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 pathways, 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). Beta-catenin is recruited to its degradation complex containing Axin2/Conductin and APC (Behrens et al., 1998). On the other hand, we have 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).
New projects of the laboratory are concerned with the role of Wnt/beta-catenin and Gab1/Shp2 signaling in stem cells of the intestine, the hair and mammary gland tumors, and in metastasis. Attempts are made to block cancer stem cells of human kidney tumors (in collaboration with the Klinik für Urologie at the Charité Berlin). We are also studying the function of the E3 ubiquitin ligase Hakai by conditional gene ablation and by proteomics approaches (together with the lab of Matthias Selbach, MDC). In cooperation with the Leibniz Institute of Molecular Pharmacology in Berlin-Buch, we develop further small molecule inhibitors of beta-catenin/Tcf and Shp2.