The role of ERK2 in controlling tumour cell invasion

von Thun, Anne (2012) The role of ERK2 in controlling tumour cell invasion. PhD thesis, University of Glasgow.

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Upregulation of the extracellular signal-regulated kinase (ERK) pathway has been shown to contribute to tumour invasion and progression. Since the two predominant ERK isoforms (ERK1 and ERK2) are highly homologous and have indistinguishable kinase activities in vitro, both enzymes were believed to be redundant and interchangeable. To challenge this view, here we show that ERK2 silencing inhibits invasive migration of MDA MB 231 cells, and re-expression of ERK2 (but not ERK1) restores the normal invasive phenotype. A detailed quantitative analysis of cell movement on 3D matrices indicates that ERK2 knockdown impairs cellular motility by decreasing the migration velocity as well as increasing the time that cells remain stationary. We used gene expression arrays to identify rab17 and liprin β2 as genes whose expression was increased by knockdown of ERK2 and restored to normal levels following re expression of ERK2 (but not ERK1). Moreover, we established that both Rab17 and Liprin β2 play inhibitory roles in the invasive behaviour of three independent cancer cell lines, indicating a suppressive role for these proteins in tumour progression. Importantly, knockdown of either Rab17 or Liprin β2 restores invasiveness of ERK2 depleted cells, indicating that ERK2 drives invasion of MDA MB 231 cells by suppressing expression of these genes.
Taken together, our data provides evidence that true functional disparities between ERK1 and ERK2 exist with regards to cell migration and identifies Rab17 and Liprin β2 as two novel motility suppressors downstream of ERK2.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: ERK signalling, isoform specificity, tumour cell migration and invasion, Rab17, Liprin-beta2
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Supervisor's Name: Norman, Prof. J.C.
Date of Award: 2012
Depositing User: Anne von Thun
Unique ID: glathesis:2012-3176
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 Apr 2012
Last Modified: 10 Dec 2012 14:04

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