University of SaskatchewanHARVEST
  • Login
  • Submit Your Research
  • About
    • About HARVEST
    • Guidelines
    • Browse
      • All of HARVEST
      • Communities & Collections
      • By Issue Date
      • Authors
      • Titles
      • Subjects
      • This Collection
      • By Issue Date
      • Authors
      • Titles
      • Subjects
    • My Account
      • Login
      JavaScript is disabled for your browser. Some features of this site may not work without it.
      View Item 
      • HARVEST
      • College of Graduate and Postdoctoral Studies
      • Electronic Theses and Dissertations
      • View Item
      • HARVEST
      • College of Graduate and Postdoctoral Studies
      • Electronic Theses and Dissertations
      • View Item

      Ligand-induced downregulation of the kinase-dead EphB6 receptor

      Thumbnail
      View/Open
      ALLONBY-DISSERTATION.pdf (11.97Mb)
      Date
      2015-06-08
      Author
      Allonby, Odette
      Type
      Thesis
      Degree Level
      Doctoral
      Metadata
      Show full item record
      Abstract
      Ligand-induced internalisation and subsequent downregulation of receptor tyrosine kinases (RTKs) serve to determine biological outputs of their signalling. Intrinsically kinase-deficient RTKs control a variety of biological responses, however, the mechanism of their downregulation is not well understood and its analysis is focused exclusively on the ErbB3 receptor. The Eph group of RTKs is represented by the EphA and EphB subclasses. Each bears one kinase-inactive member, EphA10 and EphB6, respectively, suggesting an important role for these molecules in the Eph signalling network. While EphB6 effects on cell behaviour have been assessed, the mechanism of its downregulation remains elusive. Our work reveals that EphB6 and its kinase-active relative, and signaling partner, EphB4, are downregulated in a similar manner in response to their common ligand, ephrin-B2. Following stimulation, both receptors are internalised through clathrin-coated pits and are degraded in lysosomes. Their targeting for lysosomal degradation relies on the activity of an early endosome regulator, the Rab5 GTPase, as this process is inhibited in the presence of a Rab5 dominant-negative variant. EphB6 also interacts with the Hsp90 chaperone and EphB6 downregulation is preceded by their rapid dissociation. Moreover, the inhibition of Hsp90 results in EphB6 degradation, mimicking its ligand-induced downregulation. These processes appear to rely on overlapping mechanisms, since Hsp90 inhibition does not significantly enhance ligand-induced EphB6 elimination. Taken together, our observations define a novel mechanism for intrinsically kinase-deficient RTK downregulation and support an intriguing model, where Hsp90 dissociation acts as a trigger for ligand-induced receptor removal.  
      Degree
      Doctor of Philosophy (Ph.D.)
      Department
      Medicine
      Program
      Health Sciences
      Supervisor
      Freywald, Andrew
      Committee
      McKay, Gordon; DeCoteau, John; Geyer, Ron; Chibbar, Rajni
      Copyright Date
      May 2015
      URI
      http://hdl.handle.net/10388/ETD-2015-05-2057
      Subject
      EphB6
      receptor tyrosine kinase
      downregulation
      internalization
      ligand
      Collections
      • Electronic Theses and Dissertations
      University of Saskatchewan

      University Library

      © University of Saskatchewan
      Contact Us | Disclaimer | Privacy