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Investigation of the role of different regions of the Cbl protein in its function

Başlık çevirisi mevcut değil.

  1. Tez No: 402054
  2. Yazar: NURETTİN İLTER SEVER
  3. Danışmanlar: DR. AMANDA SİMCOX
  4. Tez Türü: Doktora
  5. Konular: Biyoloji, Biyomühendislik, Biology, Bioengineering
  6. Anahtar Kelimeler: Belirtilmemiş.
  7. Yıl: 2013
  8. Dil: İngilizce
  9. Üniversite: The Ohio State University
  10. Enstitü: Yurtdışı Enstitü
  11. Ana Bilim Dalı: Belirtilmemiş.
  12. Bilim Dalı: Belirtilmemiş.
  13. Sayfa Sayısı: 90

Özet

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Özet (Çeviri)

The duration and amplitude of any signal transduction pathway should be tightly regulated for the maintenance of homeostasis in any organism. Cbl protein is one of the crucial modulators of epidermal growth factor receptor (EGFR) signaling. Cbl is a RING-type, E3 ubiquitin ligase which marks its substrates with ubiquitin and destines them for degradation. Upon stimulation by a ligand, Cbl is associated with and phosphorylated by EGFR, ubiquitinates it, helps to internalize it and directs it to the lysosomal degradation pathway. Reanalysis of the crystal structure depicted in 2000 by Zhang et al. suggested that Cbl may be present as dimers when complexed with ZAP-70 and its E2 ubiquitin-conjugating partner UbcH7. The V431 and F434 residues of the Cbl RING finger tail (RF tail), found at one interface of this putative dimer, were shown to play different roles in EGFR trafficking. For this study, the other residues in the same putative dimer interface were analyzed in terms of their necessity for Cbl to enhance EGFR degradation and ubiquitination. All mutations were presented in the context of the full length Cbl protein. Our degradation assay showed that all the tested mutants degraded EGFR as efficiently as wild type 90 minutes after EGF stimulation. All mutants could associate with EGFR and ubiquitinate it. Interestingly, even mutations that were predicted to induce major structural disruption at the putative dimer interface failed to affect the degradation of EGFR. Based on these data, I concluded that the published 2000 crystal structure from Zhang et al. did not largely reflect the active form of Cbl dimers. My finding is discussed here in the context of a new Cbl structure reported in 2012 by Dou et al.In further studies, I extended earlier research by our lab that led us to hypothesize the presence of an inhibitory activity within Cbl, which mapped C-terminal to amino acid 357. This novel activity is normally masked by the ubiquitin ligase activity of Cbl, but becomes evident when E3 activity is inhibited and ubiquitin is present in Cbl-EGFR complexes via recombinant fusion to Cbl. Using ubiquitin-fused truncated Cbl-Y371F constructs, which lack E3 activity but can bind to ubiquitin interacting motifs of the endocytosis machinery, I mapped more definitively the location of the inhibitory element. I then tested whether this inhibitory activity involved binding of the signaling adapter Grb2 to EGFR in complex with Cbl. Our findings suggest that Grb2 is not involved in this inhibitory activity.

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