The role of ERK5 in tumour angiogenesis and drug resistance

Aljasir, MA
(2016) The role of ERK5 in tumour angiogenesis and drug resistance. PhD thesis, University of Liverpool.

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Extracellular regulated signal protein kinase 5 (ERK5) is the most recently identified member of the MAPK family which are involved in cellular that contains an unusually long carboxyl-terminal tail. ERK5 is activated by growth factors and cellular stresses. Targeted deletion of erk5 in mice results in death around E9.5-11.5 due to severe defects in vasculature revealed the importance of the ERK5 signalling pathway. Aberrant ERK5 signalling has already been reported in several different cancers such as breast, prostate, hepatocellular and melanoma. This project investigated the differences in ERK5 activation between VEGF in endothelial cells and EGF in HeLa cells. It was revealed that VEGF has only the ability to induce the dual phosphorylation of the kinase domain of ERK5, without any effect on the phosphorylation of the C-terminal residues suggesting that phosphorylation of Thr218/Tyr220 in the kinase domain and C- terminal phosphorylation are not mutually inclusive events and that ERK5 can be activated in the absence of C-terminal phosphorylation. Furthermore, this study also investigated the role of ERK5 in drug resistance and tumour angiogenesis. It was showed that inhibition of MEK5/ERK5 signalling pathway by BIX02189 or XMD8-92 in combination with anti-cancer drug increased the sensitivity of melanoma and ovarian cancer cells to vemurafenib and doxorubicin respectively. VEGF plays a key role in angiogenesis and it has been reported that ERK5 is required for VEGF- mediated survival and tubular morphogenesis. Targeting MEK5/ERK5 signalling cascade resulted in inhibition of VEGF-induced angiogenesis in HDMEC/NHDF/cancer cells co-culture angiogenesis in vitro assay. Taken together, this data has suggested that the ERK5 signalling axis is a viable target to restore sensitivity to chemotherapy in drug-resistant cells and inhibit aberrant angiogenesis which could present a possibility of ERK5 serving as a therapeutic target for drug resistance in cancer. proliferation, differentiation, migration. ERK5 differs from other MAPKs, in

Item Type: Thesis (PhD)
Additional Information: permanent email address is
Divisions: Fac of Health & Life Sciences > The School of Tropical Medicine
Depositing User: Symplectic Admin
Date Deposited: 22 Dec 2016 14:42
Last Modified: 09 Jan 2021 13:22
DOI: 10.17638/03003705
  • Cross, MJ