Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 626K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sachs, M. Articles by Birchmeier, W. Search for Related Content PubMed PubMed Citation Articles by Sachs, M. Articles by Birchmeier, W. Social Bookmarking                            What's this?

© The Rockefeller University Press, 0021-9525/2000//1375 $5.00
The Journal of Cell Biology, Volume 150, Number 6, , 2000 1375-1384

Essential Role of Gab1 for Signaling by the C-Met Receptor in Vivo

^a Department of Growth and Differentiation, Max-Delbrueck-Center for Molecular Medicine, 13092 Berlin, Germany
^b Department of Medical Genetics, Max-Delbrueck-Center for Molecular Medicine, 13092 Berlin, Germany
Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Strasse 10, 13092 Berlin, Germany.49-30-9406-265649-30-9406-3810

The docking protein Gab1 binds phosphorylated c-Met receptor tyrosine kinase directly and mediates signals of c-Met in cell culture. Gab1 is phosphorylated by c-Met and by other receptor and nonreceptor tyrosine kinases. Here, we report the functional analysis of Gab1 by targeted mutagenesis in the mouse, and compare the phenotypes of the Gab1 and c-Met mutations. Gab1 is essential for several steps in development: migration of myogenic precursor cells into the limb anlage is impaired in Gab1–/– embryos. As a consequence, extensor muscle groups of the forelimbs are virtually absent, and the flexor muscles reach less far. Fewer hindlimb muscles exist, which are smaller and disorganized. Muscles in the diaphragm, which also originate from migratory precursors, are missing. Moreover, Gab1–/– embryos die in a broad time window between E13.5 and E18.5, and display reduced liver size and placental defects. The labyrinth layer, but not the spongiotrophoblast layer, of the placenta is severely reduced, resulting in impaired communication between maternal and fetal circulation. Thus, extensive similarities between the phenotypes of c-Met and HGF/SF mutant mice exist, and the muscle migration phenotype is even more pronounced in Gab1–/–:c-Met+/– embryos. This is genetic evidence that Gab1 is essential for c-Met signaling in vivo. Analogy exists to signal transmission by insulin receptors, which require IRS1 and IRS2 as specific docking proteins.

Key Words: hepatocyte growth factor • gene targeting • migration of muscle precursors • placenta development • liver development

© 2000 The Rockefeller University Press

CiteULike

Complore

Connotea

Del.icio.us

Digg

Facebook

Reddit

Technorati

Twitter

This article has been cited by other articles:

