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 (). Furthermore, we have found that beta-catenin is recruited to its degradation complex containing Axin2/Conductin and APC ( ). 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 ( ; ). Conventional ablations of beta-catenin and Gab1 in mice result in gastrulation defects and embryonic organ failures, respectively ( ; ).
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 (; ; ; ). Gab1 and Shp2 control precursors in liver, limbs, and kidney ( ; ; ). Met regulates wound healing in the skin ( ). Activation of beta-catenin and HGF/Met in adult mouse tissues induce tumors and cancer stem cells, e.g. in salivary and mammary glands ( ; ). Specific pharmacological inhibitors of the two signaling systems reduce tumor growth (in collaboration with the company ). Shp2/MAPK controls goblet/paneth cells in the intestine ( ). Gab1 regulates catagen entry and hair stem cells in the hair cycle ( ). A beta-catenin-TCF interaction inhibitor blocks cancer stem cell proliferation and tumorigenesis ( ). Wnt-Met breast cancer stem cells secrete sonic hedgehog, which promotes cancer-associated fibroblasts ( ).
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). Attempts are made to kill cancer stem cells of human kidney tumors with small molecule inhibitors (in collaboration with the ). In cooperation with , we develop further small molecule inhibitors of beta-catenin/Tcf and Shp2.