SAM domain; dimerization; signaling