• Eulenfeld, R., Schaper, F. (2009). A new mechanism for the regulation of Gab1 recruitment to the plasma membrane. J. Cell Sci. 122: 55-64 [Abstract] [Full Text]  
• Koyama, T., Nakaoka, Y., Fujio, Y., Hirota, H., Nishida, K., Sugiyama, S., Okamoto, K., Yamauchi-Takihara, K., Yoshimura, M., Mochizuki, S., Hori, M., Hirano, T., Mochizuki, N. (2008). Interaction of Scaffolding Adaptor Protein Gab1 with Tyrosine Phosphatase SHP2 Negatively Regulates IGF-I-dependent Myogenic Differentiation via the ERK1/2 Signaling Pathway. J. Biol. Chem. 283: 24234-24244 [Abstract] [Full Text]  
• Garzotto, D., Giacobini, P., Crepaldi, T., Fasolo, A., De Marchis, S. (2008). Hepatocyte Growth Factor Regulates Migration of Olfactory Interneuron Precursors in the Rostral Migratory Stream through Met-Grb2 Coupling. J. Neurosci. 28: 5901-5909 [Abstract] [Full Text]  
• Matzke, A., Sargsyan, V., Holtmann, B., Aramuni, G., Asan, E., Sendtner, M., Pace, G., Howells, N., Zhang, W., Ponta, H., Orian-Rousseau, V. (2007). Haploinsufficiency of c-Met in cd44 / Mice Identifies a Collaboration of CD44 and c-Met In Vivo. Mol. Cell. Biol. 27: 8797-8806 [Abstract] [Full Text]  
• Schaeper, U., Vogel, R., Chmielowiec, J., Huelsken, J., Rosario, M., Birchmeier, W. (2007). Distinct requirements for Gab1 in Met and EGF receptor signaling in vivo. Proc. Natl. Acad. Sci. USA 104: 15376-15381 [Abstract] [Full Text]  
• Dance, M., Montagner, A., Yart, A., Masri, B., Audigier, Y., Perret, B., Salles, J.-P., Raynal, P. (2006). The Adaptor Protein Gab1 Couples the Stimulation of Vascular Endothelial Growth Factor Receptor-2 to the Activation of Phosphoinositide 3-Kinase. J. Biol. Chem. 281: 23285-23295 [Abstract] [Full Text]  
• Chen, S.-Y., Chen, H.-C. (2006). Direct Interaction of Focal Adhesion Kinase (FAK) with Met Is Required for FAK To Promote Hepatocyte Growth Factor-Induced Cell Invasion. Mol. Cell. Biol. 26: 5155-5167 [Abstract] [Full Text]  
• Bard-Chapeau, E. A., Yuan, J., Droin, N., Long, S., Zhang, E. E., Nguyen, T. V., Feng, G.-S. (2006). Concerted Functions of Gab1 and Shp2 in Liver Regeneration and Hepatoprotection. Mol. Cell. Biol. 26: 4664-4674 [Abstract] [Full Text]  
• Brummer, T., Schramek, D., Hayes, V. M., Bennett, H. L., Caldon, C. E., Musgrove, E. A., Daly, R. J. (2006). Increased Proliferation and Altered Growth Factor Dependence of Human Mammary Epithelial Cells Overexpressing the Gab2 Docking Protein. J. Biol. Chem. 281: 626-637 [Abstract] [Full Text]  
• Vasyutina, E., Stebler, J., Brand-Saberi, B., Schulz, S., Raz, E., Birchmeier, C. (2005). CXCR4 and Gab1 cooperate to control the development of migrating muscle progenitor cells. Genes Dev. 19: 2187-2198 [Abstract] [Full Text]  
• Watson, E. D., Cross, J. C. (2005). Development of Structures and Transport Functions in the Mouse Placenta. Physiology 20: 180-193 [Abstract] [Full Text]  
• Jin, Z.-G., Wong, C., Wu, J., Berk, B. C. (2005). Flow Shear Stress Stimulates Gab1 Tyrosine Phosphorylation to Mediate Protein Kinase B and Endothelial Nitric-oxide Synthase Activation in Endothelial Cells. J. Biol. Chem. 280: 12305-12309 [Abstract] [Full Text]  
• Borowiak, M., Garratt, A. N., Wustefeld, T., Strehle, M., Trautwein, C., Birchmeier, C. (2004). Met provides essential signals for liver regeneration. Proc. Natl. Acad. Sci. USA 101: 10608-10613 [Abstract] [Full Text]  
• Lamothe, B., Yamada, M., Schaeper, U., Birchmeier, W., Lax, I., Schlessinger, J. (2004). The Docking Protein Gab1 Is an Essential Component of an Indirect Mechanism for Fibroblast Growth Factor Stimulation of the Phosphatidylinositol 3-Kinase/Akt Antiapoptotic Pathway. Mol. Cell. Biol. 24: 5657-5666 [Abstract] [Full Text]  
• van den Akker, E., van Dijk, T., Parren-van Amelsvoort, M., Grossmann, K. S., Schaeper, U., Toney-Earley, K., Waltz, S. E., Lowenberg, B., von Lindern, M. (2004). Tyrosine kinase receptor RON functions downstream of the erythropoietin receptor to induce expansion of erythroid progenitors. Blood 103: 4457-4465 [Abstract] [Full Text]  
• Podar, K., Mostoslavsky, G., Sattler, M., Tai, Y.-T., Hayashi, T., Catley, L. P., Hideshima, T., Mulligan, R. C., Chauhan, D., Anderson, K. C. (2004). Critical Role for Hematopoietic Cell Kinase (Hck)-mediated Phosphorylation of Gab1 and Gab2 Docking Proteins in Interleukin 6-induced Proliferation and Survival of Multiple Myeloma Cells. J. Biol. Chem. 279: 21658-21665 [Abstract] [Full Text]  
• Relaix, F., Rocancourt, D., Mansouri, A., Buckingham, M. (2004). Divergent functions of murine Pax3 and Pax7 in limb muscle development. Genes Dev. 18: 1088-1105 [Abstract] [Full Text]  
• Kallin, A., Demoulin, J.-B., Nishida, K., Hirano, T., Ronnstrand, L., Heldin, C.-H. (2004). Gab1 Contributes to Cytoskeletal Reorganization and Chemotaxis in Response to Platelet-derived Growth Factor. J. Biol. Chem. 279: 17897-17904 [Abstract] [Full Text]  
