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Essential role of Gab1 for signaling by the c-Met receptor in vivo

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Item Type:Article
Title:Essential role of Gab1 for signaling by the c-Met receptor in vivo
Creators Name:Sachs, M. and Brohmann, H. and Zechner, D. and Mueller, T. and Huelsken, J. and Walther, I. and Schaeper, U. and Birchmeier, C. and Birchmeier, W.
Abstract: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.
Keywords:Hepatocyte Growth Factor, Gene Targeting, Migration of Muscle Precursors, Placenta Development, Liver Development, Animals, Mice
Source:Journal of Cell Biology
Publisher:Rockefeller University Press
Page Range:1375-1384
Date:18 September 2000
Additional Information:Copyright (c) 2000 by The Rockefeller University Press
Official Publication:https://doi.org/10.1083/jcb.150.6.1375
PubMed:View item in PubMed

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