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Our research focusses on the transcription factor Serum Response Factor (SRF) and its coactivators Megakaryoblastic Leukemia 1/2 (MKL1/2, aka MRTFA/B). Many essential biological processes such as cell growth, cell migration, differentiation and organisation of the cytoskeleton underlie the transcriptional control by SRF. SRF induces the transcription of genes that are named Immediate Early Genes (IEGs) due to their rapid induction within minutes after stimulation with serum or growth factors (1).

Serum activates RhoA- and MAPK-signaling pathways. RhoA-activation leads to     increased actin polymerization. The consequent drop in G-actin levels has been shown to be responsible for serum induced MKL1 movement to the nucleus (2).

We found that nuclear export of MKL1 is facilitated by ERK1/2-MAPK-mediated phosphorylation and enhanced binding to G-actin (3) (see Fig.1).

Therefore MKL1 sits at the nexus of two essential signaling pathways, the MAPK- and RhoA-pathway. Each of these have been implicated in tumorigenesis: ERK1/2-inhibitors are in clinical trials (4), and RhoA overexpression was found in various cancers (5). Further evidence to support a role for Rho pathways in cancer has come from the identification of the tumor suppressor Deleted in Liver Cancer 1 (DLC1) whose loss potentiates RhoA activity (6, 7). We found that DLC1 loss causes nuclear localization of MKL1/2 in hepatocellular and mammary carcinoma cell lines, as well as human hepatocellular carcinomas. Nuclear accumulation of MKL1 and 2 was accompanied by activation of tumor-relevant MKL/SRF-dependent target genes. We could also demonstrate a requirement of MKL1/2 for cancer specific features caused by DLC1 loss, such as anchorage-independent cell growth, cell migration and cell proliferation (8).

In line with these findings, depletion of MKL1 and 2 completely abolished hepatocellular carcinoma (HCC) xenograft growth (9, 10). We identified oncogene-induced senescence as the molecular mechanism underlying the anti-proliferative effect of MKL1/2 knockdown. Thus, MKL1/2 represent promising novel therapeutic targets for the treatment of HCCs characterized by DLC1 loss (9, 10).

Our aim is to understand the role of MKL1 and 2 both in normal growth control and in tumorigenesis. We seek to clarify which MKL1/2 target genes mediate the effects of MKL1/2 on tumorigenesis. To answer these and other questions we use modern methods of cell- and molecular biology, protein biochemistry and mouse models.

  1. J. A. Winkles, Prog Nucleic Acid Res Mol Biol 58, 41 (1998).
  2. F. Miralles, G. Posern, A. I. Zaromytidou, R. Treisman, Cell 113, 329 (May 2, 2003).
  3. P. Kircher et al., Sci Signal 8, 420 (Nov, 2015).
  4. S. Muehlich et al., Nucleus 7, 121 (Apr, 2016).
  5. S. Muehlich et al., Mol Cell Biol 28, 6302 (Oct, 2008).
  6. M. Kohno, J. Pouyssegur, Ann Med 38, 200 (2006).
  7. T. Gomez del Pulgar, S. A. Benitah, P. F. Valeron, C. Espina, J. C. Lacal, Bioessays 27, 602 (Jun, 2005).
  8. W. Xue et al., Genes Dev 22, 1439 (Jun 1, 2008).
  9. S. Muehlich et al., Oncogene 31, 3913 (Aug 30, 2012).
  10. V. Hampl et al., EMBO Mol Med 5, 1367 (Sep, 2013).