• Holgado-Madruga, M., Wong, A. J. (2004). Role of the Grb2-Associated Binder 1/SHP-2 Interaction in Cell Growth and Transformation. Cancer Res. 64: 2007-2015 [Abstract] [Full Text]  
• Sun, Y., Yuan, J., Liu, H., Shi, Z., Baker, K., Vuori, K., Wu, J., Feng, G.-S. (2004). Role of Gab1 in UV-Induced c-Jun NH2-Terminal Kinase Activation and Cell Apoptosis. Mol. Cell. Biol. 24: 1531-1539 [Abstract] [Full Text]  
• Chan, P.-C., Chen, Y.-L., Cheng, C.-H., Yu, K.-C., Cary, L. A., Shu, K.-H., Ho, W. L., Chen, H.-C. (2003). Src Phosphorylates Grb2-associated Binder 1 upon Hepatocyte Growth Factor Stimulation. J. Biol. Chem. 278: 44075-44082 [Abstract] [Full Text]  
• Lock, L. S., Frigault, M. M., Saucier, C., Park, M. (2003). Grb2-independent Recruitment of Gab1 Requires the C-terminal Lobe and Structural Integrity of the Met Receptor Kinase Domain. J. Biol. Chem. 278: 30083-30090 [Abstract] [Full Text]  
• Nakaoka, Y., Nishida, K., Fujio, Y., Izumi, M., Terai, K., Oshima, Y., Sugiyama, S., Matsuda, S., Koyasu, S., Yamauchi-Takihara, K., Hirano, T., Kawase, I., Hirota, H. (2003). Activation of gp130 Transduces Hypertrophic Signal Through Interaction of Scaffolding/Docking Protein Gab1 With Tyrosine Phosphatase SHP2 in Cardiomyocytes. Circ. Res. 93: 221-229 [Abstract] [Full Text]  
• Gu, H., Botelho, R. J., Yu, M., Grinstein, S., Neel, B. G. (2003). Critical role for scaffolding adapter Gab2 in Fc{gamma}R-mediated phagocytosis. JCB 161: 1151-1161 [Abstract] [Full Text]  
• Laclef, C., Hamard, G., Demignon, J., Souil, E., Houbron, C., Maire, P. (2003). Altered myogenesis in Six1-deficient mice. Development 130: 2239-2252 [Abstract] [Full Text]  
• Kong, M., Mounier, C., Balbis, A., Baquiran, G., Posner, B. I. (2003). Gab2 Tyrosine Phosphorylation by a Pleckstrin Homology Domain-Independent Mechanism: Role in Epidermal Growth Factor-Induced Mitogenesis. Mol. Endocrinol. 17: 935-944 [Abstract] [Full Text]  
• Seiffert, M., Custodio, J. M., Wolf, I., Harkey, M., Liu, Y., Blattman, J. N., Greenberg, P. D., Rohrschneider, L. R. (2003). Gab3-Deficient Mice Exhibit Normal Development and Hematopoiesis and Are Immunocompetent. Mol. Cell. Biol. 23: 2415-2424 [Abstract] [Full Text]  
• Palka, H. L., Park, M., Tonks, N. K. (2003). Hepatocyte Growth Factor Receptor Tyrosine Kinase Met Is a Substrate of the Receptor Protein-tyrosine Phosphatase DEP-1. J. Biol. Chem. 278: 5728-5735 [Abstract] [Full Text]  
• Cai, T., Nishida, K., Hirano, T., Khavari, P. A. (2002). Gab1 and SHP-2 promote Ras/MAPK regulation of epidermal growth and differentiation. JCB 159: 103-112 [Abstract] [Full Text]  
• Gogg, S., Smith, U. (2002). Epidermal Growth Factor and Transforming Growth Factor alpha Mimic the Effects of Insulin in Human Fat Cells and Augment Downstream Signaling in Insulin Resistance. J. Biol. Chem. 277: 36045-36051 [Abstract] [Full Text]  
• LIU, F., SCHAPHORST, K. L., VERIN, A. D., JACOBS, K., BIRUKOVA, A., DAY, R. M., BOGATCHEVA, N., BOTTARO, D. P., GARCIA, J. G. N. (2002). Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement: potential role of glycogen synthase kinase-3{beta}. FASEB J. 16: 950-962 [Abstract] [Full Text]  
• Zhang, S. Q., Tsiaras, W. G., Araki, T., Wen, G., Minichiello, L., Klein, R., Neel, B. G. (2002). Receptor-Specific Regulation of Phosphatidylinositol 3'-Kinase Activation by the Protein Tyrosine Phosphatase Shp2. Mol. Cell. Biol. 22: 4062-4072 [Abstract] [Full Text]  
• Lock, L. S., Maroun, C. R., Naujokas, M. A., Park, M. (2002). Distinct Recruitment and Function of Gab1 and Gab2 in Met Receptor-mediated Epithelial Morphogenesis. Mol. Biol. Cell 13: 2132-2146 [Abstract] [Full Text]  
• Itoh, S., Itoh, M., Nishida, K., Yamasaki, S., Yoshida, Y., Narimatsu, M., Park, S. J., Hibi, M., Ishihara, K., Hirano, T. (2002). Adapter Molecule Grb2-Associated Binder 1 Is Specifically Expressed in Marginal Zone B Cells and Negatively Regulates Thymus-Independent Antigen-2 Responses. J. Immunol. 168: 5110-5116 [Abstract] [Full Text]  
• Grimm, J., Sachs, M., Britsch, S., Di Cesare, S., Schwarz-Romond, T., Alitalo, K., Birchmeier, W. (2001). Novel p62dok family members, dok-4 and dok-5, are substrates of the c-Ret receptor tyrosine kinase and mediate neuronal differentiation. JCB 154: 345-354 [Abstract] [Full Text]  
• Yu, C. F., Roshan, B., Liu, Z.-X., Cantley, L. G. (2001). ERK Regulates the Hepatocyte Growth Factor-mediated Interaction of Gab1 and the Phosphatidylinositol 3-Kinase. J. Biol. Chem. 276: 32552-32558 [Abstract] [Full Text]  
• Ong, S. H., Hadari, Y. R., Gotoh, N., Guy, G. R., Schlessinger, J., Lax, I. (2001). Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc. Natl. Acad. Sci. USA 98: 6074-6079 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents