Bellamy, Sofie Marta Christina;
(2019)
MRTF-SRF signalling in migration.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Serum response factor (SRF) is a widely expressed transcription factor, which in partnership with its G-actin regulated cofactors, the MRTFs, regulates hundreds of genes involved in cytoskeletal structure and cellular dynamics. The importance of SRF signalling in cell migration and tumour spread has been demonstrated in multiple studies. While this suggests that SRF might be required for all migration, we have found that SRF-null dendritic cells are able to migrate. This suggests that either SRF requirement is cell specific or that SRF is required for some modes of migration but not others. To test this hypothesis, we compare the consequence of SRF deficiency in different cell types placed in different migratory environments namely those that favour either mesenchymal or amoeboid modes of migration. We demonstrate that SRF dependency is not cell type specific per se but is required in environments that favour mesenchymal migration while being dispensable for amoeboid migration. Furthermore, we show that the impairment in mesenchymal migration is caused by defective signal transduction of a specific subclass of integrins required for binding to fibronectin RGD motif (Itgb1 and Itgb3) while signalling through Itgb2 appears unaffected. We exemplify a single MRTF/SRF target gene, NEDD9, to phenocopy the integrin dependent phenotype further supporting defects in specific signalling pathways. In addition to the environment specific phenotype of MRTF/SRF in migration we noted a prominent defect in proliferation of MRTF knockout MEFs, which is substrate dependent. I show that MRTFdko MEFs enter senescence when grown on a stiff substrate which is prevented or delayed if the cells are grown on a soft hydrogel.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | MRTF-SRF signalling in migration |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/ 4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10075208 |
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