Research Report 2010 - MDC

Walter BirchmeierStructure of the GroupGroup LeaderProf. Dr. Walter BirchmeierScientistsDr. Felix Brembeck*Dr. Marta De Rocha RosárioDr. Johannes FritzmannDr. Katja GroßmannDr. Klaus Hellmuth*Dr. Jane HollandDr. Alexandra KlausSignals Provided by Wnt/β-cateninand Met/Gab1/Shp2 in Developmentand CancerThe molecular and functional analysis of cell adhesion and signaling in development andtumor progression has been the major focus of my laboratory. We previously definedfunctions of E-cadherin/β-catenin, which mediate cell-cell adhesion of epithelial cells andprevent invasion and metastasis. Moreover, we discovered that β-catenin, which is a centralcomponent of canonical Wnt signaling (armadillo in Drosophila), binds to the transcriptionfactors LEF/TCF. This interaction allows the nuclear translocation of β-catenin, and theregulation of gene expression. Signals provided by Wnt/β-catenin are essential in manydevelopmental processes and in tumor progression. We have used conditional loss-of-andgain-of-functionmutations to study the role of β-catenin in the skin, and in development oflimbs and brain, and observed essential functions of β-catenin signaling in these organs.In the skin, specification of stem cells to the hair, but not the epidermal lineage requiresβ-catenin signals. In the dorsal spinal cord, Wnt/β-catenin signaling controls the transcriptionfactor Olig3, which is required for the specification of two types of neurons, dI2 and dI2.Moreover, our genetic analysis of two other members of the armadillo gene family,plakoglobin (γ-catenin) and plakophilin2, established a role of theses molecules in the stabilityof cell junctions in the heart, and implicate these molecules in heart disease. We recentlydiscovered that the β-catenin-binding protein BCL9-2, a homologue of legless in Drosophila,induces epithelial-mesenchymal transition and activation of canonical Wnt signaling.In addition, we have a long standing interest in the biochemistryof scatter factor/hepatocyte growth factor(SF/HGF) and Met receptor signaling, and have analyzedfunctions of these molecules in development andtumor progression. We characterized the downstreameffectors of Met, Gab1 and Shp2. We were able to show,by genetic means, that signaling of Gab1 through thetyrosine phosphatase Shp2 controls migration of muscleprecursor cells to the limbs. Shp2 acts also downstreamof many other receptor and non-receptorkinases.In the present report period, we have performed the followinginvestigations on Wnt/β-catenin and receptortyrosine kinase signaling:A colorectal cancer expression profile thatincludes the β-catenin target and TGFβ inhibitorBAMBI predicts metastatic potentialJohannes Fritzmann, Daniel Besser, Frauke Kosel, Felix H.Brembeck, Ulrike Stein, Iduna Fichtner, Peter M. Schlag,Walter Birchmeier, Markus Morkel (MPI for MolecularGenetics, Berlin) and Jan Budczies (Charité Berlin)82 Cancer Research