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Title: Phosphorylation mediated regulation of MRTF-A
Author: Panayiotou, R.
ISNI:       0000 0004 5365 8586
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2015
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The transcription factor SRF (Serum Response Factor) regulates expression of target genes in response to changes in actin dynamics, by virtue of association with the Myocardin Related Transcription Factor (MRTF) family of transcription cofactors. MRTF-A senses changes in actin dynamics via direct G-actin binding to its RPEL domain. While bound to actin MRTF-A continuously shuttles between the nucleus and cytoplasm, but localises to the cytoplasm due to a high export rate. Because MRTF-A is exported by Crm1 in an actin dependent manner, dissociation from actin leads to nuclear accumulation and SRF activation. Concomitantly, MRTF-A is phosphorylated on multiple residues. The aim of this thesis was to determine the role of phosphorylation in MRTF-A function. An MRTF-A derivative lacking all 26 identified phosphorylation sites was generated. Evidence is presented that phosphorylation of MRTF-A is required for its full capacity to activate SRF. One phosphorylation site, S98, is located within the RPEL domain. Phosphorylation of S98 attenuates actin binding to the RPEL domain and promotes nuclear accumulation of MRTF-A. I found that S98 is phosphorylated by ERK, which relies on an ERK binding motif just N-terminal of S98. Thus S98 represents a means by which MAP kinase signalling can impinge on MRTF-A regulation. In contrast, S33 phosphorylation promotes export of MRTF-A conferred by a Crm1 NES that was identified within its N-terminus. I have shown that this NES can act as an autonomous NES, but cooperates with the RPEL domain to confer actin dependent Crm1 mediated export. MRTF-A phosphorylation, can therefore fine-tune MRTF-A regulation by affecting both localisation and activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available