Time-resolved live-cell spectroscopy reveals EphA2 multimeric assembly.

Autor: Shi X; Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center, Cleveland, OH 44109, USA.; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., Lingerak R; Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center, Cleveland, OH 44109, USA.; Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., Herting CJ; Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA 30322, USA., Ge Y; Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Kim S; Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center, Cleveland, OH 44109, USA.; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., Toth P; Department of Chemistry, University of Akron, Akron, OH 44325, USA., Wang W; Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center, Cleveland, OH 44109, USA., Brown BP; Department of Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA., Meiler J; Department of Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA., Sossey-Alaoui K; Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center, Cleveland, OH 44109, USA., Buck M; Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA., Himanen J; Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Hambardzumyan D; Departments Oncological Sciences and Neurosurgery, Tisch Cancer Institute, Icahn School of Medicine, Mount Sinai, New York, NY 10029, USA., Nikolov DB; Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Smith AW; Department of Chemistry, University of Akron, Akron, OH 44325, USA., Wang B; Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center, Cleveland, OH 44109, USA.; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.; Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2023 Dec; Vol. 382 (6674), pp. 1042-1050. Date of Electronic Publication: 2023 Nov 16.
DOI: 10.1126/science.adg5314
Abstrakt: Ephrin type-A receptor 2 (EphA2) is a receptor tyrosine kinase that initiates both ligand-dependent tumor-suppressive and ligand-independent oncogenic signaling. We used time-resolved, live-cell fluorescence spectroscopy to show that the ligand-free EphA2 assembles into multimers driven by two types of intermolecular interactions in the ectodomain. The first type entails extended symmetric interactions required for ligand-induced receptor clustering and tumor-suppressive signaling that inhibits activity of the oncogenic extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) protein kinases and suppresses cell migration. The second type is an asymmetric interaction between the amino terminus and the membrane proximal domain of the neighboring receptors, which supports oncogenic signaling and promotes migration in vitro and tumor invasiveness in vivo. Our results identify the molecular interactions that drive the formation of the EphA2 multimeric signaling clusters and reveal the pivotal role of EphA2 assembly in dictating its opposing functions in oncogenesis.
Databáze: MEDLINE
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