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Kircher, Philipp (2016): Filamin A interacts with the co-activator MKL1 to promote the activity of transcription factor SRF and cell migration. Dissertation, LMU München: Fakultät für Chemie und Pharmazie



Megakaryoblastic Leukemia 1 (MKL1, MRTF-A, MAL) is a transcriptional co-activator of Serum response factor (SRF) that promotes the expression of genes involved in cell proliferation, motility, adhesion and differentiation-processes. It thereby holds an essential part in controlling fundamental biological processes like heart, cardiovascular system or brain development. MKL1 is inactive when bound to monomeric actin (G-actin), thus nuclear access is denied. However, signals that activate the small GTPase RhoA cause actin polymerization (F-actin) and MKL1 dissociation from G-actin, this way allowing successful MKL1 shuttling into the nucleus and conveying signals from RhoA into SRF activity. Filamin A (FLNA) belongs to the group of actin-binding proteins. It is indispensable for filamentous F-actin cross-linking, thus contributes to cytoskeletal dynamics, cell mobility and stability in a crucial way. In this work, we found a new central mechanism of MKL1 activation that is mediated through its binding to FLNA as a novel interaction partner. We provide evidence that the interaction of MKL1 and FLNA is required for the expression of MKL1 target genes and MKL1-dependent cell motility. We map MKL1 and FLNA regions responsible for the interaction and demonstrate, that cells expressing a MKL1 mutant unable to bind FLNA showed reduced expression of MKL1 target genes and impaired cell motility. Furthermore we indicate that induction and repression of MKL1 target genes correlate with increased or decreased quantity of the MKL1-FLNA interaction. A dynamic flow was revealed, as lysophosphatidic acid-induced RhoA activity in primary human fibroblasts promoted the association of endogenous MKL1 with FLNA, whereas exposure to an actin polymerization inhibitor dissociated MKL1 from FLNA and decreased MKL1 target gene expression in melanoma cells. Thus FLNA binding to MKL1 functions as a novel cellular transducer linking actin polymerization to SRF activity, counteracting the known repressive complex of MKL1 and monomeric G-actin, which advances to our mechanistic understanding of MKL1 regulation.