Signal Transduction in Development and Cancer
The Walter Birchmeier Laboratory,
Max Delbrück Center for Molecular Medicine (MDC), Berlin-Buch, Germany
Our lab is primarily focused on two signaling systems, Wnt/beta-catenin signaling and receptor tyrosine kinase (RTK) signaling pathways. Components of both signaling systems are frequently mutated or deregulated in a variety of developmental disorders and cancers in humans.
In the previous years, the laboratory has studied adhesion and signaling of E-cadherin/Wnt/beta-catenin by biochemical means. We have shown that beta-catenin binds to the transcription factors Lef1/Tcf, and that this translocates beta-catenin to the nucleus (Behrens et al., 1996). Furthermore, we have found that beta-catenin is recruited to its degradation complex containing Axin2/Conductin and APC (Behrens et al., 1998). We have also investigated the role of scatter factor/hepatocyte growth factor (SF/HGF) and its receptor, the Met tyrosine kinase, in the morphogenesis of epithelial cells. Signals of Met are transmitted by the multi-adapter protein Gab1 and the tyrosine phosphatase Shp2 (Weidner et al., 1996; Schaeper et al., 2000). Conventional ablations of beta-catenin and Gab1 in mice result in gastrulation defects and embryonic organ failures, respectively (Huelsken et al., 2000; Sachs et al., 2000).
In recent years, we have examined the role of Wnt/beta-catenin and Met/Gab1/Shp2 by conditional mutagenesis in mice. Beta-catenin regulates precursor and stem cells in the nervous system, the hair and the heart (Huelsken et al., 2001; Zechner et al., 2003; Klaus et al., 2007; Grigoryan et al., 2013). Gab1 and Shp2 control precursors in liver, limbs, and kidney (Schaeper et al., 2007; Grossmann et al., 2009; Willecke et al., 2011). Met regulates wound healing in the skin (Chmielowiec et al., 2007). Activation of beta-catenin and HGF/Met in adult mouse tissues induce tumors and cancer stem cells, e.g. in salivary and mammary glands (Wend et al., 2013; Holland et al. 2013). Specific pharmacological inhibitors of the two signaling systems reduce tumor growth (in collaboration with the company EPO in Berlin-Buch). Shp2/MAPK controls goblet/paneth cells in the intestine (Heuberger et al., 2014). Gab1 regulates catagen entry and hair stem cells in the hair cycle (Akilli Öztürk et al., 2015). A beta-catenin-TCF interaction inhibitor blocks cancer stem cell proliferation and tumorigenesis (Fang et al., 2016). Wnt-Met breast cancer stem cells secrete sonic hedgehog, which promotes cancer-associated fibroblasts (Valenti et al., 2017).
New projects of the laboratory are concerned with the role of Wnt/beta-catenin and the histone methyl transferase Mll1 in stem cells of the intestine and mammary gland tumors (in collaboration with Francis Stewart and collaborators, TU Dresden). Attempts are made to kill cancer stem cells of human kidney tumors with small molecule inhibitors (in collaboration with the Klinik für Urologie at the Charité Berlin). In cooperation with the Leibniz Institute of Molecular Pharmacology in Berlin-Buch, we develop further small molecule inhibitors of beta-catenin/Tcf and Shp2.