Research Report 2000 - MDC

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Cell Adhesion and Signal Transduction Jürgen Behrens Our group studies the dual role of the cytoplasmic component β-catenin in cadherin-mediated cell adhesion and the wnt signaling pathway. As part of the cell adhesion machinery β-catenin binds to the cytoplasmic domain of cadherins and provides a link to the actin cytoskeleton. In the wnt pathway b-catenin transmitts signals to the nucleus by interacting with members of the LEF/TCF family of transcription factors. The wnt pathway controls cellular interactions during embryonal development, and the inappropriate activation of wnt signals leads to cancer. In tumors, mutation of the tumor suppressor gene product APC or of β-catenin lead to the stabilisation of β-catenin and activation of oncogenic target genes by TCF/β-catenin complexes. 78 Regulation of b-catenin by conductin in the wnt signal transduction pathway Boris Jerchow, Martin Würtele, Thomas Schwarz-Romond in cooperation with W. Birchmeier (<strong>MDC</strong>) In the past three years, we could identify new components that interact with β-catenin and mediate essential steps in the wnt pathway. In 1996, we identified the functional interaction of β-catenin with the HMG box transcription factor LEF-1. In 1998, we found that β-catenin interacts with the novel protein conductin. We could show that conductin induces the degradation of β-catenin and blocks wnt signaling in Xenopus embryos. We could further demonstrate that conductin is a scaffold protein which assembles a multiprotein complex by binding to β-catenin, APC and the serine/threonine kinase GSK3b at separate domains. GSK3b is responsible for the phosphorylation of β-catenin which leads to ubiquitination of β-catenin and its subsequent degradation in proteasomes. We propose that conductin coordinates the interplay of β-catenin, APC and GSK3β in the bcatenin-degradation process by providing a platform for the assembly of these factors. Conductin negatively controls wnt signaling and might act as a tumor suppressor. We are currently studying the role of conductin in vivo by gene ablation in the mouse. We will in particular analyse whether the conductinnegative mice are prone to tumor formation and show lack of control of β-catenin. We also analyse the expression of conductin in tumors and search for possible mutations in the conductin gene (collaboration with P.M. Schlag, Robert-Rössle-Klinik). Further studies aim at the analysis of cellular consequences of conductinmediated degradation of β-catenin in tumor cells, and the identification of regulators of conductin function by using yeast two hybrid screening methods. Interaction of β-catenin with SWI/SNF factors Ralph Wirtz Transcription of many genes is controlled by a multiprotein complex composed of SWI and SNF proteins, which regulate chromatin assembly by altering nucleosome positioning. We found that β-catenin interacts with a mouse homolog of the yeast SWI3 protein named BAF155. Interestingly, BAF155 and TCF factors associate with different parts of the central arm repeat domain of β-catenin, indicating that β-catenin may provide a link between the two transcriptional regulators. Indeed, in immunoprecipitation experiments LEF-1 co-precipitates with BAF155 which is dependent on the b-catenin binding domain of LEF-1. We propose that β-catenin recruits the SWI/SNF complex to TCFs to promote transcription of wnt target genes. We could also show that SNF5, which is a component of the SWI/SNF complex, competes with β-catenin for binding to BAF155. SNF5 has been assigned a role as a tumor suppressor in early childhood rhabdoid tumors. Mutations of the SNF5 gene lead to C-terminal truncations of the protein. We found that SNF5 mutant proteins show reduced binding to BAF155 and compete less efficiently with βcatenin than wild-type SNF5. We also found that TCF/β-catenin dependent gene transcription is active in rhabdoid tumor cells and can be blocked by re-introduction of wildtype but not mutant SNF5. We suggest that SNF5 prevents the interaction of the TCF/β-catenin complexes with the SWI/SNF machinery. The loss of functional SNF5 in rhabdoid tumors may allow recruitment of the SWI/SNF complex to oncogenic wnt target genes.
