Lab focus
Signal Transduction, Epithelial Differentiation, Invasion and Metastasis
The Walter Birchmeier Laboratory,
Max-Delbrueck-Center of Molecular Medicine, Berlin, Germany
Our laboratory concentrates on the molecular analysis of epithelial morphogenesis and differentiation. In the previous years, we have defined the adhesion and signaling capacities of the E-cadherin/beta-catenin/Wnt system. Moreover, we have investigated the role of scatter factor/hepatocyte growth factor (SF/HGF) and its receptor, the c-met tyrosine kinase, in morphogenesis of epithelial cells. Components of the Wnt- and c-met pathways are mutated is a variety of human tumors.
Epithelial cells can lose expression of E-cadherin during tumor progression, and this loss correlates with the appearance of highly invasive carcinoma cells. The function of cadherins strictly depends on cytoplasmic linkage molecules, beta-catenin and plakoglobin, which mediate interaction of cadherins with the cytoskeleton. We have shown that beta-catenin also binds to the transcription factors LEF-1/TCF, and that this interaction translocates beta-catenin to the cell nucleus and regulates gene expression (Behrens et al., 1996). This provides a molecular mechanism for transmission of signals from cell adhesion components and the Wnt signalling pathway to the cell nucleus.
The scatter factor/c-met system transduces various signals in epithelial cells, such as scattering, differentiation and proliferation. An unique activity of SF/HGF and c-met on epithelial cells in culture is the ability to induce branching or other morphogenic events. We have recently identified a new substrate of c-met, Gab1, which mediates the signal responsible for branching morphogenesis (Weidner et al., 1996). Gab1 is a member of the family of membrane-bound multiadapter proteins, which transmits signaling of tyrosine kinase receptors.
beta-catenin in the nucleus of MDCK cells