Research Report 2000 - MDC

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Coupling of Gab1 to c-Met, Grb2 and downstream effectors mediate biological responses Ute Schaeper, Martin Sachs, Niels H. Gehring, Renate Franke and Ingrid Walther. In collaboration with Bettina Kemkes (GSF Munich) and Carmen Birchmeier (MDC) Gab1, like the insulin receptor substrates (IRS), the FGF receptor substrate FRS/SNT, and p62dok family members belongs to a newly identified group of docking proteins that function as specific substrates of tyrosine kinases. Gab1 contains an Nterminal PH domain and a novel phosphotyrosine recognition domain which mediate direct association with the c-Met receptor. Gab1 binds to two sites of the cytoplasmic tail of c-Met, Y14 (Y1349) and to a lesser extent Y15 (Y1356). Gab1 also forms a constitutive complex with Grb2 and this interaction is mediated via the C-terminal SH3 domain of Grb2. 76 We have now mapped the c-Met and Grb2 interaction sites using reverse yeast two-hybrid technology. The c- Met binding site is localized to a 13 amino acid region unique to Gab1. Insertion of this site into the Gab1related protein p97/Gab2 was sufficient to confer c-Met binding activity. Association with Grb2 was mapped to two sites: a classical SH3 binding site (PXXP) and a novel Grb2 SH3 consensus binding motif (PP(V/I)(D/N)RXXKP). To detect phosphorylation-dependent interactions of Gab1 with downstream substrates, we have developed a modified yeast two-hybrid assay and identified PI(3)K, Shc, Shp2 and CRKL as interaction partners of Gab1. In a trk-met specific branching morphogenesis assay, association of Gab1 with Shp2, but not PI(3)K, CRKL or Shc was essential to induce branching morphogenesis in MDCK cells. A fundamental role of Gab1 for c-Met specific signaling is also supported by gene ablation experiments in the mouse: Gab1 -/embryos produced in our laboratory are characterized by strongly reduced and delayed migration of myogenic precursor cells into the limbs, a phenotype reminiscent of HGF/SF -/and c-Met -/- mutant embryos. Figure 29: Ablation of the β-catenin gene in mice results in a defect of anterior-posterior axis formation at embryonal day 6.0. The marker Cerberus is mislocated in the -/- βcatenin embryos (arrow at the distal tip in d) whereas, in the wild-type embryo, Cerberus marks the anterior side (arrow in c). Subsequent head development at the anterior side is abrogated (as shown by the marker Otx2, compare e and f). Embryonal and extraembryonal tissues are properly developed (as shown by expression of BMP4, see a and b). Work by J. Hülsken, R. Vogel, V. Brinkmann, B. Erdmann, C. Birchmeier, W. Birchmeier. J. Cell Biol. 2000.
Selected Publications Hartmann, G., Prospero, T., Brinkmann, V., Ozcelik, Ö., Winter, G., Hepple, J., Batley, S., Bladt, F., Sachs, M., Birchmeier, C., Birchmeier, W., and Gherardi, E. (1997) Engineered mutants of HGF/SF with reduced binding to heparan sulphate proteoglycans, decreased clearance and enhanced activity in vivo. Curr. Biol. 8, 125- 134. Behrens, J., Jerchow, B.-A., Würtele, M., Grimm, J., Asbrand, C., Wirtz, R., Kühl, M., Wedlich, D., and Birchmeier, W. (1998) Functional interaction of an axin homolog, conductin, with β-catenin, APC, and GSK3β. Science 280, 596-599. Meiners, S., Brinkmann, V., Naundorf, H., and Birchmeier, W. (1998) Role of morphogenetic factors in metastasis of mammary carcinoma cells. Oncogene 16, 9-20. Niemann, C., Brinkmann, V., Spitzer, E., Hartmann, G., Sachs, M., Naundorf, H., and Birchmeier, W. (1998) Reconstitution of mammary gland development in vitro: Requirement of c-met and c-erbB2 signalling for branching and alveolar morphogenesis. J. Cell Biol. 143, 533- 545. Hülsken, J., Vogel, R., Brinkmann, V., Erdmann, B., Birchmeier, C., and Birchmeier, W. (2000) Requirement for β-catenin in anterior-posterior axis formation in mice. J. Cell Biol. 148, 567-578. Structure of the Group Group leader Prof. Dr. Walter Birchmeier Scientists Dr. Martin Behrend Dr. Volker Brinkmann* Dr. Yasuyuki Fujita Dr. Jens-Peter von Kries Dr. Markus Morkel* Dr. Patricia Ruiz* Dr. Jörg Hülsken Dr. Martin Sachs Dr. Ute Schaeper Dr. Martin Seidensticker Dr. Dietmar Zechner* Graduate students Christian Asbrand Silvana Di Cesare Jan Grimm Gunnar Schütz* Natalia Sochnikova* Michael Tönjes Georgia Winbeck Diploma students Niels Gehring* Technical assistants Andrea Dell’Oro Renate Franke Regina Vogel Ingrid Walther Secretariat Irmgard Wiznerowicz Gerhild Richter *part of the period reported 77
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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
Page 25 and 26: 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: Epithelial Differentiation, Invasio
Page 79 and 80: Selected Publications Behrens, J.,
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
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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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