Selected Publications Behrens, J., Jerchow, B.-A., Würtele, M., Asbrand, C., Wirtz, R., Grimm, J., Wedlich, D., and Birchmeier, W. (1998) Functional interaction of an axin homolog, conductin, with bcatenin, APC, and GSK3 β. Science 280, 596-599. Batsche, E., Muchardt, C., Behrens, J., Hurst, H.C., and Cremisi, C. (1998) RB and c-Myc activate expression of the E-cadherin gene in epithelial cells through interaction with transcription factor AP-2. Mol. Cell. Biol. 18, 3647-3658. Ghadimi, B.M., Behrens, J., Hoffmann, I., Birchmeier, W., and Schlag, P.M. (1999) Immunohistochemical analysis of Ecadherin, α-, β-, and γ-catenin expression in colorectal cancer: implications for cell adhesion and signaling. Europ. J. Cancer 35, 60-65. Behrens, J. (1999) Cadherin/cateninmediated signal transduction. In: Guidebook to the Extracellular Matrix, Anchor, and Adhesion Proteins. Th. Kreis, R.Vale (eds.) Oxford. Behrens, J. (1999) Cadherins and catenins: role in signal transduction and tumor progression. Cancer Metastasis Rev 18, 15-30. Patent Application “Mittel zur Diagnose und Therapie von Tumorerkrankungen” Structure of the Group Group leader Dr. Jürgen Behrens Scientist Dr. Lepu Zhou Graduate and undergraduate students Boris Jerchow Thomas Schwarz-Romond Ralph Wirtz Martin Würtele* Technical assistant Katharina Feller *part of the time reported 79
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Research Report 2000 Covers the Per
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Molecular Therapy Molecular and Dev
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The quantum theory, that provided a
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Introduction Clinical Research The
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Genome Research in Berlin- Brandenb
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External Evaluation Over the period
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Congresses In the years reported, t
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Awards A number of prestigious priz
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Genetics, Bioinformatics and Struct
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disorders. Various MDC groups have
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Steen R.G., Kwitek-Black A.E., Glen
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Selected Publications Binas, B., Da
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Technology transfer Based on the fu
Page 27 and 28: Selected Publications Müller, D.N.
Page 29 and 30: Selected Publications Hennies, H.C.
Page 31 and 32: Somatic genetic alterations in brea
Page 33 and 34: Clinical and Molecular Genetics of
Page 35 and 36: Selected Publications Toka, H.R., B
Page 37 and 38: Lbx1, c-met and the control of cell
Page 39 and 40: Selected Publications Moore, A., Mc
Page 41 and 42: Selected Publications Herz, J., Wil
Page 43 and 44: We aim to study the genetic epidemi
Page 45 and 46: Nucleation Nucleation as a pre-requ
Page 47 and 48: Selected Publications Damaschun, G.
Page 49 and 50: Selected Publications Yuan, T., Wal
Page 51 and 52: stability. By determining the struc
Page 53 and 54: Role of Protein Dynamics in Enzyme
Page 55 and 56: Modeling Nucleic Acid Structure and
Page 57 and 58: Conformation, Stability and Interac
Page 59 and 60: Protein Structure Analysis and Prot
Page 61 and 62: Cell Growth and Differentiation 61
Page 63 and 64: dendritic cells (DC). Adoptive tran
Page 65 and 66: developmental pathway that may invo
Page 67 and 68: Regulation of Transcription in Mamm
Page 69 and 70: Differentiation and Growth Control
Page 71 and 72: Cell cycle-dependent transcriptiona
Page 73 and 74: Cell Cycle Regulation Hans-Dieter R
Page 75 and 76: Epithelial Differentiation, Invasio
Page 77: Selected Publications Hartmann, G.,
Page 81 and 82: Selected Publications Karsten, U.,
Page 83 and 84: Depressed contractility in human he
Page 85 and 86: Understanding calcium handling prot
Page 87 and 88: VSMCs. We have cloned and character
Page 89 and 90: Surgical Oncology Peter M. Schlag T
Page 91 and 92: Ubiquitin System and Endoplasmic Re
Page 93 and 94: P450 Cytochromes and the Endoplasmi
Page 95 and 96: Vascular Biology Hermann Haller Thi
Page 97 and 98: Selected Publications Gollasch, M.,
Page 99 and 100: Electron Microscopy Members of the
Page 101 and 102: Molecular Therapy 101
Page 103 and 104: Hematology, Oncology and Tumor Immu
Page 105 and 106: Selected Publications Sturm, I., K
Page 107 and 108: Selected Publications Westermann, J
Page 109 and 110: fractions. The hematopoietic potent
Page 111 and 112: Interaction of pharmacologically ac
Page 113 and 114: Molecular Basis of Congestive Heart
Page 115 and 116: Selected Publications Schneider, G.
Page 117 and 118: different murine and human tumor ce
Page 119 and 120: Molecular and Cell Biology of Hemat
Page 121 and 122: Phospholipids Dietrich Arndt Cytoto
Page 123 and 124: Regulation and Deregulation of Cell
Page 125 and 126: Evolution, Regulation and Genetic A
Page 127 and 128: Molecular and Developmental Neurosc
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Cellular Neurosciences Helmut Kette
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Growth Factor and Regeneration Gary
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Synapse Formation and Function Fran
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Developmental Neurobiology Fritz G.
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Selected Publications Volkmer, H.,
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Structure and Organization 139
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Prof. Dr. Hans Meyer President of t
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Supporting Divisions Safety The div
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Press and Public Relations Research
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Purchasing and Materials Management
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Computing The computing group of th
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Awards Thomas Biederer Boehringer-M
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Index A Abdul, Yetunde 90 Aguirre-A
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H Haase, Hannelore 85, 97, 100, 142
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Q Qin, Zhihai 107, 117 Quass, Petra
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Board of Trustees Chair Wolf-Michae
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