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Title: Identification of degradation pathways for HSP90 client proteins
Author: Li, Zhaobo
ISNI:       0000 0004 6061 7854
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2017
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Heat shock protein 90 (HSP90) is an ATP-dependent molecular chaperone that plays critical roles in regulating the folding, stabilization, post-translational modification, activation and maturation of its various client proteins, of which many are oncoproteins. Impairing the function of HSP90 by the inhibition of its ATPase cycle with inhibitors such as AUY922 promotes the ubiquitylation and proteasomal degradation of its client proteins. However, we currently do not fully understand the mechanism for ATPase-inhibited triggered degradation of client proteins, and which E3 ligase systems are involved. Although previous studies revealed a number of E3 ligases including CHIP and CUL5 as potentially E3 ligases involved in the degradation of HSP90-dependent client protein, these have often used cancer cells that may have dysregulated systems. Additionally, other components of such E3 ligase systems have not been well characterised. Using a Reverse Transfection Format (RTF) siRNA screen system we identified two E3 ligases that are involved in two independent pathways for mediating proteasomal degradation of the HSP90-dependent protein kinase CRAF in HEK293 cells. The elongin BC-CUL5-SOCS-box protein (ECS) complex operates one pathway for the degradation of CRAF, while a novel but poorly described HECTD3 from the HECT-family was identified as the main E3 ligase for degrading CRAF following the pharmaceutical inhibition of HSP90. We revealed a potential complexes consisting of CRAF, HSP90 and HECTD3, which may contribute towards identifying the pathway for the degrading of such HSP90-dependent client protein kinases. We were also able to show that depriving access of CRAF to CDC37 and therefore HSP90 resulted in an HECTD3 and CUL5 independent degradation pathway. These studies form the basis of establishing the complex network of pathways that help to regulate CRAF protein levels.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD0415 Biochemistry