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EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics.
Freed, Daniel M; Bessman, Nicholas J; Kiyatkin, Anatoly; Salazar-Cavazos, Emanuel; Byrne, Patrick O; Moore, Jason O; Valley, Christopher C; Ferguson, Kathryn M; Leahy, Daniel J; Lidke, Diane S; Lemmon, Mark A.
Afiliación
  • Freed DM; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA.
  • Bessman NJ; Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, USA.
  • Kiyatkin A; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA.
  • Salazar-Cavazos E; Department of Pathology and UNM Comprehensive Cancer Center, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.
  • Byrne PO; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
  • Moore JO; Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, USA.
  • Valley CC; Department of Pathology and UNM Comprehensive Cancer Center, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.
  • Ferguson KM; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA.
  • Leahy DJ; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
  • Lidke DS; Department of Pathology and UNM Comprehensive Cancer Center, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.
  • Lemmon MA; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, USA. El
Cell ; 171(3): 683-695.e18, 2017 Oct 19.
Article en En | MEDLINE | ID: mdl-28988771
Epidermal growth factor receptor (EGFR) regulates many crucial cellular programs, with seven different activating ligands shaping cell signaling in distinct ways. Using crystallography and other approaches, we show how the EGFR ligands epiregulin (EREG) and epigen (EPGN) stabilize different dimeric conformations of the EGFR extracellular region. As a consequence, EREG or EPGN induce less stable EGFR dimers than EGF-making them partial agonists of EGFR dimerization. Unexpectedly, this weakened dimerization elicits more sustained EGFR signaling than seen with EGF, provoking responses in breast cancer cells associated with differentiation rather than proliferation. Our results reveal how responses to different EGFR ligands are defined by receptor dimerization strength and signaling dynamics. These findings have broad implications for understanding receptor tyrosine kinase (RTK) signaling specificity. Our results also suggest parallels between partial and/or biased agonism in RTKs and G-protein-coupled receptors, as well as new therapeutic opportunities for correcting RTK signaling output.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores ErbB / Epigen / Epirregulina Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cell Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores ErbB / Epigen / Epirregulina Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cell Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos